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关键词： adalimumab   infliximab   TDM  

摘要： ObjectivesMucosal healing (MH) is a key therapeutic target in Crohn's disease (CD) and is associated with improved outcomes. While adult studies indicate a positive correlation between serum anti-tumor necrosis factor (TNF) levels and MH, data in pediatric patients is limited. We aimed to define the association of serum anti-TNF levels with MH in pediatric patients with CD during maintenance *** data (2014-2023) was collected from pediatric CD patients treated with infliximab or adalimumab who performed an ileocolonoscopy at least 26 weeks after initiating therapy. Serum anti-TNF levels around endoscopic time were compared with endoscopic findings. MH was defined as complete absence of inflammatory or ulcerative lesions across all segments of the gastrointestinal tract. Univariable and multivariable logistic regression analysis was conducted to identify factors associated with *** were obtained from 107 patients (41 infliximab and 66 adalimumab), with a median age at diagnosis of 12.6 (9.9-14.0) years. Median time until ileocolonoscopy following anti-TNF initiation was 89.0 (56.3-152.3) weeks. MH was identified in 31 (29.0%) patients. Anti-TNF serum levels were comparable in the MH and non-MH groups (9.5 [4.9-13.9] vs. 9.3 [6.4-15.7] mu g/mL;p = 0.73), without differences in patients treated with infliximab or adalimumab. In multivariable analysis, diagnosis weight Z-score (odds ratio [OR] = 2.860, 95% confidence interval [CI] = 1.005-8.138;p = 0.049), along with C-reactive protein (OR = 0.037, 95% CI = 0.002-0.687;p = 0.027) and fecal calprotectin (OR = 0.995, 95% CI = 0.990-1.000;p = 0.037) at time of ileocolonoscopy were significantly associated with *** our cohort, anti-TNF levels during maintenance were not associated with MH in pediatric CD.

关键词： EGF receptor   epithelial polarity   inflammatory cytokines   PI3K/Akt signaling   unconventional protein secretion  

摘要： This manuscript describes a novel unconventional secretory pathway that facilitates EGF receptor (EGFR) signaling from apical membranes in polarized epithelial cells responding to immune cell mediators. Epithelial tissues provide a physical barrier between our bodies and the external environment and share an intimate relationship with circulating and local immune cells. Our studies describe an unexpected connection between the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and EGFR typically localized to basolateral membranes in polarized epithelial cells. These two molecules sit atop complex biological networks with a long history of shared investigative interest from the vantage point of signaling pathway interactions. We have discovered that TNF-alpha alters the functional landscape of fully polarized epithelial cells by changing the speed and direction of EGFR secretion. Our results show apical EGFR delivery occurs within minutes of de novo synthesis likely via a direct route from the endoplasmic reticulum without passage through the Golgi complex. Additionally, our studies have revealed that apical cellular compartmentalization constitutes an important mechanism to specify EGFR signaling via phosphatidylinositol-4,5-bisphosphate 3-kinase/protein-kinase-B pathways. Our study paves the way for a better understanding of how inflammatory cytokines fine-tune local homeostatic and inflammatory responses by altering the spatial organization of epithelial cell signaling systems.

关键词： HLA-A   NGS   novel allele   russian  

摘要： Genomic sequence of HLA-A*01:475, -A*01:476Q, -A*11:482, -A*25:93 and -A*68:91:02 alleles in Russian individuals.

关键词： data-independent acquisition   HLA peptides   immunopeptidomics   ion mobility   quantification   ACN   acetonitrile   CCS   collisional cross sections   DDA   data-dependent acquisition   DIA   data-independent acquisition   FDR   false discovery rate   HLA   human leukocyte antigen   MS   mass spectrometry   RT   retention   TFA   trifluoroacetic acid   TIMS   trapped ion mobility spectrometry  

