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关键词： IL-11   Peptide   Phage display   Inhibitor   Antagonist   AlphaLISA   Cytokine  

摘要： Interleukin-11 (IL-11), a member of the IL-6 cytokine family, has potential pro-inflammatory and pro-fibrotic roles in pulmonary, hepatic, cardiovascular, renal and intestinal disease pathogenesis, including oncogenesis. The potential for therapeutic intervention in these disease spaces has therefore made the IL-11 signaling axis an attractive target in drug discovery, and antibody inhibitors of IL-11 signaling are currently under evaluation in Phase I/II clinical trials. While lower molecular weight small molecule and peptide inhibitors may offer the potential for improved tissue penetration, developability and manufacturing cost compared with a protein therapeutic, reports of such chemical matter in the literature are limited. In this work, a series of cyclic peptides derived from phage display biopanning campaigns against both IL-11 and its cognate receptor IL-11R alpha are presented. The most active IL-11 binder (peptide 4, KD 140 nM) exhibited inhibition of IL-11/IL-11R alpha dimerization in a biochemical AlphaLISA assay (Ki 300 nM), and alanine scanning was carried out on this sequence to identify residues important for target binding and inhibitory activity. Further structural optimization yielded lead peptide 15 (Ki 180 nM), which exhibited at least 70-fold greater activity than IL-11 inhibitors previously reported in the literature. The de novo peptide macrocycles presented serve as a robust starting point for development of therapeutic inhibitors of the IL-11/IL-11R alpha interaction.

关键词： 幽门螺杆菌阳性   慢性萎缩性胃炎   四联疗法   活性氧   白细胞介素33  

摘要： 目的探讨幽门螺杆菌(hp)阳性慢性萎缩性胃炎(CAG)患者血清活性氧(ROS)、白细胞介素33(IL-33)水平与四联疗法hp根除率的关系。方法选取2022年1月至2024年8月本院收治的hp阳性CAG患者218例,均实施四联疗法治疗14 d,统计hp根除率。将hp未根除者纳入观察组,hp根除者纳入对照组。两组均在治疗前检测血清ROS、IL-33水平。分析血清ROS、IL-33水平与hp阳性CAG患者hp根除率的关系及预测价值。结果218例hp阳性CAG患者四联疗法治疗14 d后hp根除率为80.73%(176/218)。hp未根除者42例纳入观察组,hp根除者176例纳入对照组。两组治疗前血清ROS、IL-33水平比较,观察组高于对照组(P<0.05)。治疗依从性、阿莫西林耐药、克拉霉素耐药、hp类型、ROS、IL-33为hp阳性CAG患者hp根除率的独立影响因素(P<0.05)。无论是否调整混杂因素,ROS、IL-33水平升高均会增加hp阳性CAG患者hp根除失败风险。血清ROS、IL-33水平预测hp阳性CAG患者hp根除率的AUC值分别为0.774,0.790,二者联合预测的AUC值为0.860。血清ROS、IL-33联合预测hp阳性CAG患者hp根除率的AUC值大于单一指标的预测值(P<0.05)。结论血清ROS、IL-33高水平是hp阳性CAG患者四联疗法hp根除失败的独立危险因素,通过检测二者血清水平可判定患者hp根除失败风险,对患者治疗方案的制定及调整有一定指导意义。

关键词： 动静脉内瘘   狭窄   中性粒细胞-淋巴细胞比率   血小板-淋巴细胞比率   血液透析  

摘要： 目的:探讨中性粒细胞-淋巴细胞比值(neutrophil-lymphocyte ratio,NLR)和血小板-淋巴细胞比值(plateletlymphocyte ratio,PLR)与血液透析(hemodialysis,HD)患者动静脉内瘘(arteriovenous fistula,AVF)狭窄的关系。方法:收集2021年1月至2022年6月在川北医学院附属医院肾内科就诊的625例使用动静脉内瘘透析的患者资料,其中资料完善且符合纳入标准的患者395例,有AVF狭窄的患者245例被分为1组,无AVF狭窄的患者150例为2组。记录患者的常规生化值和全血细胞计数值。结果:①1组患者NLR5.07(4.00,6.66)vs.3.46(2.63,4.15),PLR169.52(127.56,227.11)vs.125.66(89.31,165.31)及超敏C-反应蛋白(C-reactive protein,Hs-CRP)1.90(0.80,2.99)vs.0.82(0.42,1.27),水平均高于2组患者,差异有统计学意义(均P<0.001)。②多因素logistic回归分析,校正年龄、性别、体质指数(body mass lndex,BMI)、AVF吻合方式、穿刺方式、是否合并糖尿病等因素,结果显示NLR(OR=2.195,95%CI=1.674~2.878,P<0.001),PLR(OR=1.008,95%CI=1.002~1.012,P=0.007),Hs-CRP(OR=2.170,95%CI=1.607~2.751,P<0.001)三者均是HD患者AVF狭窄的独立危险因素。③接受者操作特性曲线(receiver operating characteristic curve,ROC)析显示,NLR曲线下面积(Area Under Curve,AUC)0.799(95%CI=0.756~0.838,P<0.001),PLR 0.694(95%CI=0.646~0.740,P<0.001),Hs-CRP 0.717(95%CI=0.670~0.761,P<0.001),三者均可预测AVF狭窄,预测最佳临界值分别为NLR 4.08,PLR 122.49,Hs-CRP 1.62,并且3个指标联合预测效果更佳(AUC 0.870,95%CI=0.833~0.901,P<0.001),灵敏度79.18%,特异度81.33%。结论:NLR、PLR和Hs-CRP均是AVF狭窄的独立危险因素和预测因子,且三者联合检测预测价值更高。

