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关键词： Upadacitinib   biologics   inflammatory bowel diseases   infliximab   risankizumab  

摘要： BACKGROUND AND AIMS:We sought to ascertain how prior exposure to TNF antagonists impacts treatment response with various classes of advanced therapies in patients with ulcerative colitis (UC), through a systematic review and meta-analysis. METHODS:Through a systematic review of multiple databases through June 30, 2024, we identified 17 RCTs in 8871 adults with moderate-severe UC who were treated with different advanced therapies vs. placebo, and reported efficacy in induction of clinical remission, stratified by prior exposure to TNF antagonists. We calculated the ratio of odds ratio of achieving remission with active drug vs. placebo, in TNF antagonist-naïve vs. TNF antagonist-exposed patients. We grouped advanced therapies based on primary mechanism of action: lymphocyte trafficking inhibitors (anti-integrins and sphingosine-1 phosphate [S1P] receptor modulators), anti-interleukins (interleukin-12/23 antagonist and selective IL-23 antagonists) and Janus kinase inhibitors. RESULTS:Lymphocyte trafficking inhibitors were more efficacious in TNF antagonist-naïve vs. exposed patients (five trials; ratio of OR,1.88 [95% CI, 1.02-3.49]), whereas JAK inhibitors were less efficacious in TNF antagonist-naïve vs. exposed patients (six trials; ratio of OR,0.47 [0.22-1.01]). No significant difference was observed in efficacy of selective IL-23 antagonists vs. placebo in TNF antagonist-naïve vs. exposed patients (six trials; ratio of OR,1.07 [0.64-1.80]). There was minimal heterogeneity across analyses. CONCLUSION:There is significant heterogeneity of treatment efficacy with different advanced therapies in inducing remission in patients with UC based on prior exposure to TNF antagonists, with plausible potentiation of JAK inhibitors and attenuation of lymphocyte trafficking inhibitors. Future studies on the mechanistic basis for these observations are warranted.

关键词： GATA‐6   PPARα   cardiac differentiation   polycomb protein complex   ubiquitylation  

摘要： Transcription factors collaborate with epigenetic regulatory factors to orchestrate cardiac differentiation for heart development, but the underlying mechanism is not fully understood. Here, we report that GATA-6 induces cardiac differentiation but peroxisome proliferator-activated receptor α (PPARα) reverses GATA-6-induced cardiac differentiation, possibly because GATA-6/PPARα recruits the polycomb protein complex containing EZH2/Ring1b/BMI1 to the promoter of the cardiac-specific α-myosin heavy chain (α-MHC) gene and suppresses α-MHC expression, which ultimately inhibits cardiac differentiation. Furthermore, Ring1b ubiquitylates PPARα and GATA-6. By overexpression and knockout of EZH2/BMI1, it was demonstrated that the polycomb protein complex inhibits cardiac differentiation induced by GATA-6 and PPARα. Together, our results demonstrate that the polycomb protein complex interacts with GATA-6/PPARα to inhibit cardiac differentiation, a finding that could facilitate the development of new therapies for congenital heart disease.

关键词： Adaptive introgression   Balancing selection   HLA   Machine learning   Population genetics  

关键词： Macrophages   SPP1 + macrophages   Single-cell RNA sequencing   TNF-α   IL-1β  

