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关键词： Unresectable hepatocellular carcinoma   Atezolizumab plus bevacizumab   Interleukin-6  

摘要： Background This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC). Methods 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens. Results In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group;in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (rho = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (rho = -0.4, p < 0.01). Conclusion Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment.

关键词： Breast cancer   HLA-A   HLA-B/C   PD-1   PD-L1   prognosticator   survival  

摘要： Background/Aim: Class 1 human leukocyte antigen (HLA) ensures that cytotoxic T lymphocytes (CTLs) attack tumor cells. As part of tumor de-differentiation, the expression of HLA on the tumor cell surface may decrease, which can facilitate tumor growth. Therefore, reduced expression of HLA is generally negatively associated with overall survival (OS). The reverse is true for programmed cell death protein (PD-1) and programmed death ligand 1 (PD-L1). The presence of PD-1 and PD-L1 on the surface of cancer cells inhibits immune defense mechanisms against cancer cells. Therefore, one would expect that increased PD-1/PDL-1 expression would result in decreased 5-year survival. The aim of this study was to correlate the expression levels of HLA-A and HLA-B/C with the expression levels of PD-1 and PDL-1 to evaluate the reliability of their prediction of 5-year OS. Materials and Methods: This study retrospectively examined patients upon the start of a new therapy line for metastatic breast cancer (MBC). The pilot cohort fulfilling very demanding inclusion criteria consisted of 34 patients. The diagnostics were primarily carried out using RT-qPCR.

关键词： HLA   HLA-C novel allele   sequencing-based typing  

摘要： The novel allele HLA-C*07:1102 differs from HLA-C*07:02:01:01 by one non-synonymous nucleotide substitution in exon 2.

关键词： HLA   HLA-DQB1   novel allele   sequencing-based typing  

摘要： The novel allele HLA-DQB1*06:02:60 differs from HLA-DQB1*06:02:01:01 by one synonymous nucleotide substitution in exon 2.

关键词： Severe Asthma   Mast Cells   Progenitors   Biologics   Phenotypes  

摘要： Atrial fibrillation (AF) is more prevalent in patients with elevated interleukin (IL)-1 beta levels. Here we show that daily administration of IL-1 beta for 15 days sensitizes mice to AF, leading to fibrosis, accumulation of beta-pleated sheet proteins in the left atrium, and systemic inflammation, resembling the pathophysiological changes observed in patients with AF. IL-1 beta administration creates a positive feedback loop, dependent on the IL-1 receptor (IL-1R) activity in cardiac resident macrophages. This results in increased caspase-1 maturation in the left atrium and elevated Il1b and Casp1 transcription in atrial macrophages. IL-1 beta treatment accelerated action potential and Ca2+ restitution in the left atrium, leading to action-potential shortening. This, along with increased caspase-1 maturation and IL-1R signaling, was essential for inducing AF. Lack of IL-1R in macrophages, but not cardiomyocytes, prevented IL-1 beta-induced AF sensitivity. By depleting recruited macrophages or deleting IL-1R specifically in cardiac resident macrophages, we further demonstrate that IL-1 beta/IL-1R signaling in these resident macrophages is responsible for increased AF susceptibility. These findings offer insights into the therapeutic potential of targeting IL-1 beta/IL-1R signaling in patients with AF and emphasize the importance of recognizing different underlying causes in this patient group.

关键词： Sus scrofa RNase L   Porcine reproductive and respiratory syndrome   virus   Antiviral   Innate immunity   2-5 A  

摘要： Porcine reproductive and respiratory syndrome virus (PRRSV) has become one of the most economically important diseases to the global pig industry. RNase L is a ubiquitous cellular endoribonuclease that is activated upon the binding of a specific ligand, 2 ',5 '-linked oligoadenylates (2-5 A), which is synthesized by oligoadenylate synthetases (OASs). However, whether Sus scrofa RNase L (sRNase L) could inhibit PRRSV replication and its mechanism have not been fully elucidated. In this study, sRNase L was cloned and characterized in homology and structure firstly. Then the antiviral activity of sRNase L against PRRSV was explored. Overexpression of sRNase L significantly inhibited the propagation of PRRSV when treated with 2-5 A or poly(I: C) or mock treated. Furthermore, sRNase L induced degradation of cellular and viral ssRNAs, enhanced the activation of IFN-beta promoter and IFN-beta expression, and induced apoptosis to inhibit PRRSV replication. Taken together, we have first elucidated the anti-PRRSV function and the underlying mechanism of sRNase L, which may provide a new strategy for preventing PRRSV infection.