关键词： Specialized pro-resolving lipid mediators   Autoimmune disease   Innate immunity   Adaptive immunity  

摘要： Uncontrolled hyperactivation of the immune system is the central mechanism underlying the pathogenesis of autoimmune *** control of the inflammatory response is essential to prevent inflammation progression and organ *** pro-resolving lipid mediators(SPMs)are autacoid molecules derived from essential polyunsaturated fatty acids during acute inflammatory *** promote the resolution of inflammation and orchestrate endogenous reparative *** SPM superfamily includes lipoxins,resolvins,protectins,and maresins,as well as novel conjugates involved in tissue *** work has been done focusing on the actions of SPMs in autoimmunity and has identified their deficiencies and therapeutic effects in autoimmune *** this review,we provide a brief introduction of SPMs,summarize their effects on key cells involved in innate and adaptive immunity,and highlight their role and therapeutic potential in autoimmune diseases.

关键词： 慢性阻塞性肺疾病   辅助性T淋巴细胞17/调节性T淋巴细胞平衡   白葡奈氏菌片   免疫调节   剂量依赖性   作用机制  

摘要： 目的探讨白葡奈氏菌片对慢性阻塞性肺疾病(COPD)小鼠辅助性T淋巴细胞17(Th17)/调节性T淋巴细胞(Treg)平衡的影响及其可能的作用机制。方法将40只C57BL/6小鼠随机分为对照组(CON组)、慢阻肺模型组(COPD组)、白葡奈氏菌低剂量干预COPD组(SANTL组)、白葡奈氏菌高剂量干预COPD组(SANTH组),每组10只。使用8周烟熏方法构建COPD模型。SANTL组及SANTH组在造模成功后分别给予低剂量(10μg/kg,3次/d)及高剂量(20μg/kg,3次/d)白葡奈氏菌片混悬液灌胃4周,而COPD组给予对应体积生理盐水灌胃4周,结束后处死小鼠。通过苏木精-伊红(HE)染色评估肺组织病理学改变,酶联免疫吸附试验(ELISA)检测支气管肺泡灌洗液(BALF)中IL-17、IL-22、IL-10、IL-35、IL-6及肿瘤坏死因子(TNF-α)水平,流式细胞术分析脾脏Th17和Treg细胞占CD4+淋巴细胞比率(Th17%、Treg%),采用Spearman相关性分析法分析BALF中IL-6及TNF-α与IL-17、IL-22、IL-10、IL-35表达水平的相关性。结果与CON组比较,COPD组小鼠体质量增长明显降低,差异有统计学意义(P<0.05);HE染色肺组织呈现广泛炎症浸润、肺泡壁断裂等典型病理特征;与CON组比较,COPD组小鼠的Th17%、IL-17、IL-22、IL-6、TNF-α表达水平明显上升,而Treg%、IL-10及IL-35表达水平明显下降,差异均有统计学意义(P<0.05);经白葡奈氏菌片干预的两组小鼠Th17%[SANTL:(1.26±0.18)%;SANTH:(0.68±0.16)%]、IL-17[SANTL:(65.79±12.03)ng/L;SANTH:(46.52±4.87)ng/L]、IL-6[SANTL:(55.17±3.35)ng/L;SANTH:(48.16±3.51)ng/L]、TNF-α[SANTL:(217.71±19.26)ng/L;SANTH:(193.15±9.20)ng/L]表达水平均低于COPD组,但均高于CON组,其中SANTH组低于SANTL组,差异均有统计学意义(P<0.05);经白葡奈氏菌片干预的两组小鼠Treg%[SANTL:(7.98±1.11)%;SANTH:(9.25±0.73)%]、IL-10[SANTL:(9.31±0.67)ng/L;SANTH:(11.52±1.26)ng/L]及IL-35[SANTL:(12.99±1.69)ng/L;SANTH:(17.73±3.17)ng/L]表达水平均高于COPD组,但均低于CON组,其中SANTH组高于SANTL组,差异均有统计学意义(P<0.05);Spearman相关性分析结果显示,各组小鼠BALF中IL-6与IL-17(r=0.97)、IL-22(r=0.98)表达水平均呈正相关(P<0.05),而与IL-10(r=-0.97)、IL-35(r=-0.95)表达水平均呈负相关(P<0.05),且各组小鼠BALF中TNF-α分别与IL-17(r=0.87)、IL-22(r=0.90)表达水平呈正相关(P<0.05),分别与IL-10(r=-0.87)、IL-35(r=-0.88)表达水平呈负相关(P<0.05)。结论白葡奈氏菌片通过剂量依赖性调节Th17/Treg平衡,抑制促炎因子释放并促进抗炎因子表达,从而缓解COPD气道炎症。