摘要： Human leukocyte antigen class I (HLA-I) molecules present short peptide sequences from endogenous or foreign proteins to cytotoxic T cells. The low abundance of HLA-I peptides poses significant technical challenges for their identification and accurate quantification. While mass spectrometry is currently a method of choice for direct system-wide identification of cellular immunopeptidomes, there is still a need for enhanced sensitivity in detecting and quantifying tumor-specific epitopes. As gas phase separation in data-dependent MS data acquisition increased HLA-I peptide detection by up to 50%, here, we aimed to evaluate the performance of data-independent acquisition (DIA) in combination with parallel accumulation serial fragmentation ion mobility (diaPASEF) for high-sensitivity identification of HLA presented peptides. Our streamlined diaPASEF workflow enabled identification of 11,412 unique peptides from 12.5 million A375 cells and 3426 8-11mers from as low as 500,000 cells with high reproducibility. By taking advantage of HLA binder-specific in silico predicted spectral libraries, we were able to further increase the number of identified HLA-I peptides. We applied SILAC-DIA to a mixture of labeled HLA-I peptides, calculated heavy-to-light ratios for 7742 peptides across five conditions and demonstrated that diaPASEF achieves high quantitative accuracy up to 5-fold dilution. Finally, we identified and quantified shared neoantigens in a monoallelic C1R cell line model. By spiking in heavy synthetic peptides, we verified the identification of the peptide sequences and calculated relative abundances for 13 neoantigens. Taken together, diaPASEF analysis workflows for HLA-I peptides can increase the peptidome coverage for lower sample amounts. The sensitivity and quantitative precision provided by DIA can enable the detection and quantification of less abundant peptide species such as neoantigens across samples from the same background.

关键词： innate immunity   IRF3   PKZ   TDP43   type I interferon  

摘要： Transactive response DNA binding protein 43 kD (TDP43), encoded by the tardbp gene, is a member of heterogenous nuclear ribonucleoproteins family. In this study, a gradual upregulation of TDP43 messenger RNA was observed in either Ctenopharyngodon idella kidney cells or zebrafish following stimulation with B-DNA, grass carp reovirus, or spring viremia of carp virus. Moreover, grass carp reovirus stimulation enhances the dimerization, phosphorylation, and cytoplasm-to-nucleus translocation of TDP43 in zebrafish (DrTDP43). Type I interferon (IFN I) expression is inhibited in a dose-dependent manner in the cells transfected with DrTDP43 under GCRV stimulation. These results indicated that DrTDP43 is involved in innate immune response and serves as a negative regulator of IFN I expression. To determine DrTDP43-dependent downstream pathway in innate immunity, the substrate of DrTDP43 was studied. It is known that IFN I expression can be activated by PKZ via IRF3 dependent pathway. Our results found that DrTDP43 can be interacted with PKZ, suggesting that the downregulation of IFN I by DrTDP43 may attribute to the inhibition of PKZ activity. Multiple DrTDP43 mutants were constructed to further reveal the mechanism of TDP43-PKZ-mediated IFN I response. Apart from the N-terminal domain, RNA recognition motif 1, RNA recognition motif 2, and low-complexity domain domains of DrTDP43 were all found to be involved in inhibiting phosphorylation of PKZ. In vivo, knockdown of TDP43 in zebrafish embryos improved embryo survival rate upon viral infection and upregulated expression of IFN I. In summary, our findings demonstrate that DrTDP43 is a negative regulator of IFN I expression through the inhibition of the PKZ-IRF3-dependent pathway.

关键词： 急性期   精神分裂症   攻击行为   IL-10   Acute Phase   Schizophrenia   Aggressive Behavior   IL-10  

