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关键词： anti-PD-1   bioinformatic analysis   colorectal cancer   combinatorial immunotherapy   interferon-alpha   RIG-I  

摘要： BackgroundsImmunotherapy is a promising and effective approach that has achieved significant curative effects in colorectal cancer (CRC). Recently, retinoic acid-inducible gene I (RIG-I) has been shown to play a critical role in tumor immunity. However, the correlation between RIG-I and immunotherapy in CRC remains ***-I expression was measured in CRC and normal samples based on analysis of the public databases, a tissue microarray, and CRC cell lines. The correlation between RIG-I and immune microenvironment was explored using well-established biological algorithms and in vitro and in vivo *** discovered that RIG-I expression was downregulated in CRC compared with normal samples. The bioinformatic algorithms indicated that high RIG-I-expressing samples showed a positive correlation with IFN-alpha response and enrichment of antitumor immune cells, especially CD8+ T cells. Furthermore, knockdown of RIG-I expression efficiently reduced the cell death, STAT1 phosphorylation, and CXCL10/11 expression induced by IFN-alpha in CRC cells. Finally, an in vivo study showed that the infiltration of CD3+ CD8+ T cells was significantly decreased in the RIG-I knockout group. An animal model further confirmed that the inhibition of tumor growth induced by IFN-alpha plus anti-PD-1 therapy was dependent on RIG-I ***-I is a promising biomarker for CRC immunotherapy, which provides a novel concept for combinatorial immunotherapy.

关键词： HLA-DRB1*11:340   HLA   novel allele   sequencing-based typing  

摘要： HLA-DRB1*11:340 differs from HLA-DRB1*11:01:01:01 by one nucleotide substitution in codon 36 in exon 2.

关键词： Extracellular vesicles   IAV   Lactobacillus reuteri   Inflammation   IL-17  

摘要： The influenza A virus (IAV) damages intestinal mucosal tissues beyond the respiratory tract. Probiotics play a crucial role in maintaining the balance and stability of the intestinal microecosystem. Extracellular vesicles (EVs) derived from probiotics have emerged as potential mediators of host immune response and anti-inflammatory effect. However, the specific anti-inflammatory effects and underlying mechanisms of probiotics-derived EVs on IAV remain unclear. In the present study, we investigated the therapeutic efficacy of Lactobacillus reuteri EHA2-derived EVs (LrEVs) in a mouse model of IAV infection. Oral LrEVs were distributed in the liver, lungs, and gastrointestinal tract. In mice infected with IAV, oral LrEVs administration alleviated IAV-induced damages in the lungs and intestines, modified the microbiota compositions, and increased the levels of short-chain fatty acids in those organs. Mechanistically, LrEVs exerted their protective effects against IAV infection by blunting the proinflammatory IL-17 signaling. Furthermore, FISH analysis detected miR-4239, one of the most abundant miRNAs in LrEVs, in both lung and intestinal tissues. We confirmed that miR-4239 directly targets IL-17a. Our findings paved the ground for future application of LrEVs in influenza treatment and offered new mechanistic insights regarding the anti-inflammatory role of miR-4239.

关键词： HLA-B*35:186   sequence-based typing   the novel allele  

摘要： HLA-B*35:186 differs from HLA-B*35:01:01:01 by 12 nucleotide substitutions in exon 2.

摘要： Hypoimmunogenic universal induced pluripotent stemn (iPS) cells were generated through the targeted disruption of key genes, including human leukocyte antigen (HLA)-A, HLA-B and HLA-DR alpha (DRA), using the CRISPR-Cas9 system. This approach aimed to minimize immune recognition and enhance the potential of iPS cells for allogeneic therapy. Heterozygous iPS cells were used for guide RNA design and validation to facilitate the knockout (KO) of the HLA-A, HLA-B and HLA-DRA genes. The electroporation of iPS cells using the selected guide RNAs enabled the generation of triple-KO iPS cells, followed by single-cell cloning for clone selection. Clone A7, an iPS cell with targeted KOs of the HLA-A, HLA-B and HLA-DRA genes, was identified as the final candidate. Messenger RNA analysis revealed robust expression of pluripotency markers, such as octamer-binding transcription factor 4, sex-determining region Y box 2, Kr & uuml;ppel-like factor 4, Lin-28 homolog A and Nanog homeobox, while protein expression assays confirmed the presence of octamer-binding transcription factor 4, stage-specific embryonic antigen 4, Nanog homeobox and tumor rejection antigen 1-60. A karyotype examination revealed no anomalies, and three-germ layer differentiation assays confirmed the differentiation potential. After interferon gamma stimulation, the gene-corrected clone A7 lacked HLA-A, HLA-B and HLA-DR protein expression. Immunogenicity testing further confirmed the hypoimmunogenicity of clone A7, which was evidenced by the absence of proliferation in central memory T cells and effector memory T cells. In conclusion, clone A7, a triple-KO iPS cell clone that demonstrates immune evasion properties, retained its intrinsic iPS cell characteristics and exhibited no immunogenicity.

