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关键词： CGD   WAS   dried blood spot   inborn errors of immunity   interferonopathy   neonate   newborn   proteome   signature  

摘要： BACKGROUND:Type I interferonopathy is characterized by aberrant upregulation of type I interferon (IFN) signaling. The mRNA-IFN signature is a useful marker for activation of the IFN pathway, and for diagnosis of type I interferonopathy; however, early diagnosis is challenging. OBJECTIVE:This study sought to identify the proteomic IFN signature in dried blood spot (DBS) samples. The aim was to evaluate the usefulness of the IFN signature for neonatal screening, and to gain insight into pre-symptomatic state of neonates with inborn errors of immunity (IEIs). METHODS:DBS samples from healthy newborns/adults, patients with type I interferonopathy or other IEIs, and from neonates with viral infections, including some samples obtained during the pre-symptomatic neonatal period, were examined by non-targeted proteome analyses. Expression of IFN-stimulated genes (ISGs) was evaluated and a DBS-IFN signature was defined. Differential expression/pathway analysis were also performed. RESULTS:ISG products IFIT5, ISG15, and OAS2 were detected. Expression of IFIT5 and ISG15 was upregulated significantly in individuals with type I interferonopathy. We defined the sum of the z-scores for these as the DBS-IFN signature, and found that patients with IEIs other than type I interferonopathy, such as chronic granulomatous disease (CGD), also showed significant elevation. Additionally, neonatal samples of type I interferonopathy and CGD patients showed high IFN signatures. Pathway analysis of neonatal CGD samples revealed upregulation of systemic lupus erythematosus-like pathways. CONCLUSION:Upregulation of the IFN pathway exists already at birth not only in neonates with type I interferonopathy but also with other IEIs, including CGD.

摘要： Human induced pluripotent stem cells (iPSCs) offer a promising source for chimeric antigen receptor (CAR)-engineered natural killer (NK) products. However, complex iPSC-NK (iNK) manufacturing challenges clinical use. Here, we identified LiPSC-GR1.1 as a superior iPSC line for iNK production. By engineering LiPSC-GR1.1 with a mesothelin (MSLN)-targeting CAR and interleukin-15 (IL-15), we achieved robust differentiation of iPSCs into mature activated iNK cells with enhanced tumor killing efficacy, superior tumor homing, and vigorous proliferation. Single-cell transcriptomic analysis revealed that transforming growth factor-beta (TGF-beta)-producing tumor cells up-regulated major histocompatibility complex molecules and down-regulated MSLN post-CAR-IL-15 iNK treatment. Tumor-infiltrating CAR-IL-15 iNK cells exhibited high levels of CAR, IL-15, and NK-activating receptors, negligible checkpoint exhaustion markers, and extremely low levels of NK suppressive factors CISH, TGFBR2, and BATF, enabling them to sustain activation, metabolic fitness, and effective tumor killing within TGF-beta-rich hypoxic tumor microenvironment. Overall, we developed ***-IL-15-engineered GR1.1-iNK therapy with enhanced antitumor efficacy for solid tumor treatment.

关键词： Immunotherapy   Tumor microenvironment - TME   Major histocompatibility complex - MHC   T cell  

摘要： Background Immune evasion is a crucial event in the progression of pancreatic ductal adenocarcinoma (PDAC). The identification of new immunotherapeutic targets may provide a promising platform for advancing PDAC treatment. This study aims to investigate the role of beta-1,4-galactosyltransferase-5 (B4GALT5) in immune evasion by pancreatic cancer cells and evaluate its potential as an immunotherapeutic *** We conducted a comprehensive analysis using RNA sequencing data and tissue microarrays from patients with PDAC to investigate the association between B4GALT5 expression and patient prognosis. Using animal models, we further explored the impact of B4GALT5 on the quantity and activity of tumor-infiltrating CD8+ T cells. RNA sequencing and co-immunoprecipitation were used to explore the mechanism by which B4GALT5 regulates major histocompatibility complex (MHC-I) *** Our study demonstrates that high expression of B4GALT5 in tumor cells is significantly associated with poor prognosis in patients with PDAC and reduced cytotoxic activity of tumor-infiltrating CD8+ T cells. Specifically, B4GALT5 suppresses MHC-I expression in tumor cells through the endoplasmic reticulum-associated degradation pathway, enabling them to evade immune surveillance by CD8+ T *** B4GALT5 impairs CD8+ T-cell recognition of tumor cells by regulating MHC-I levels, thereby promoting immune evasion. This makes B4GALT5 a highly promising immunotherapeutic target for improving the poor prognosis of patients with PDAC.