摘要： 目的：本研究旨在探索急性期精神分裂症患者攻击性行为与血浆中白细胞介素-10 (IL-10)水平的相关性。方法：本研究选取69例急性期精神分裂症住院患者作为研究对象，根据外显攻击行为量表(MOAS)评分分为攻击行为组(37例)和非攻击行为组(32例)，同期选择与其年龄、性别相匹配的健康对照组(30例)采用酶联免疫吸附试验(ELISA)检测三组患者血浆IL-10水平。采用外显攻击行为量表(MOAS)评估精神分裂症患者的攻击行为，采用临床总体印象量表–严重程度量表(CGI-SI)、阳性和阴性症状量表(PANSS)、阳性和阴性症状量表–兴奋因子(PANSS-EC)等评估患者的临床症状及病情严重程度。通过统计分析控制混杂因素对结果的影响。结果：在控制药物治疗、吸烟、合并症等混杂因素中，精神分裂症患者血浆IL-10水平(Z = −4.903, P < 0.001)明显低于健康对照组。攻击行为组患者血浆IL-10水平低于无攻击行为组(P < 0.001)。血浆IL-10平与PANSS总分(r = −0.439, P < 0.001)、阳性症状分(r = −0.327, P = 0.006)、PANSS-EC分(r = −0.377, P = 0.002)呈显著负相关。结论：血浆IL-10水平与急性期精神分裂症患者攻击行为及病情严重程度具有显著相关性，炎性反应异常可能参与暴力攻击行为的发生机制。

关键词： 胸腺基质淋巴细胞生成素   心血管疾病   炎症   免疫   Thymic Stromal Lymphopoietin   Cardiovascular Diseases   Inflammation   Immunity  

摘要： 胸腺基质淋巴细胞生成素(TSLP)是一种多效性细胞因子，在免疫调节和炎症反应中发挥重要作用。近年来，越来越多的研究表明TSLP在心血管疾病(CVD)的发生发展中起着重要作用。TSLP通过调节炎症免疫反应参与动脉粥样硬化、冠状动脉粥样硬化性心脏病、心力衰竭、心肌纤维化等心血管疾病的病程进程。本文将综述TSLP在CVD中的最新研究进展，探讨其作为潜在治疗靶点的可能性。

关键词： IL-37   固有免疫   抑炎细胞因子   炎症性疾病   IL-37   Innate Immunity   Anti-Inflammatory Cytokine   Inflammatory Diseases  

摘要： 固有免疫是生物体防御病原微生物感染的第一道防线，在识别并清除病原体及维持组织稳态中发挥重要作用。IL-37是新发现的IL-1细胞因子家族的成员，是免疫应答和炎症反应的天然抑制剂。IL-37通过调控病原微生物免疫识别、调节固有免疫细胞的功能、保护组织屏障等参与固有免疫应答环节，在多种疾病模型中表现出显著的抗炎作用，提示其可能作为炎症性疾病的潜在治疗靶点。

关键词： Cytokine   Immunomodulation   Memory T cell   anti-tumor immune response   Tumor microenvironment  

摘要： Successful immunotherapy requires systemic activation of the immune system. Radio-immunotherapy has a synergistic effect, enhancing this activation, but still faces many challenges, requiring methods to further improve its efficacy. Interleukin 15 (IL-15) is considered a potential therapeutic agent because of its broad immunoregulatory activity. This study found that in various tumor-bearing mouse models, systemic immune activation mediated by memory T cells in secondary lymphoid organs was crucial after radio-immunotherapy and IL-15 played a key role in this process. Radio-immunotherapy stimulated the expression of IL-15R alpha on macrophages in the tumor microenvironment. When macrophages were depleted, the IL-15 levels in the tumor microenvironment and spleen tissues significantly decreased. Co-culture models confirmed that radioimmunotherapy enhanced the anti-tumor immune response by activating macrophages to secrete IL-15. Applying IL-15 significantly enhances the effects of radio-immunotherapy, stimulating systemic immune activation and providing long-term memory effects and tumor protection. Under co-culture conditions, IL-15 combined with radio-immunotherapy stimulated the proliferation of CD8+ T cells, secretion of IFN-gamma and TNF-alpha, and secretion of chemokines by macrophages, especially CCL5, increasing the recruitment of effector T cells and enhancing the immune response. The synergistic effect of IL-15 and radio-immunotherapy was macrophage- dependent. Our study revealed the mechanism of IL-15 in systemic immune activation after radioimmunotherapy and explored the potential use of IL-15 to enhance the efficacy of radio-immunotherapy, providing new avenues for future treatment strategies.