摘要： BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease characterized by a heterogeneous tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs) constitute the major innate immune population in the TIME where they facilitate crucial regulatory processes that participate in malignant tumor progression. SPP1 + macrophages (SPP1 + Macs) are found in many cancers, but their effects on HNSCC remain unknown. This study aimed to identify and validate the role and function of SPP1 + Macs in the malignant progression of HNSCC. METHODS:In this study, we applied single-cell RNA sequencing (scRNA-seq) analyses of paired tumor and normal tissues from 5 HNSCC patients to identify tumor-specific SPP1 + Macs. RT-qPCR and multiplex immunohistochemical and multiplex immunofluorescence staining were used to verify the presence of SPP1 + Macs in the clinical samples. Gene set variation analysis suggested that SPP1 + Macs were actively involved in cytokine production. Thus, we constructed SPP1-OE macrophages and SPP1-KD macrophages (both differentiated from THP-1 cells), performed a Luminex liquid suspension chip detection assay to detect differential cytokines, and further assessed their biological functions and mechanisms in several HNSCC cell lines and adjacent macrophages. An in vivo experiment was used to verify the function of SPP1 + Macs in HNSCC progression. RESULTS:The scRNA-seq results revealed that myeloid cells were heterogeneous and strongly correlated with tumor cells in the TIME in HNSCC and identified tumor-specific SPP1 + Macs, which were positively correlated with poor prognosis of HNSCC patients. Gene set variation analysis (GSVA) suggested that SPP1 + Macs were actively involved in cytokine production. Luminex liquid suspension chip detection assay indicated that SPP1 + Mac-derived TNF-α and IL-1β played important roles. Both in vitro and in vivo experiments and the use of VGX-1027, an inhibitor of macrophage-derived TN

关键词： 白血病,髓系,急性   急性淋巴细胞白血病   流式细胞术   抗肿瘤联合化疗方案  

摘要： 目的 提高对细胞形态似急性淋巴细胞白血病的急性髓系白血病（AML）的认识。 方法 回顾性分析延安大学咸阳医院2023年11月收治的1例细胞形态似急性淋巴细胞白血病（ALL）的AML患者的临床资料，并复习相关文献。 结果 患者为62岁男性，以乏力、发热就诊，三系减低。外周血涂片、骨髓涂片、骨髓活组织检查示细胞形态似ALL，且过氧化物酶、氯乙酸AS-D萘酚酯酶、α-乙酸萘酚酯酶（ANAE）、ANAE+NaF染色均阴性，但流式细胞术检出50%原始细胞，表达CD34、CD13、CD117、HLA-DR，骨髓免疫组织化学检测出MPO阴性、CD34 80%阳性、CD117 80%阳性，检测到BCOR、BCORL1、FLT3-TKD、RUNX1、U2AF1基因突变。最终结合细胞形态学、免疫分型、细胞遗传学以及分子生物学综合评估，确诊为AML。给予阿扎胞苷联合CAG（阿柔比星、阿糖胞苷、粒细胞集落刺激因子）方案化疗1个疗程，复查示骨髓象缓解。因患者存在FLT3-TKD突变，第2个疗程调整为吉瑞替尼+阿扎胞苷+HAG（阿糖胞苷、高三尖杉酯碱、粒细胞集落刺激因子）方案，截至2024年6月，患者处于持续缓解状态。 结论 细胞形态似ALL的AML临床较少见，其细胞形态不典型，诊断不能仅依靠细胞形态学和化学染色，还应行流式细胞术、染色体核型分析以及基因检测等。其治疗主要以化疗为主。

关键词： 登革病毒   NS1蛋白   单克隆抗体   配对抗体  

摘要： 登革热是由登革病毒（Dengue virus,DENV）感染引起的急性虫媒传播疾病。早期诊断和控制疾病发展可以降低严重登革热的发病率和死亡率。虽然已有的DENV NS1抗原检测试剂可以早期诊断登革热，但都不能区分DENV四种血清型。本研究通过制备DENV2 NS1抗原的单克隆抗体，筛选特异性识别DENV2 NS1的抗体对，建立特异检测DENV2 NS1抗原的双抗体夹心ELISA技术，用于DENV NS1抗原的快速分型检测。利用昆虫细胞-杆状病毒系统表达重组DENV2 NS1蛋白（rDENV2 NS1），通过镍柱亲和层析纯化rDENV2 NS1。用纯化的rDENV2 NS1蛋白免疫BALB/c鼠，分离免疫小鼠的脾脏淋巴细胞与SP2/0细胞融合，筛选阳性杂交瘤细胞系，获得三株阳性单克隆抗体F1、B12、A2，亚型依次为IgG1（κ）、IgG2a（κ）、IgG1（κ），间接ELISA和Western blot鉴定结果显示B12、A2单抗能与rDENV2 NS1特异性结合，F1单抗与其他DENV血清型NS1有交叉反应。细胞培养生产纯化单克隆抗体，HRP标记单抗，双抗体夹心ELISA法筛选可特异识别DENV2 NS1抗原的抗体对。结果显示，B12作为捕获抗体，A2-HRP作为检测抗体，能特异性结合DENV2 NS1蛋白，与其他DENV血清型NS1没有交叉反应，成功筛选出特异性识别DENV2型NS1的配对抗体，并初步建立了特异检测DENV2 NS1抗原的双抗体夹心ELISA检测技术，为研发登革病毒早期分型快速诊断试剂奠定基础。