关键词： Basic fibroblast growth factor (bFGF)   Nodular goiter   Papillary thyroid cancer   Tumor necrosis factor beta (TNF-beta)  

摘要： Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, accounting for approximately 80% of cases. Considering the lack of available blood diagnostic tests for detecting thyroid cancer, as well as the issue of overdiagnosis and overtreatment, our study aimed to investigate whether the concentrations of 48 selected proteins, including chemokines, interleukins, cytokines, and growth factors, could serve as indicators to distinguish patients with PTC from individuals with nodular goiter. The study group included 32 PTC patients and 26 nodular goiter patients as a comparative group. Serum protein concentrations were evaluated in venous blood collected in tubes without anticoagulant, using the multiplexed immunoassay method. The concentrations of basic FGF (bFGF), IL-9, IL-18, TNF-alpha, and TNF-beta were significantly higher (p < 0.05) in patients with PTC compared to those with nodular goiter. The highest area under the ROC curve (AUC), equal to 0.720 +/- 0.066, along with a diagnostic specificity of 92% and a positive predictive value of 89% for differentiating PTC patients from nodular goiter patients, was found for TNF-beta. The combined evaluation of TNF-beta and bFGF concentrations proved most useful in differentiating papillary thyroid cancer from benign nodular goiter, revealing a diagnostic specificity of 96%. Further studies should be conducted with an appropriate sample size and across other histopathological types of thyroid cancer to confirm that the combined evaluation of bFGF and TNF-beta concentrations is useful in differentiating PTC patients from individuals with benign nodular goiter.

关键词： Squamous cell carcinoma   CD109   IL6R alpha   STAT3   NRF2   Stemness   Antioxidant pathway  

摘要： BackgroundSquamous cell carcinoma (SCC) is a prevalent malignancy and there are limited options to block the recurrence and metastasis that often occur in SCC patients. Although IL-6, a proinflammatory cytokine, is strongly implicated in SCC pathogenesis, its mechanism of action is poorly understood. The GPI-anchored membrane protein CD109 is frequently overexpressed in SCC and is associated with malignant transformation. The current study aims to investigate whether CD109 interacts with IL-6 receptor alpha (IL6R alpha) and promotes IL-6-mediated oncogenic signaling to drive SCC ***6R alpha interaction with CD109 was determined by coimmunoprecipitation, immunohistochemistry, immunofluorescence and FACS analysis using human SCC (oral and vulvar) cell lines and human oral SCC tumors versus control tissue. Regulation of IL-6-induced signaling and antioxidant responses by CD109 was analyzed via STAT3/NRF2/SOD1/HO1 pathway activation. Regulation of IL-6-mediated tumorigenicity by CD109 was determined using stem cell marker expression and a spheroid formation assay. Clinical validation was achieved using genomic and proteomic analysis of oral SCC tumors and of head and neck SCC patient *** show that CD109 interacts with and stabilizes IL6R alpha expression and promotes IL-6/STAT3/NRF2 pathway in oral and vulvar SCC cells. Loss of CD109 attenuates this pathway leading to loss of cancer cell stemness and decreased expression of superoxide dismutase1 and heme oxygenase-1, antioxidant proteins important for cell survival after chemotherapy. Furthermore, clinical validation of these findings was achieved through multi-omic analysis of oral SCC tumors and of head and neck SCC patient *** work uncovers a previously unidentified mechanism in which CD109 serves as an essential regulator of IL6R alpha expression and IL-6 mediated signaling in SCC cells, promoting stemness and antioxidant state, mechanisms known to mediate therapy resist

关键词： Bladder cancer   Glycosylation   alpha 1,3-mannosyltransferase   Diagnosis   Glycobiomarker   Molecular docking  