摘要： BACKGROUND: Antibodies directed against donor-specific HLA allele(s)/antigen(s) (DSAs) represent a known risk factor for hematopoietic stem cell transplantation (HSCT) engraftment. Still, the overall management needs to be standardized. MATERIAL AND METHODS: GITMO and AIBT ran a survey on DSAs in Italian Transplant Programs including mismatched HSCT performed between January 2014 and June 2017. RESULTS: One-thousand-thirty-three patients were proposed for the study, 804 were evaluable. Overall, 355 (44%) were screened: 91/355 (25.6%) showed anti-HLA antibodies, 23 DSAs (6.5%). Female gender and at least 4 previous pregnancies showed an impact on alloimmunization. Eleven patients with DSAs underwent desensitization. In seven cases no desensitization was employed. An alternative donor was selected for five patients. Neutrophil and platelet engraftment were obtained in 93.6% and 86.6% of the whole population, respectively, and were statistically associated with the absence of anti-HLA antibodies, ABO match, a higher number of infused nucleated cells and lack of a-GvHD. In addition, significant factors for platelet engraftment were the use of leuco-depleted transfusions, HLA match, younger age of the patient. Graft failure (GF) was associated with bone marrow stem cell source, and a lower number of infused CD34+. The detection of antibodies directed against both HLA classes, donor and patient age, the hematologic and molecular remission at HSCT, HLA match, ANC and PLTS engraftment, full donor engraftment within 28 days after HSCT, early and late GF, grade>II a-GVHD showed an impact on OS. DISCUSSION: Anti-HLA antibodies and DSAs were confirmed as risk factors affecting OS. DSAs were managed with various approaches resulting in stable engraftment in 81.9% of patients. Our study supports the clinical relevance of DSAs detection and management in mmHSCT. A standardized approach of DS is warranted.

关键词： 肺癌   T淋巴细胞   PD-1   CD28  

摘要： 目的:探讨肺癌患者外周血T淋巴细胞表面PD-1及CD28表达水平变化。方法:纳入2024年1月至2024年12月就诊于我院662例肺癌患者,其中包括556例肺癌未转移患者,66例肺癌伴转移患者。将同期送检的39例健康人作为对照组。采用流式细胞术检测外周血PD-1/CD28阳性的T淋巴细胞数量及比率。结果:与健康对照组相比,肺癌患者T淋巴细胞(CD45^(+)CD3^(+))和辅助性T淋巴细胞(CD45^(+)CD3^(+)CD4^(+))数量显著降低(P<0.05)。并且,与肺癌未转移组相比,肺癌伴转移组患者T淋巴细胞和辅助性T淋巴细胞数量显著降低(P<0.05)。与健康对照组相比,CD3^(+)PD-1^(+)T淋巴细胞比率在肺癌患者中显著升高(P<0.05),而在肺癌伴转移与未转移患者中无显著差异(P=0.303)。肺癌未转移组样本中CD3^(+)CD4^(+)PD-1^(+)T淋巴细胞比率和数量均显著高于健康对照组(P<0.05),肺癌转移组CD3^(+)CD4^(+)PD-1^(+)T细胞比率显著升高(P<0.05)。与健康对照组和肺癌未转移组相比,肺癌转移组中CD3^(+)CD8^(+)PD-1^(+)T淋巴细胞比率显著升高(P<0.05)。与健康对照组相比,肺癌患者CD3^(+)CD28^(+)、CD3^(+)CD4^(+)CD28^(+)以及CD3^(+)CD8^(+)CD28^(+)T淋巴细胞数量均显著降低(P<0.05)。结论:肺癌患者外周血中PD-1^(+)T淋巴细胞比率上调,而CD28^(+)T淋巴细胞数量下降,表明肺癌患者T细胞免疫功能受抑,可能与肺癌的发生发展密切相关。

