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摘要： BackgroundInterleukin (IL)-23p19 and IL-17 inhibitors have demonstrated high efficacy for psoriasis in randomized controlled trials, though real-world data, particularly for risankizumab (IL-23p19 inhibitor) and brodalumab (IL-17 receptor (IL-17R) inhibitor), is *** assess drug survival of IL-23p19 and IL-17 inhibitors compared to other biologics for *** conducted a cohort study using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) from November 2007 to June 2023. Multivariable flexible parametric models assessed drug survival, with discontinuation due to ineffectiveness and adverse effects reported separately. The primary outcome measure was the absolute difference in restricted mean survival time at 2 years, referred to as adjusted survival time, between all *** 19,034 treatment courses (median follow-up: 2.3 years), treatments included adalimumab (tumour necrosis factor-alpha (TNF-a) inhibitor, n = 6,815), ustekinumab (IL-12/23p40 inhibitor, n = 5,639), secukinumab (IL-17A inhibitor, n = 3,051), ixekizumab (IL-17A inhibitor, n = 1,072), brodalumab (n = 367), guselkumab (IL-23p19 inhibitor, n = 1,258) and risankizumab (n = 832). Guselkumab and risankizumab had the highest adjusted survival times (years [interquartile ranges]) for effectiveness (1.93 [1.91-1.95] and 1.93 [1.90-1.96], respectively). Risankizumab had the highest survival for safety (1.94 [1.92-1.96]) followed by guselkumab (1.92 [1.90-1.94]) and ustekinumab (1.92 [1.91-1.93]). Brodalumab showed lower adjusted survival time for effectiveness (1.75 [1.69-1.81]) than most biologics except secukinumab and adalimumab;and similar survival for safety (1.85 [1.81-1.90]) compared to IL-17A inhibitors and adalimumab. In patients with psoriatic arthritis, ustekinumab showed reduced drug survival. Prior biologic exposure was associated with a dose-response reduction in survival which was significantly large

摘要： In this issue of Blood, Gibson et alp have identified the impact of HLA alloimmunization in autologous gene-modified hematopoietic cell transplantation (GM-HCT) for transfusion-dependent thalassemia (TDT). Nickel et al have previously reported increased need for platelet and red cell transfusions after MSD HCT due to preexisting HLA and red cell antibodies in patients with sickle cell disease (SCD).

关键词： 胃癌   术后复发   淋巴细胞亚群   IL-6   PCT   预测价值  

摘要： 目的 探讨外周血淋巴细胞亚群及白细胞介素-6（IL-6）、降钙素原（PCT）的表达对胃癌患者术后复发的预测价值。方法 选取2021年4月至2023年5月于黄石市中心医院行根治性手术治疗的206例胃癌患者作为研究对象,根据是否复发将其分为复发组（58例）和未复发组（148例）。抽取复发组和未复发组静脉血,应用流式细胞术（FCM）对外周血T细胞亚群、NK细胞、B细胞进行测定,应用循环增强荧光免疫发光法对外周血IL-6、PCT进行检测,比较两组人群中各指标的表达情况,绘制受试者工作特征（ROC）曲线评估外周血淋巴细胞亚群及IL-6、PCT的表达水平对胃癌术后复发的预测价值。结果复发组和未复发组中CD3+、CD3+CD8+、CD3+CD4+、CD4+/CD8+均无明显差异（P均>0.05）;复发组CD3-CD19+、CD3-CD56+、IL-6、PCT水平均高于未复发组（P均<0.05）;CD3-CD19+、CD3-CD56+、IL-6、PCT预测胃癌术后复发的曲线下面积（AUC）分别为0.656、 0.682、0.888、0.868,四者联合预测术后复发的AUC为0.919,优于各指标单独预测（P<0.05）。结论 外周血淋巴细胞亚群及IL-6、PCT的表达水平与胃癌患者术后复发有着紧密联系,联合检测可能为胃癌术后复发患者提供更优质的诊断效能和预测价值。