摘要： BackgroundBladder cancer (BCa) is the most prevalent malignancy of the urinary system. Aberrant glycosylation, driven by specific glycosyltransferases (GTs), plays a pivotal role in various carcinogenic processes. However, the role of GTs-related glycobiomarkers and their underlying mechanisms in BCa remain poorly *** diagnostic model based on GTs was constructed and validated using multiple bioinformatics tools. The diagnostic and prognostic value, biological functions and potential targeted drugs were assessed using R packages, K-M plotter and molecular docking. The functional impact and mechanism of ALG3 in BCa were investigated through functional assays, RNA sequencing, immunoprecipitation, and lectin pull down *** diagnostic model comprising six GTs (ALG3, POMT2, UGCG, XXYLT1, COLGALT1, and A4GALT) was established, demonstrating high diagnostic accuracy for BCa (AUC: 0.966;sensitivity: 88.5%;specificity: 92.6%), which was further validated. Among these, ALG3 and POMT2 belong to the mannosyltransferase family, with ALG3 identified as a more reliable diagnostic glycobiomarker than POMT2 for BCa detection. GSVA analysis revealed that ALG3 was significantly enriched in Umbrella cells, suggesting its potential role in influencing BCa cell fate. Overexpression of ALG3 promoted cell proliferation and metastasis by modulating CD44 N-glycosylation and activating the TNF signaling pathway, confirming its role as a tumor promoter and oncogene in BCa progression. Moreover, ALG3 was identified as a novel target of miR-142-5p. Four potential small molecule inhibitors of ALG3 were identified, with selumetinib emerging as a promising ***3 contributed to BCa progression via CD44 N-glycosylation and TNF pathway, positioning it as a promising serum glycobiomarker, a feasible therapeutic target, and a valuable reference for personalized and precision medicine in BCa.

关键词： 前列腺癌   前列腺特异性膜抗原   前列腺活检   靶向穿刺   系统穿刺  

摘要： 目的 探究是否可以在进行前列腺活检时,通过检测穿刺组织的^(123)I标记的前列腺特异性膜抗原(^(123)I-PSMA)放射值达到术中实时、快速、准确分辨良恶性前列腺组织,用以改善当前临床活检策略,以更少的穿刺针数实现前列腺癌的术中准确诊断。方法 前瞻性、诊断性试验中纳入疑似前列腺癌病人29例,所有病人均在注射^(123)I-PSMA 24小时内,进行超声引导下经会阴联合活检,共穿刺435针,用伽马计数器术中实时测量穿刺组织的放射值。Pearson检验放射值与组织病理性相关联。结果 前列腺癌组织放射值中位值(1 906.50 cpm)高于良性前列腺组织(415.00 cpm),区分良恶性前列腺组织的放射值的最佳截止值为828.50 cpm;临床显著性前列腺癌组织的放射值中位值(2 652.50 cpm)显著高于无临床意义前列腺癌(1 386.00 cpm),区分临床显著性前列腺癌组织与无临床意义前列腺癌组织的放射值的最佳截止值为1 767.00 cpm。穿刺组织放射值与组织病理分级之间具有显著正相关性(r=0.834)。结论 通过检测前列腺穿刺组织的^(123)I-PSMA放射值可实现术中实时、快速、准确地分辨良恶性前列腺组织。

关键词： 骨质疏松性椎体压缩性骨折   经皮椎体成形术   肺部感染   可溶性髓系细胞触发受体1   肿瘤坏死因子α  

摘要： 目的探讨血清可溶性髓系细胞触发受体1(sTREM-1)、肿瘤坏死因子α(TNF-α)水平与骨质疏松性椎体压缩性骨折(OVCF)患者经皮椎体成形术(PVP)术后肺部感染的关系及其检测价值。方法选择2019年1月至2022年5月于河南省第二人民医院就诊的183例OVCF患者,根据PVP术后是否发生肺部感染,分为感染组(43例)及未感染组(140例)。比较两组患者的一般资料、血清sTREM-1和TNF-α水平、免疫功能,分析血清sTREM-1、TNF-α水平对患者术后肺部感染的预测价值,随访1 a比较两组预后。结果两组性别、吸烟史、麻醉方式、是否合并高血压、是否合并糖尿病比较,差异无统计学意义(P>0.05),两组年龄、是否合并慢性阻塞性肺疾病(COPD)比较,差异有统计学意义(P<0.05);感染组的血清sTREM-1、TNF-α水平均高于未感染组(P<0.05);感染组血清CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)水平均低于未感染组(P<0.05),而两组的CD8^(+)水平比较,差异无统计学意义(P>0.05)。采用受试者工作特征(ROC)曲线分析,两项指标联合诊断OVCF患者PVP术后发生肺部感染的曲线下面积(AUC)为0.911,均高于单一sTREM-1、TNF-α的0.846、0.831。随访1 a后,感染组的优良率低于未感染组,差异有统计学意义(P<0.05)。结论血清sTREM-1、TNF-α水平与OVCF患者PVP术后肺部感染相关,临床需关注血清sTREM-1、TNF-α水平,积极进行感染预防。

