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关键词： Model for End-Stage Liver Disease   MELD   Interleukin-1b   Alcohol-Related Hepatitis  

摘要： BACKGROUND AND AIMS: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1(3 has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1(3, in the treatment of patients with AH. METHODS: Participants with biopsy-confirmed AH and discriminant function >= 32 but Model for End-Stage Liver Disease <= 27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS: CAN therapy in severe AH participants with Model for End-Stage Liver Disease <= 27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79;***, Number: NCT03775109.

关键词： Porcine epidemic diarrhea virus   nsp14   RIG-I   IFN-beta   Innate immunity  

摘要： Porcine epidemic diarrhea virus (PEDV) is enteropathogenic coronavirus, and mainly damages intestines, causing diarrhea, vomiting, anorexia, and depression. PEDV highly pathogenic strains spread rapidly and pose significant economic and public health concerns in our country. After virus invasion, RIG-I detects viral double- stranded RNA to activate antiviral innate immunity, inducing IFN responses. PEDV genome encodes 16 non- structure proteins (nsp1-nsp16). These nsps have been effectively involved in the interaction of PEDV and host. PEDV nsp14 is a bi-functional enzyme that is responsible for proofreading and RNA cap G-N-7 methylation during viral infection. In this study, we confirmed that PEDV nsp14 was an interferon antagonist and inhibited IFN production induced by SeV and Poly(I:C). Further, we declared that PEDV infection decreased protein level of RIG-I, and the PEDV nsp14 played a part in this inhibitory effect. PEDV nsp14 induced cell apoptosis and then degraded RIG-I through caspase 8 and caspase 9 pathway during PEDV infection. The N7 MTase domain was critical for nsp14-mediated degradation of RIG-I. Our results revealed the novel function of PEDV nsp14 in virus- host interaction and provided a potential antiviral drug target.

关键词： asthma   biologics   biomarkers  

摘要： BackgroundIn patients with severe asthma, treatment with anti-interleukin-5 (IL-5) biologics can lead to a reduction in fractional exhaled nitric oxide (FeNO) in some patients. The clinical implications of varying FeNO responses to anti-IL-5 biologics remain unclear. This study aims to categorise patients based on their FeNO response to anti-IL-5 biologics and evaluate the association of these categories with clinical *** used the Danish Severe Asthma Register (DSAR) to identify the early FeNO response profiles in patients receiving anti-IL5 biologics. We defined FeNO responders as patients with elevated FeNO levels at baseline and a decrease corresponding to the minimal clinically important difference (MCID) at 4 months of follow-up and FeNO non-responders as those who did not experience a *** identified 403 patients on anti-IL5 treatment in DSAR, and 265 (66%) had elevated FeNO levels at baseline. After 4 months of treatment, 151 (57%) patients showed a significant decrease in FeNO levels, and 114 (43%) did not. FeNO responders were more likely to achieve clinical remission of asthma (34% vs. 19%, p = 0.01, OR 2.11, CI 1.04, 5.18, p = 0.03) than FeNO non-responders after 12 months of treatment. The higher remission rates in FeNO responders mainly reflected a higher rate of normalisation of lung *** levels were reduced after anti-IL5 treatment in a significant proportion of patients treated with anti-IL5, and this was associated with clinical remission. Early FeNO response to anti-IL5 could potentially be used as a biomarker to guide management decisions with biologics towards remission of disease in severe asthma.

关键词： HLA class I   HLA-B   HLA-C   novel alleles  

摘要： Sequencing of the novel alleles HLA-B*15:727 and HLA-C*04:01:01:194Q.

关键词： bispecific antibodies   bystander killing   cancer immunotherapy   T-cells  

摘要： Bispecific antibodies (bsAbs) bridging CD3 on T-cells to tumor-associated antigens (TAA) on tumor cells can direct T-cell immunity to solid tumors. "Bystander killing", where T-cell targeting of TAA-positive tumor cells also leads to the eradication of TAA-negative cells, may overcome TAA heterogeneity. While bystander activity of activated, engineered T-cells has been shown to be robust and wide-reaching, spatiotemporal aspects of bsAb-mediated bystander activity are unresolved. Here, we developed a model where breast cancer tumoroids varying in HER2 expression were printed in to extracellular matrix (ECM) scaffolds. We generated (1) mixed tumors containing different ratios of HER2+ and HER2- tumor cells, and (2) HER2+ and HER2- tumoroids spaced at different distances within the ECM scaffold. Subsequently, tumors were exposed to peripheral blood-derived T-cells in the presence of CD3xHER2 bsAbs. We find that CD3xHER2 bsAb-mediated interaction of resting, nonactivated T-cells with HER2+ tumor cells is sufficient (1) to eliminate 50% HER2- cells in mixed tumor areas, and (2) to eradicate distant HER2- tumor areas. Such bystander killing involves paracrine IFN gamma and TNF alpha activity but does not require T-cell accumulation in HER2- areas. These findings indicate that bystander eradication of TAA-negative cells can significantly contribute to bsAb therapy for solid tumors.