关键词： monoclonal antibodies   psoriasis   pharmacokinetics   plaque psoriasis   interleukin-23   psoriasis area and severity index  

摘要： Importance Psoriasis is a chronic, immune-mediated skin disease with an unmet need for biologic treatment options. Objective To assess the safety, pharmacokinetics, and efficacy of QX004N in healthy individuals and patients with moderate to severe plaque psoriasis in China. Design, Setting, and Participants This randomized clinical trial was composed of 2 parts. Part 1 was a first-in-human, single-ascending-dose, phase 1a clinical trial conducted from November 2, 2021, to January 16, 2023. Part 2 was a double-blind, multiple dose-escalation, phase 1b clinical trial conducted from February 15, 2023, to January 5, 2024, at 5 clinical centers in China, involving patients with moderate to severe plaque psoriasis. Interventions In part 1, healthy participants in each cohort were assigned in a 4:1 ratio to receive a single subcutaneous injection of QX004N (ranging from 10 mg to 600 mg) or placebo. In part 2, patients in each cohort were assigned in a 4:1 ratio to receive QX004N or placebo at doses of 150 mg, 300 mg, and 600 mg once every 2 weeks. Main Outcomes and Measures For part 1, the primary outcome was the safety of a single dose of QX004N in healthy participants, and the secondary outcome was the pharmacokinetic profile. For part 2, the primary efficacy end point was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) by week 12;other efficacy end points were considered secondary. Results The phase 1a clinical trial (part 1) enrolled 55 healthy participants (mean [SD] age, 35.9 [6.0] years;30 [54.5%] female), and the phase 1b clinical trial (part 2) enrolled 30 patients with moderate to severe plaque psoriasis. The mean (SD) age of QX004N-treated participants in part 2 was 41.4 (7.5) years, and 19 of 24 QX004N-treated participants (79.2%) were male. The mean (SD) age of the placebo cohort in part 2 was 35.3 (8.4) years, and 5 of 6 placebo-treated participants (83.3%) were male. QX004N exhibited linear pharmac

摘要： BackgroundEvidence suggested that IL-17A was associated with renal function in type 2 diabetes. We used ultra-sensitive measurement to detect the concentration of IL-17A in human peripheral blood and explored the association of IL-17A with diabetic kidney disease (DKD).MethodsWe recruited 138 participants from the Shanghai Diabetes Institute Inpatient Database of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Eighty-four individuals diagnosed as DKD were cases, and 54 type 2 diabetes individuals without DKD or diabetic retinopathy (DR) were controls. The concentration of serum IL-17A was detected by the High Sensitivity Immunoassay Quantitative Kit. Data was analysed by *** concentration of serum IL-17A in our population ranged from 0.07 pg/mL to 2.96 pg/mL with the median of 0.502 pg/mL. Our results suggested that the level of serum IL-17A in DKD case group was higher than in the control (P unadjusted = 0.0496, P adjusted = 0.0298). And serum creatinine, eGFR, ACR were used as indicators of renal function. Serum creatinine and ACR were positive correlated with the level of serum IL-17A (P adjusted = 0.0148;P adjusted = 0.0369), while eGFR showed a negative correlation (P adjusted = 0.0167). Additionally, the level of serum IL-17A was also significantly higher in DR case group compared with the control group (p = 0.0224).ConclusionSerum IL-17A level is associated with renal function decline and diabetic retinopathy in patients with type 2 diabetes in a Chinese Han population. Our results suggested that IL-17A may be a potential biomarker of DKD and DR.