关键词： BCL6   GPR61   IL-1 beta   osteoarthritis  

摘要： Osteoarthritis (OA) is the most common joint disease and its pathogenic mechanism remains to be ensured. This study focused on the regulatory relation between B-cell lymphoma 6 (BCL6) and G-protein-coupled receptor 61 (GPR61) underlying IL-1 beta in OA. Real-time quantitative polymerase chain reaction and western blot were performed for mRNA and protein detection. Oxidative injury was assessed by reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) via kits. Fe2+ level was measured via an iron assay kit. Relation analysis between BCL6 and GPR61 was implemented employing ChIP assay and dual-luciferase reporter assay. GPR61 was downregulated in OA samples and IL-1 beta-induced C28/I2 cells. IL-1 beta-induced cell inflammation, extracellular matrix (ECM) degradation, oxidative stress, and ferroptosis were all returned by overexpression of GPR61. BCL6 downregulation was detected in OA patients and IL-1 beta-exposed C28/I2 cells. BCL6 could promote the transcription of GPR61. BCL6 suppressed IL-1 beta-induced OA progression by upregulating GPR61. The BCL6/GPR61 axis activated the PKA/CREB pathway in IL-1 beta-treated C28/I2 cells. The above results suggested that BCL6 mitigated OA progression induced by IL-1 beta by enhancing transcription of GPR61. BCL6/GPR61/PKA/CREB axis may be considered as a novel regulatory mechanism in OA, and BCL6 has the potential to act as a novel target for OA.

关键词： HLA-A*02:1133   NGS   novel allele  

摘要： HLA-A*02:1133 differs from HLA-A*02:01:01:01 by a single nucleotide substitution at position 37 C>T in exon 1.

关键词： Crohn's disease   Pediatrics   Anti-TNF therapy   Steroid-free remission   Biomarkers  

关键词： HLA   HLA-DPA1*01:03:61   novel allele   sequencing-based typing  

摘要： HLA-DPA1*01:03:61 differs from HLA-DPA1*01:03:01:02 by one nucleotide substitution in codon 81 in exon 2.

关键词： Mechanical stress   Cytokines   Focal adhesion kinase   Ion channels   Gingival epithelial cells  

摘要： Objectives: Mechanical stress on the teeth and alveolar bone caused by bruxism, orthodontics, and implants affects the periodontal tissues, causing gingival recession and alveolar bone resorption, and entire body, including the heart and vascular system. Although the same forces exerted on the alveolar bone and teeth are exerted on gingival epithelial cells, little is known about the effects of mechanical stress on these cells. This study investigated the effects of mechanical stress on gingival epithelial cells. Methods: Ca9-22 cells (human gingival epithelial cells) were used. They were seeded onto the silicone and stretched cyclically. Mechanical stress-stimulated Ca9-22 cells were evaluated for pro-inflammatory interleukin (pro-IL)-1(3 production using Western blotting and analyzed to assess the phosphorylation level of intracellular signaling molecules. Results: Mechanical stress induced pro-IL-1(3 upregulation in Ca9-22 cells, which was significantly inhibited by ruthenium red. Ruthenium red significantly inhibited mechanical stress-induced phosphorylation of focal adhesion kinase (FAK), P130cas, and extracellular signal-regulated kinase 1 and 2 (ERK1/2) induced by mechanical stress. Additionally, Y15 significantly inhibited the upregulation of pro-IL-1(3 expression and phosphorylation of FAK, P130cas, and ERK1/2 stimulated by mechanical stress. Conclusions: In Ca9-22 cells, mechanical stress may increase pro-IL-1(3 production via mechanosensitive ion channels and FAK. These findings revealed the mechanisms of inflammation in mechanically-stressed Ca9-22 cells and may aid in the development of therapeutic approaches to prevent bone resorption.