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关键词： ulcerative colitis   hla-drb1 gene   biological markers  

关键词： Combination therapy   Cytokine   Immune Checkpoint Inhibitor   Immune modulatory  

摘要： Background Immune checkpoint blockade is a promising anticancer therapy, whereas the presence of T cells in tumor sites is indispensable for its therapeutic efficacy. To promote the infiltration of T cells and dendritic cells (DCs) into the tumor, we previously proposed a local cell therapy using chemokine (C-C motif) ligand 19 (CCL19)-expressing immortalized syngeneic immortalized mesenchymal stem cells (syn-iMSC/CCL19). However, the preparation of syngeneic/autologous MSC from individual hosts limits the clinical application of this cell therapy. Methods In this study, we further developed a new cell therapy using allogeneic iMSC/CCL19 (allo-iMSC/CCL19) using several tumor mice models. Results The allo-iMSC/CCL19 therapy exerted drastic antitumor effects, in which the host's T cells were induced to respond to allogeneic MSC. In addition, the allo-iMSC/CCL19 therapy promoted the infiltration of CD103+ interleukin (IL)-12-producing DCs and priming of CD8+ T cells at tumor sites compared with that using syn-iMSC/CCL19. The antitumor effect of allo-iMSC/CCL19 therapy was not influenced by fingolimod, a sphingosine 1-phosphate receptor modulator, implying no involvement of draining lymph nodes in the priming of tumor-specific T cells. Conclusion These results suggest that allo-iMSC/CCL19 therapy exerts dramatic antitumor effects by promoting the infiltration of CD103(+) IL-12-producing DCs and thereby priming tumor-specific CD8(+ )T cells at tumor sites. This local cell therapy could be a promising approach to anticancer therapy, particularly for overcoming dysfunction in the cancer-immunity cycle.

关键词： 胰岛素样生长因子结合蛋白-1   白细胞介素-6   D-二聚体   早产  

摘要： 目的 对比分析宫颈阴道分泌液胰岛素样生长因子结合蛋白-1(IGFBP-1)联合白细胞介素-6(IL-6)检测与血清D-二聚体联合C反应蛋白(CRP)检测预测妊娠期妇女早产的价值。 方法 回顾性抽取2021年7月至2023年10月于安阳市第三人民医院就诊的92例先兆早产妇女作为研究对象，收集其宫颈阴道分泌液并检测IGFBP-1和IL-6水平，采集空腹前臂肘静脉血并检测D-二聚体和CRP水平，并跟踪随访14 d。比较两种检测方法以及联合检测诊断早产的敏感性、特异性、阴性预测值和阳性预测值。 结果 92例先兆早产妇女中，采用IGFBP-1和IL-6联合检测的敏感性、特异性、阳性预测值、阴性预测值和准确度分别为96.3%、97.6%、89.7%、99.2%及97.3%；D-二聚体和CRP联合检测的敏感性、特异性、阳性预测值、阴性预测值和准确度分别为51.9%、98.4%、87.5%、90.3%及90.0%。D-二聚体和CRP联合检测的敏感性高于IGFBP-1和IL-6联合检测(96.3%比51.9%， P <0.05)，但IGFBP-1和IL-6联合检测的阴性预测值高于D-二聚体和C反应蛋白联合检测(99.2%比90.3%， P <0.05)。 结论 宫颈阴道分泌液IGFBP-1和IL-6联合检测与血清D-二聚体和CRP联合检测这两种检测方法对早产均有较高的预测价值，但前者在敏感性和阴性预测值方面的准确度更高。联合采用两种方法是预测有症状妇女早产的可行方法。

摘要： Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return. Here we show that expression of SRY-box transcription factor 2 (SOX2) in precancerous lesions imparts an irreversible risk that recruits suppressive myeloid cells by promoting the release of CCL2. We developed a unique genetically engineered mouse model (GEMM) to recapitulate the malignant transformation of epithelial dysplasia to SCC in the oral mucosa with high histologic and phenotypic fidelity. Using a combination of longitudinal human specimens and the Sox2-GEMM, we found that the myeloid cells in precancerous epithelial dysplasia exhibit a distinctive dichotomous profile featuring high levels of IL-1α-SLC2A1 and low levels of type-I interferon (IFN-I) signatures, which occurs before SCC emerges histologically. Brief priming of myeloid cells with IL-1α desensitizes them to IFN-I agonists and makes myeloid-derived suppressor cells (MDSC) even more suppressive of T-cell activation. Mechanistically, IL-1 activation represses the expression of DHHC3/7 enzymes, which are responsible for the palmitoylation of stimulator of interferon genes (STING). Early blockade of IL1 signaling using pharmacologic and genetic approaches similarly reduces MDSC and SLC2A1 myeloid cells, suppresses epithelial dysplasia transformation, and extends survival. This work establishes a previously unrecognized SOX2-CCL2-IL1 pathway that leads to irreversible immune escape when precancerous epithelial lesions transform.