摘要： Unresolved tissue damage is a common feature of Inflammatory Bowel Disease (IBD) that facilitates disease progression. Here, we showed that high animal fat diets (HFD), an environmental risk factor associated with IBD pathogenesis, suppress intestinal macrophage production of critical tissue repair responses after damage. This includes reduced IL-23 production, which drives downstream production of the IL-22, which is needed for barrier repair. Indicating that dietary lipids interfere with responses to microbial molecules needed to induce barrier protective functions, we found oleic acid could directly suppress macrophage induction after lipopolysaccharide (LPS) treatment. Deleting the lipid transporter CD36 on macrophages restored the and response, reducing intestinal damage in HFD-fed DSS-treated mice. We found that CD36-mediated intracellular lipid accumulation, mainly oleic acid, in macrophages leads to peroxisome proliferator-activated receptor delta (PPARd)release of the transcriptional repressor protein B-cell lymphoma 6 (BCL6). BCL6 suppresses transcription in microbe-exposed macrophages. The studies suggest dietary lipid modulation of the macrophage PPARd/BCL6 transcriptional repressor complex is a key mechanism of fat-associated defects in intestinal damage repair and immune dysregulation. Overall, our findings provide new insights into dietary lipid contribution to intestinal disease progression and identify new potential therapeutic targets to decrease diet-associated risk for IBD.

关键词： HLA haplotype frequencies   immunogenetics   population genetics   next-generation sequencing (NGS)  

摘要： Human Leukocyte Antigen (HLA) genes are remarkable for their structural complexity and polymorphism. Located on chromosome 6 within the Major Histocompatibility Complex (MHC), these genes exhibit significant frequency variations across human populations and play a crucial role in immune responses, disease susceptibility, and transplant compatibility. This study aimed to assess the genetic profiles and HLA-A/HLA-B/HLA-C/HLA-DRB1 haplotype frequencies in a Romanian cohort. Whole venous blood samples were collected from 405 healthy, unrelated Romanian volunteers. Using next-generation sequencing (NGS), the study population was genotyped for HLA class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1) loci. Haplotype frequencies were estimated using the expectation-maximization algorithm, addressing phase and allelic ambiguity. The Romanian cohort was compared with multiple populations sourced from the Allele Frequencies Net Database. The study identified 635 different HLA-A/HLA-B/HLA-C/HLA-DRB1 haplotypes. Among them, two haplotypes had frequencies close to 3%: HLA-A*01:01:01/HLA-B*08:01:01/HLA-C*07:01:01/HLA-DRB1*03:01:01, with a frequency of 3.33%, and HLA-A*02:01:01/HLA-B*18:01:01/HLA-C*17:01:01/HLA-DRB1*11:04:01, with a frequency of 2.84%. All other 633 haplotypes (approximately 99.7% of the total) had frequencies below 1%. The results of the current study underscore the extremely high diversity of HLA haplotypes in this population and the fact that even the most frequent haplotypes are relatively low in prevalence (each under 5% in this cohort). These findings and the great haplotypical diversity detected highlight the importance of NGS and high-resolution HLA typing in hematopoietic stem cell and solid organ transplantation, while also contributing to the better understanding of the area-specific population genetics resulting from historical regional dynamics. Further research with larger cohorts is necessary to validate these findings and expand upon their clin

关键词： Mesenchymal stem cells   Inflammation   Phagocytosis   Microglia   Exosome   CD44  

