The negative regulators in the interferon (IFN) signaling pathway inhibit intrahepatic immune response, resulting in suboptimal therapeutic response to IFNα treatment in chronic hepatitis B (CHB) patients. Identifying the key negative factors and elucidating the regulating mechanism are essential for improving anti‐HBV (hepatitis B virus) efficacy of IFNα. From the Gene Expression Omnibus (GEO) database, we downloaded and analyzed gene expression profiles of CHB patients with different responses to IFNα (GSE54747), and found that innate immune status was associated with the IFNα‐based therapeutic response in CHB patients. Through PCR array, we found higher baseline level of IFN‐induced transmembrane protein 2 (IFITM2) mRNA and lower baseline level of IFNα mRNA in peripheral blood mononuclear cells (PBMCs) of CHB patients with suboptimal response to IFNα treatment. Increased IFITM2 protein was also found in the serum of IFNα nonresponsive patients. With further experiments, we found that overexpressing IFITM2 in Huh7 cells suppressed endogenous IFNα synthesis by inhibiting phosphorylation of extracellular signal–regulated kinase (ERK), TANK‐binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3); knocking out IFITM2 enhanced activation of the endogenous IFNα synthesis pathway, exhibiting better inhibition on HBV replication. We also found that IFITM2 protein was shuttled by exosomes to dendritic cells (DCs), the main source of endogenous IFNα. Exosome‐mediated transport of IFITM2 inhibited synthesis of endogenous IFNα in DCs whereas the inhibitory effect was abolished when IFITM2 was knocked out. Furthermore, we demonstrated that both palmitoylation inhibitor and mutation on 70/71 sites of IFITM2 protein influenced its incorporation into exosomes. Mutated IFITM2 protein increased the effect of IFNα against HBV. Conclusion: Exosome‐mediated transport of IFITM2 to DCs inhibits IFNα pathway activation and blocks anti‐HBV efficacy of exogenous IFNα. The findings provide an explanation to the suboptimal response of CHB patients to IFNα treatment.

Background Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). Methods The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

Background: Patients with acute-on-chronic liver failure (ACLF) might be at risk for citrate accumulation during plasma adsorption plus plasma exchange (PE) therapy with regional citrate anticoagulation (RCA). Objectives: To assess the safety and efficacy of RCA during double plasma molecular adsorption system (DPMAS) plus PE therapy for patients with ACLF. Method: A prospective nonrandomized controlled pilot study was conducted at West China Hospital of Sichuan University. Patients with ACLF were enrolled to heparin anticoagulation (HA) group and RCA group. Serial blood samples were taken. Patients were followed up for 3 months. Results: Twenty-four patients with 94 sessions of HA and 28 patients with 106 sessions of RCA were enrolled. RCA method did not affect the therapeutic efficacy, the function of extracorporeal circulation, and the prognosis of these patients. The occurrences of citrate accumulation in RCA group were 0.0, 67.0, 100.0, 34.0, and 0.0% before DPMAS therapy, at the end of DPMAS therapy, immediately after PE therapy, 2 h after PE therapy, and the next morning, while that in HA group were 0.0, 0.0, 100.0, 7.4, and 0.0%, respectively. The occurrences of citrate accumulation at the end of DPMAS therapy and at 2 h after PE therapy in RCA group were much higher than that in HA group (67.0 vs. 0.0%, p = 0.000; 34.0 vs. 7.4%, p = 0.000, respectively). Although the trend of citrate accumulation in RCA group was much more obvious than that in HA group during and after DPMAS plus PE therapy (p = 0.000), the values on the next morning were similar between the 2 groups (p > 0.05). The main alteration of acid–base status was metabolic alkalosis with no difference between the 2 groups. Conclusions: RCA might be safe and effective in patients with ACLF receiving plasma adsorption plus PE therapy. RCA method might offer an alternative anticoagulation method for them.

Background: Epidemiological data of coeliac disease are lacking from the central Asian region. Aims: To verify the occurrence of coeliac disease amongst four major ethnic groups of Xinjiang Uyghur Autonomus Region, China. Methods: 2277 in-patients with gastrointestinal symptoms (1391 Han, 608 Uyghur, 146 Kazakh and 132 Hui; mean age: 54 ± 12.8 years) were included. Total IgA, antideamidated gliadin peptide (DGP)-IgG, and anti-tissue transglutaminase (anti-tTG)-IgA were analysed. All antibody-positive subjects were further tested for endomysial (EMA) antibodies and were HLA genotyped. All subjects with antibody positivity were asked to undergo intestinal biopsy. In addition, a subset of antibody-negative subjects were tested for HLA-DQA1and DQB1.Results: Among the 2277 subjects, 29 subjects were defined as coeliac disease autoimmune (positive results for anti-tTG IgA and EMA-IgA) (1.27%; 95% confidence interval, 0.81%-1.73%), eight of them underwent biopsy and all showed coeliac disease histology (0.35%; 95% Cl, 0.11%-0.59%). The frequency of coeliac disease autoimmunity was lowest among the Han (0.79%), followed by the Uyghur (1.81%), the Kazakh (2.05%) and the Hui (3.03%). The frequency of the HLA-DQ2 and/or DQ8 haplotype was highest in the Uyghur (52.1%), followed by the Hui (44.4%), the Kazakh (40.0%) and the Han (39.4%). Besides, a three times higher frequency of coeliac disease autoimmunity was found among rural living subjects with significantly higher wheat consumption compared to urban living subjects (3.16% vs 0.97%, P < 0.01). Conclusions:In Xinjiang, coeliac disease does occur, especially in the rural area. The HLA haplotype and environment play key roles in the development of coeliac disease. | 1117ZHOU et al.

Wear particle-induced inflammation is a major factor contributing to aseptic loosening in peri-prosthetic tissue. The effects of cannabinoid receptor 2 (CB(2)) on wear particle-induced inflammation remain unclear. Reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were used to assess the effects of a CB(2)-selective antagonist, AM630, on regulation of the inflammatory reaction and production of pro-inflammatory cytokines in response to in vitro and in vivo stimulation with titanium particles. In vitro studies, in a model for pre-osteoclast-like cells, demonstrated that AM630 inactivation of CB(2) profoundly inhibited interleukin (IL)-1β and tumour necrosis factor (TNF)-α production by RAW264.7 cells stimulated with titanium particles. In vivo findings in a murine air-pouch model of titanium-induced inflammatory osteolysis indicated that AM630 reduced titanium-induced tissue inflammation, seen as a reduction in pouch membrane thickness, inflammatory infiltration and levels of the pro-inflammatory cytokines IL-1β and TNF-α. Thus, inactivation of CB(2) by AM630 inhibited the titanium particle-induced inflammatory reaction by reducing pro-inflammatory cytokines in vitro and in vivo.