关键词： 帕金森病   骨髓基质细胞抗原1基因   多态性  

摘要： 目的 探讨骨髓基质细胞抗原1 (BST1)基因rs11931532位点、rs4698412位点多态性与帕金森病(PD)的相关性。方法 应用竞争性等位基因特异PCR(KASP)技术对新疆地区200例散发性PD(IPD)患者和197例健康对照者进行BST1基因rs11931532位点、rs4698412位点多态性分析。结果(1)在总体样本中,PD组和对照组间rs11931532的基因型分布频率比较差异均无统计学意义(P>0.05)。进一步按照性别、年龄进行分层,在男性PD组和男性对照组间、女性PD组和女性对照组间、年龄≤68岁的PD组和年龄≤68岁对照组间、在年龄>68岁的PD组和年龄>68岁对照组间,其基因型分布频率比较差异均无统计学意义(^(均)P> 0.05)。(2)在总体样本中,PD组和对照组间rs4698412基因型、等位基因频率比较差异无统计学意义(^(均)P> 0.05)。进一步按照性别、年龄进行分层,在男性PD组和男性对照组间、女性PD组和女性对照组间、年龄≤68岁的PD组和年龄≤68岁对照组间rs4698412基因型、等位基因频率比较差异无统计学意义(^(均)P> 0.05),在年龄> 68岁的PD组和年龄> 68岁的对照组间,PD组A/A基因型频率(20.4%)高于对照组(8.40%),差异有统计学意义(P=0.036),两组间的等位基因分布差异无统计学(P> 0.05)。结论 BST1基因rs11931532位点多态性不是新疆地区PD的潜在易感位点。BST1基因rs4698412位点多态性可能是新疆地区年龄> 68岁PD患者的潜在易感位点,rs4698412 A/A是其易感基因型。

关键词： 糖类抗原125   人附睾蛋白4   乳腺癌改良根治术   复发转移  

摘要： 目的探讨糖类抗原125(CA125)联合人附睾蛋白4(HE4)对乳腺癌改良根治术后复发转移的预测价值,为临床诊疗提供参考。方法选取2020年5月至2023年5月于烟台市蓬莱人民医院行乳腺癌改良根治术的295例乳腺癌患者的临床资料,进行回顾性分析。根据术后复发转移情况分成复发转移组(44例)和未复发转移组(251例)。比较两组患者临床资料,采用多因素Logistic回归分析影响乳腺癌改良根治术后复发转移的独立危险因素,绘制受试者工作特征(ROC)曲线分析CA125联合HE4对乳腺癌改良根治术后复发转移的预测价值。结果两组患者年龄、BMI、生育状况、绝经状况、病理类型比较,差异均无统计学意义(均P>0.05)。复发转移组患者肿瘤最大直径>5 cm占比、腋窝淋巴结转移数1~3个占比、CA125水平、HE4水平均高于未复发转移组(均P<0.05)。多因素Logistic回归分析结果显示:肿瘤最大直径>5 cm、腋窝淋巴结转移数1~3个、CA125水平高、HE4水平高均为影响乳腺癌改良根治术后复发转移的独立危险因素(均P<0.05)。ROC曲线分析结果显示:CA125联合HE4预测乳腺癌改良根治术后复发转移的曲线下面积(AUC)为0.887,敏感度为0.818,特异度为0.849,均高于各项单一诊断。结论肿瘤最大直径>5 cm、腋窝淋巴结转移数1~3个、CA125水平高、HE4水平高均为影响乳腺癌改良根治术后复发转移的独立危险因素,CA125和HE4均是能有效反映乳腺癌患者乳腺癌改良根治术后复发和转移风险的重要生物标志物,两者联合应用在术后监测中具有重要临床价值,可为后续治疗决策提供依据。

关键词： 奥司他韦   帕拉米韦   病毒性肺炎   免疫球蛋白水平  

摘要： 探讨和分析奥司他韦联合帕拉米韦在病毒性肺炎患儿免疫球蛋白水平改善中的效果。方法 选取80例病毒性肺炎患儿随机分成两组,参考组接受奥司他韦治疗,研究组联合帕拉米韦治疗;对比两组临床疗效以及患儿免疫球蛋白水平的改善情况。结果 研究组患者总有效率高于参考组,症状消失时间短于参考组;治疗后血气指标PaO2高于参考组,PaCO2低于参考组;炎症因子指标小于参考组;免疫球蛋白指标IgA、IgM、IgG均显著大于参考组,P<0.05。不良反应两组无统计差异,P>0.05。结论 为病毒性肺炎患儿提供奥司他韦联合帕拉米韦联合治疗,不但能够快速缓解症状,控制炎症水平,而且能够改善患者的免疫功能,且具有较高的治疗安全性。