关键词： 小儿感冒   肺炎   帕拉米韦   T淋巴细胞亚群   免疫球蛋白  

摘要： 目的探讨帕拉米韦治疗小儿感冒并发肺炎的临床效果。方法回顾性分析2023年7月至2024年8月医院接受治疗的90例感冒并发肺炎患儿病历资料,依据治疗方法不同分为对照组和观察组,各45例。两组均给予常规对症治疗,对照组加用磷酸奥司他韦颗粒治疗,观察组加用帕拉米韦氯化钠注射液治疗,均持续治疗1周,比较两组临床疗效、症状缓解时间、炎症介质[C反应蛋白(CRP)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)]、T淋巴细胞亚群、免疫球蛋白水平[免疫球蛋白G(IgG)、免疫球蛋白M(IgM)、免疫球蛋白A(IgA)]及不良反应发生情况。结果观察组治疗总有效率高于对照组(P<0.05);观察组鼻塞流涕、咽喉肿痛、咳嗽缓解时间及退热时间均短于对照组(P<0.05);观察组治疗后CRP、IL-6、TNF-α水平均低于对照组(P<0.05);观察组治疗后CD4^(+)、CD3^(+)水平均高于对照组,CD8^(+)水平低于对照组(P<0.05);观察组治疗后IgG、IgM、IgA水平均高于对照组(P<0.05);两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论帕拉米韦治疗小儿感冒并发肺炎疗效确切,可在短时间内缓解患儿临床症状,有效抑制炎症反应,改善患儿免疫功能,且不会明显增加不良反应。

关键词： 股骨粗隆间骨折   视椎蛋白样蛋白1   白细胞介素-17   8-羟脱氧鸟苷   老年   认知功能障碍  

摘要： 目的研究血清白细胞介素-17(IL-17)、视椎蛋白样蛋白1(VILIP-1)及8-羟脱氧鸟苷(8-OHdG)对老年股骨粗隆间骨折(IFF)患者发生术后认知功能障碍(POCD)的预测价值,为临床诊疗提供参考。方法选取2020年1月至2023年12月南京同仁医院骨科收治的87例老年IFF患者作为研究对象,术后7 d采用蒙特利尔认知功能量表(MoCA)评估患者POCD情况,分为POCD组(MoCA评分<26分)、无POCD组(MoCA评分≥26分)。比较2组术前、术后1 d、术后3 d血清IL-17、VILIP-1及8-OHdG水平,并分析血清IL-17、VILIP-1及8-OHdG对老年IFF患者发生POCD的预测价值,分析血清IL-17、VILIP-1、8-OHdG不同水平老年IFF患者发生POCD的危险度,以相对危险度(RR)表示。结果POCD组26例、无POCD组61例。重复测量方差分析结果显示,2组不同时间血清IL-17、VILIP-1、8-OHdG变化存在时间效应、组间效应、交互效应,差异均有统计学意义(P<0.05)。2组术后1 d、术后3 d血清IL-17、VILIP-1、8-OHdG水平均高于术前(P<0.02),2组术后3 d血清IL-17、VILIP-1、8-OHdG水平均高于术后1 d(P<0.02)。多变量方差分析结果显示,POCD组术后1、3 d血清IL-17、VILIP-1、8-OHdG水平均高于无POCD组(P<0.05)。术后1、3 d血清IL-17、VILIP-1、8-OHdG 3项指标联合预测老年IFF患者发生POCD的曲线下面积(AUC)分别为0.925(95%CI:0.848~0.970)、0.945(95%CI:0.874~0.983)。术后1、3 d血清IL-17、VILIP-1、8-OHdG高水平的老年IFF患者发生POCD的风险均是IL-17、VILIP-1、8-OHdG低水平患者的数倍(术后1 d:RR=2.901、4.903、3.258,P<0.001;术后3 d:RR=6.171、6.429、4.298,P<0.001)。结论血清IL-17、VILIP-1、8-OHdG水平与老年IFF患者发生POCD关系密切,可作为预测POCD的标志物。