摘要： Identifying the specific bioactive molecules produced by mesenchymal stem cells (MSCs) and the signaling pathways and cell types upon which they act is critical to developing MSC-based therapeutics for inflammatory diseases with high unmet needs. Our study aimed to investigate the impact of extracellular vesicle (EV)-derived TNF-Stimulated Gene-6 (TSG-6, from adipose tissue-derived mesenchymal stem cell concentrated conditioned medium, ASC-CCM or TSG-6 overexpression in ASC using ORF expression-ready clone) on microglia and its potential anti-inflammatory effects. EV but not non-vesicular secretome prepared by ultracentrifugation confirmed the expression of TSG-6 exclusively in the small EV (sEV) fraction. sEV ranged from 50-150 nm as determined by Zetasizer, demonstrated bilipid membrane evidenced by transmission electron microscopy, expressed positive exosomal (e.g. CD63) markers, and were endocytosed by BV2 cells confirmed by DiI fluorescently labeled exosomes. BV2 microglia cultured under serum-free conditions stimulated with TLR4 agonists (LPS and IFN gamma) for 12 h in the presence of p-ASC-EV (sEV derived from ASC after cytokine stimulation) and TSG-6-ORF-EV significantly reduced nitrite release (p < 0.001), phagocytic activity (p < 0.001) and reduced CD44 expression (p < 0.05). CD44 knockdown in BV2 cells ablated TSG-6-ORF-EV mediated nitrite release, IL1 beta downregulation, and phagocytosis with TLR4 agonists. Our results revealed that under cytokine stimulation, the EV portion of ASC-CCM becomes enriched with TSG-6. Overexpressing TSG-6 in ASC leads to an increased concentration of TSG-6 in sEVs. This enriched EV fraction, containing TSG-6, regulates microglial dynamics through a feedback loop with CD44. EV-associated TSG-6 can influence immune cell behavior and signaling, mitigating excessive inflammation or immune dysfunction.

关键词： Adhesion GPCR   IL-6   Cytoskeletal remodelling   GPR56   Melanoma   Signalling  

摘要： BackgroundGPR56/ADGRG1 is an adhesion G protein-coupled receptor involved in cell-matrix interactions and metastasis of human melanoma cells. Previously, we demonstrated that GPR56 activation in melanoma cells triggers G alpha 12/13-RhoA signaling, leading to increased IL-6 production and enhanced cell migration. Yet little is known of the downstream signaling effectors and their specific roles in regulating melanoma cellular *** this study, we show that GPR56 activation induces Rho-ROCK-MLC and JAK-STAT3 signaling, which temporally and differentially drive amoeboid-like morphology and IL-6 upregulation. Interestingly, GPR56-induced JAK-STAT3 activation is partially regulated by Rho-ROCK-MLC signaling but not vice versa. Moreover, receptor auto-proteolysis modulates the magnitude of GPR56-mediated signaling, and its unique intracellular regions contribute to the selective regulation of unique signaling pathways and associated cellular *** findings reveal complex GPR56-mediated biased signaling through the Rho-ROCK-MLC and JAK-STAT3 pathways, highlighting these networks as potential therapeutic targets for modulating distinct tumorigenic phenotypes in human melanoma cells.

关键词： 挂线引流术   抗TNF-α单抗   免疫抑制剂   克罗恩病   肛瘘  

摘要： 对接受挂线引流术治疗的克罗恩病合并肛瘘患者术后分别应用抗TNF-α单抗、免疫抑制剂治疗,观察并分析两种不同治疗方案的疗效,促进临床治疗方案的改进与优化,加快患者康复进度。方法 选取2023年1月-2024年12月本院收治的56例克罗恩病合并肛瘘患者,通过随机数据表法予以分组。所有患者均接受挂线引流术和术后抗感染治疗。研究组在术后加入抗TNF-α单抗医治(英夫利西单抗静脉滴注),对照组则加入联合免疫抑制剂治疗(硫唑嘌呤片口服)。评估两组治疗效果。结果 研究组疗效优于对照组(P<0.05);研究组CD4+、CD4+/CD8+较对照组明显降低,CD8+较对照组明显升高(P<0.05);研究组IL-10较对照组明显升高,IL-12、TNF-α较对照组明显降低(P<0.05);研究组不良反应发生率远低于对照组(P<0.05)。结论 对于患有克罗恩病并伴有肛瘘的病人,在进行挂线引流手术后,采用英夫利西单抗进行联合治疗,其效果优于使用硫唑嘌呤片的联合疗法。这种治疗方式能够显著提升患者的免疫系统功能,缓解炎症状况,并减少不良反应的可能性。

摘要： We report our single center experience demonstrating that HLA Class I alloimmunization predicts longer time to platelet engraftment, increased bleeding complications and higher transfusion requirements in patients undergoing gene-modified hematopoietic stem cell transplant for transfusion-dependent beta thalassemia.