关键词： 免疫球蛋白A肾病   凋亡   自噬   焦亡   铁死亡   铜死亡  

摘要： 免疫球蛋白A肾病（immunoglobulin A nephropathy, IgAN）是一种免疫介导的慢性炎症性疾病，其发病机制复杂，临床表现多样，目前尚无特定的治疗方案。细胞程序性死亡是体内由基因所控制的细胞主动的有序的死亡方式，通过参与多种分子信号通路来维持机体的稳态和器官、组织的发育。近年来，细胞程序性死亡在IgAN的发生发展中起着重要的调控作用，其机制涉及复杂的信号通路，在病理条件下可能通过减轻氧化应激、抑制炎症、改善能量代谢等多种途径来缓解肾脏损伤。该文就IgAN在凋亡、自噬、焦亡、铁死亡和铜死亡方面的研究进展作一综述，以期为IgAN提供新的治疗靶点。

关键词： Brain   Glucogan-like peptide 1   Gut   Interleukin-6   Obesity  

摘要： Obesity is a chronic metabolic disease characterized by excessive nutrient intake leading to increased subcutaneous or visceral fat, resulting in pathological and physiological changes. The incidence rate of obesity, an important form of metabolic syndrome, is increasing worldwide. Excess appetite is a key pathogenesis of obesity, and the inflammatory response induced by obesity has received increasing attention. This review focuses on the role of appetite-regulating factor (Glucogan-like peptide 1) and inflammatory factor (Interleukin-6) in the gut and brain in individuals with obesity and draws insights from the current literature.

关键词： CD4+ T cell   CP: Immunology   Tfh   Th1   immune memory  

摘要： It is not clear how CD4 memory T cells are formed from a much larger pool of earlier effector cells. We found that transient systemic bacterial infection rapidly generates several antigen-specific T helper (Th)1 and T follicular helper (Tfh) cell populations with different tissue residence behaviors. Although most cells of all varieties had transcriptomes indicative of cell stress and death at the peak of the response, some had already acquired a memory cell signature characterized by expression of genes involved in cell survival. Each Th1 and Tfh cell type was maintained long term by interleukin (IL)-7, except germinal center Tfh cells, which depended on a T cell antigen receptor (TCR) signal. The results indicate that acute infection induces rapid differentiation of Th1 and Tfh cells, a minority of which quickly adopt the gene expression profile of memory cells and survive by signals from the IL-7 receptor or TCR.

关键词： Expression regulation   Immune checkpoint inhibitors   MHC I   Small molecule compounds  

摘要： Major histocompatibility complex (MHC) class I load antigens and present them on the cell surface, which transduces the tumor-associated antigens to CD8 T cells, activating the acquired immune system. However, many tumors downregulate MHC I expression to evade immune surveillance. The low expression of MHC I not only reduce recognition by- and cytotoxicity of CD8 T cells, but also seriously weakens the anti-tumor effect of immunotherapy by restoring CD8 T cells, such as immune checkpoint inhibitors (ICIs). Accumulated evidence suggested that restoring MHC I expression is an effective strategy for enhancing tumor immunotherapy. This review focuses on mechanisms underlying MHC I downregulation include gene deletion and mutation, transcriptional inhibition, reduced mRNA stability, increased protein degradation, and disruption of endocytic trafficking. We also provide a comprehensive review of small molecules that restore or upregulate MHC I expression, as well as clinical trials involving the combination of ICIs and these small molecule drugs.