关键词： AC005165.1   Apoptosis   Inflammation   miR-199a-3p   TXNIP  

摘要： Osteoarthritis (OA) is a chronic musculoskeletal disease and often causes impaired joint mobility and disability. Long noncoding RNAs (lncRNAs) play pivotal roles in OA development. This study was done to explore the role and mechanism of the lncRNA AC005165.1 in the cell model of interleukin-1 beta (IL)-1 beta-treated chondrocytes. This study recruited 20 surgically treated OA patients and 12 age- and gender-matched controls. Real-time reverse transcription quantitative polymerase chain reaction was used to examine the expression levels of AC005165.1, miR-199a-3p, and thioredoxin-interacting protein (TXNIP) in articular cartilage of patients and IL-1 beta-treated human chondrocytes. Cell viability and apoptosis were evaluated by cell counting kit-8 and flow cytometry assays, respectively. The protein levels of inflammatory cytokines were assessed by western blotting. Enzyme-linked immunosorbent assay was conducted to detect the concentrations of the inflammatory cytokines in chondrocytes. Luciferase reporter assay and Pearson's correlation analysis were used for analyzing the interaction and the correlation among AC005165.1, miR-199a-3p, and TXNIP. AC005165.1 expression was downregulated in cartilage of OA patients and chondrocytes treated with IL-1 beta, compared to that in the control groups. AC005165.1 knockdown increased apoptosis and aggravated inflammatory response in IL-1 beta-treated chondrocytes. AC005165.1 interacted with miR-199a-3p, and TXNIP was targeted by miR-199a-3p. In rescue assay, miR-199a-3p knockdown and TXNIP overexpression significantly reduced apoptosis and mitigated inflammatory response in IL-1 beta-treated chondrocytes with AC005165.1 knockdown. AC005165.1 knockdown promoted apoptosis and inflammatory response in IL-1 beta-treated chondrocytes via the miR-199a-3p/TXNIP axis.

关键词： HLA   HLA‐A*01:470   novel allele   sequencing‐based typing  

摘要： HLA-A*01:470 differs from HLA-A*01:01:01:01 by one nucleotide substitution in codon 119 in exon 3.

关键词： HLA‐A*02:924   HLA   Taiwanese   novel allele   sequence‐based typing  

摘要： One nucleotide mutation in exon 4 of HLA-A*02:07:01:01 results in the novel allele, HLA-A*02:924.

关键词： Alveolar bone   Anti-inflammatory   Flavonoid   Forastero cacao bean (Theobroma cacao L.) extract gel   NF- KB   Orthodontic tooth movement  

摘要： Background: Malocclusion can be corrected with orthodontic treatment to improve function and aesthetics. Orthodontic treatment patients have the potential to produce greater Reactive Oxygen Species (ROS), as evidenced by an increase in the Oxidative Status Index (OSI) a week after treatment. As a result, oxidative stress may induce an imbalance of bone remodeling through intensifying osteoclastogenesis by expressing pro- inflammatory cytokine, namely Interleukin-6 (IL-6). The worst pathological condition that can occur is Orthodontic-Induced Root Resorption (OIRR), a resorptive area on the root that is unwanted from orthodontic treatment. OIRR incidence is reported to be more than 90 % asymptomatic. Using Forastero cacao bean (Theobroma cacao L.) extract gel as a natural antioxidant and anti-inflammatory compound is expected to be able to prevent excess ROS, which triggers an increase in various pro-inflammatory cytokines, especially IL-6, which plays a role in the bone resorption pathway, thus reducing the incidence of OIRR and making orthodontic treatment successful through balanced bone remodeling. Aim: This study aimed to investigate the effect of Forastero cacao bean (Theobroma cacao L.) extract gel on the decrease of IL-6 cytokine expressed by osteoblasts, osteoclasts, and osteocytes in the OIRR model of male Wistar rats. Results: IL-6 positive osteoblasts, osteoclasts, and osteocytes decreased significantly after 8 % Forastero cacao bean extract gel-treated, as seen in T7 and T14 groups compared to C-7 and C-14 groups (p < 0.05). Conclusions: 8 % Forastero cacao bean extract gel decreased IL-6-positive osteoblasts, osteoclasts, and osteocytes in the tension side of the alveolar bone.