关键词： Familial Mediterranean fever   biomarkers   interleukin 18  

摘要： Motivation The human leukocyte antigen (HLA) system is the main cause of organ transplant loss through the recognition of HLAs present on the graft by donor-specific antibodies raised by the recipient. It is therefore of key importance to identify all potentially immunogenic B-cell epitopes on HLAs in order to refine organ allocation. Such HLAs epitopes are currently characterized by the presence of polymorphic residues called "eplets". However, many polymorphic positions in HLAs sequences are not yet experimentally confirmed as eplets associated with a HLA epitope. Moreover, structural studies of these epitopes only consider 3D static *** We present here a machine-learning approach for predicting HLA epitopes, based on 3D-surface patches and molecular dynamics simulations. A collection of 3D-surface patches labeled as Epitope (2117) or Nonepitope (4769) according to Human Leukocyte Antigen Eplet Registry information was derived from 207 HLAs (61 solved and 146 predicted structures). Descriptors derived from static and dynamic patch properties were computed and three tree-based models were trained on a reduced non-redundant dataset. HLA-Epicheck is the prediction system formed by the three models. It leverages dynamic descriptors of 3D-surface patches for more than half of its prediction performance. Epitope predictions on unconfirmed eplets (absent from the initial dataset) are compared with experimental results and notable consistency is *** and implementation Structural data and MD trajectories are deposited as open data under doi: 10.57745/GXZHH8. In-house scripts and machine-learning models for HLA-EpiCheck are available from https://***/***_codes/hla-epicheck.

关键词： neurodegenerative diseases   nose-to-brain delivery   neuroinflammation   CNS delivery   antibody treatment  

摘要： Treatment of neuroinflammation and neurodegenerative diseases using biologic therapies is limited due to the blood-brain barrier (BBB). This study explores a clinically validated approach to bypass the BBB for the purposes of direct central nervous system (CNS) delivery of antibodies using the Minimally Invasive Nasal Depot (MIND) technique. Using a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation, we evaluated the efficacy of MIND in delivering a BBB impermeant full-length anti-IL-1 beta antibody. The results demonstrated that MIND delivery resulted in a significant reduction in IL-1 beta levels and microglial activation in relevant brain regions, notably outperforming conventional intravenous (IV) administration. These results underscore the ability of the MIND approach to transform the treatment landscape for a range of neurodegenerative diseases by enabling the targeted delivery of otherwise BBB impermeant therapeutics.

关键词： 非霍奇金淋巴瘤   淋巴细胞与C反应蛋白比值   预后  

摘要： 目的 分析非霍奇金淋巴瘤患者初诊淋巴细胞与C反应蛋白比值(LCR)与预后的关系。 方法 回顾性分析2018年12月至2020年12月安阳市肿瘤医院确诊的82例非霍奇金淋巴瘤患者的临床资料。所有患者初诊时均检测外周血淋巴细胞、C反应蛋白，并计算LCR。通过受试者工作特征曲线确定LCR预测非霍奇金淋巴瘤预后的最佳截断值，并根据最佳截断值分为低LCR组与高LCR组。比较两组患者的临床病理特征和预后生存情况，采用Cox比例风险回归模型分析影响非霍奇金淋巴瘤预后的因素。 结果 经绘制受试者工作特征曲线显示，外周血LCR诊断非霍奇金淋巴瘤预后的曲线下面积为0.745(95% CI ：0.695～0.795)，临界值为0.311，其中LCR≤0.311患者25例(低LCR组)，LCR>0.311患者57例(高LCR组)。低LCR组与高LCR组非霍奇金淋巴瘤结外侵犯、有无B症状、Ann Arbor分期、危险度比较差异有统计学意义( P <0.05)；且低LCR组结外侵犯≥2处、B症状、Ⅲ＋Ⅳ期、中高危占比高于高LCR组( P <0.05)。82例非霍奇金淋巴瘤患者3年总生存率为63.41%(52/82)，3年无疾病进展生存率为48.78%(40/82)。低LCR组3年总生存率(40.00%，10/25)、3年无疾病进展生存率(32.00%，8/25)均低于高LCR组(73.68%，42/57；56.14%，32/57)， P <0.05。多因素COX回归分析结果显示，Ann Arbor分期Ⅲ＋Ⅳ期、中高危、B症状、低LCR水平均是影响非霍奇金淋巴瘤患者预后生存率的独立危险因素( P <0.05)。 结论 初诊时LCR低水平与非霍奇金淋巴瘤患者病理特征以及预后生存率密切相关，可作为临床诊断非霍奇金淋巴瘤患者预后的有效生物学指标。

关键词： Cadaveric lung transplantation   HLA mismatch   De novo donor-specific antibody   Chronic lung allograft dysfunction  

摘要： ObjectivesGenerally, HLA matching between donors and recipients is not performed in lung transplantation (LTx). Therefore, whether HLA mismatch between donors and recipients (D/R mismatch) influences postoperative outcomes after LTx remains uncertain. In this study, we investigated the influence of D/R mismatch on postoperative outcomes after cadaveric LTx (CLT).MethodsA total of 140 CLT procedures were performed between 2012 and 2020. After excluding 5 recipients with preformed DSA and 1 recipient undergoing re-LTx, 134 recipients were enrolled in this retrospective study. The postoperative outcomes were compared between recipients with higher and lower D/R *** median D/R mismatch (A/B/DR loci) was 4.0 (range, 1-6). When dividing these 134 recipients into two groups (H group [D/R mismatch >= 5, n = 57] and L group [D/R mismatch <= 4, n = 77]), there were no significant differences in the patient backgrounds. The lengths of hospital and intensive care unit stays were similar (p = 0.215 and p = 0.37, respectively). Although the overall survival was not significantly better in the H group than in the L group (p = 0.062), chronic lung allograft dysfunction-free survival was significantly better in the H group than in the L group (p = 0.027). Conversely, there was no significant difference in the cumulative incidence of de novo donor-specific anti-HLA antibodies (dnDSAs) between the two groups (p = 0.716).ConclusionsNo significant difference in dnDSA development was observed between patients with higher and lower D/R HLA mismatches. Given the favorable outcomes in the high HLA mismatch group, CLTs can be performed safely in recipients with high D/R HLA mismatches.