火针膝周密刺对膝关节骨性关节炎鼠关节形态及软骨LOXL2的影响

目的:探讨火针膝周密刺对膝关节骨性关节炎(Knee Osteoarthritis,KOA)大鼠行为学、关节形态及软骨中赖氨酰氧化酶相关蛋白2(LOXL2)影响性。方法:选择30只健康雄性大鼠,10只作为对照不作任何处理。20只大鼠建立KOA模型,成模后随机分成2组,分别予普通针刺和火针膝周密刺,1次/3 d,连续6次。观察各组大鼠Leauesne MG评分、关节软骨细胞情况,外周血及关节软骨转化生长因子-β1(TGF-β1)、肿瘤坏死因子-α(TNF-α)、基质金属蛋白酶3(MMP-3)、LOXL2水平变化。结果:治疗后火针组Leauesne MG评分中的局部疼痛刺激反应、步态、关节活动范围、关节肿胀度较对照组、模型组差异有统计学意义(P<0.05)。血清及关节软骨MMP-3、TGF-β1、TNF-α含量水平显著低于模型组(P<0.05),LOXL2显著高于模型组(P<0.05)。火针组电镜下软骨细胞形状规则、细胞核完整且饱满,微绒毛少量存在,内质网丰富,有散在的染色质。结论:火针膝周密刺能减轻K0A关节软骨损伤,降低炎性反应,改善软骨LOXL2水平,这可能是火针治疗KOA一个作用机制。     

Isolation and characterization of new human carrier peptides from two important vaccine immunogens

In the preparation of glycoconjugate vaccines in clinical practice, two highly immunogenic carrier proteins, CRM₁₉₇ and tetanus toxoid (TT), are predominantly conjugated with the capsular polysaccharides (CPSs) of bacterial pathogens. In addition, TT has long been used as an effective vaccine to prevent tetanus. While these carrier proteins play an important role in immunogenicity and vaccine design alike, their defined human major histocompatibility complex class II (MHCII) T cell epitopes are inadequately characterized. In this current work, we use mass spectrometry to identify the peptides from these carrier proteins that are naturally processed and presented by human B cells via MHCII pathway. The MHCII-presented peptides are screened for their T cell stimulation using primary CD4+ T cells from four healthy adult donors. These combined methods reveal a subset of eleven CD4+ T cell epitopes that proliferate and stimulate human T cells with diverse MHCII allelic repertoire. Six of these peptides stand out as potential immunodominant epitopes by responding in three or more donors. Additionally, we provide evidence of these natural epitopes eliciting more significant T cell responses in donors than previously published TT peptides selected from T cell epitope screening. This study serves toward understanding carrier protein immune responses and thus enables the use of these peptides in developing novel knowledge-based vaccines to combat persisting problems in glycoconjugate vaccine design.     

高危型人乳头瘤病毒感染宫颈病变患者体质特点探析

目的探究高危型人乳头瘤病毒(HR-HPV)感染的宫颈病变患者中医体质分布特点,分析其临床特征与体质类型的关系,为中医药防治HR-HPV感染导致的宫颈病变提供依据。方法采用流行病学研究方法,以问卷调查的方式收集135例HR-HPV感染的宫颈病变患者相关信息,进行体质判定,分析其体质分布特点及主要体质类型与宫颈病变程度、HR-HPV感染特点、年龄及p16抑癌蛋白表达强度的关系。结果HR-HPV感染的宫颈病变患者体质类型所占比例由高到低依次为湿热质、阳虚质、平和质、气虚质、气郁质、阴虚质、痰湿质、血瘀质、特禀质,差异有统计学意义(P<0.05)。不同体质类型患者的宫颈病变程度、HR-HPV感染特点、年龄、p16抑癌蛋白表达强度比较,差异有统计学意义(P<0.05)。结论HR-HPV感染的宫颈病变患者体质类型以湿热质、阳虚质为主,其体质类型与宫颈病变程度、HR-HPV感染特点、年龄、p16抑癌蛋白表达强度有关。     

Design,synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.     

Association between de novo lipogenesis susceptibility genes and coronary artery disease

Background and aimsCoronary artery disease (CAD) is the principal cause of death in individuals with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to use genetic epidemiology to study the association between de novo lipogenesis (DNL), one of the major pathways leading to NAFLD, and CAD risk.Methods and resultsDNL susceptibility genes were used as instruments and selected using three approaches: 1) genes that are associated with both high serum triglycerides and low sex hormone-binding globulin, both downstream consequences of DNL (unbiased approach), 2) genes that have a known role in DNL (biased approach), and 3) genes that have been associated with serum fatty acids, used as a proxy of DNL. Gene-CAD effect estimates were retrieved from the meta-analysis of CARDIoGRAM and the UK Biobank (～76014 cases and ～264785 controls). Effect estimates were clustered using a fixed-effects meta-analysis. Twenty-two DNL susceptibility genes were identified by the unbiased approach, nine genes by the biased approach and seven genes were associated with plasma fatty acids. Clustering of genes selected in the unbiased and biased approach showed a statistically significant association with CAD (OR:1.016, 95%CI:1.012; 1.020 and OR:1.013, 95%CI:1.007; 1.020, respectively), while clustering of fatty acid genes did not (OR:1.004, 95%CI:0.996–1.011). Subsequent exclusion of potential influential outliers did reveal a statistically significant association (OR:1.009, 95%CI:1.000; 1.018).ConclusionsDNL susceptibility genes are associated with an increased risk of CAD. These findings suggest that DNL may be involved in the pathogenesis of CAD and favor further development of strategies that target NAFLD through DNL.     

超敏C反应蛋白与自发性脑出血患者血肿量及预后的相关性分析

目的探讨超敏C反应蛋白(hs-CRP)与自发性脑出血患者(SICH)血肿量和预后的相关性。方法选取2016-01-2018-10萍乡市人民医院收治的SICH患者162例。将其分为大量血肿组、小量血肿组,选择同时期江西萍乡市人民医院80例门诊体检者为对照组。检测和比较3组入院时hs-CRP水平,比较预后良好和不良患者的hs-CRP水平,评价血清hs-CRP水平与血肿体积、预后的相关性。结果大量及小量血肿组hs-CRP水平显著高于对照组(P<0.01),且大量血肿组hs-CRP水平显著高于小量血肿组(P<0.05)。预后良好组hs-CRP水平显著低于预后不良组(P<0.05)。SICH患者hs-CRP水平与血肿量大小和GOS评分呈正相关(r=0.452,0.433,P<0.05)。结论SICH患者血清hs-CRP水平显著升高,与血肿量大小和预后明显相关。     

尿阿尔茨海默病相关神经丝蛋白联合血浆同型半胱氨酸测定在阿尔茨海默病诊断中的研究

目的 探讨尿阿尔茨海默病（AD）相关神经丝蛋白（AD7c-NTP）含量测定联合血浆同型半胱氨酸（Hcy）在AD诊断中的价值。方法 纳入轻度阿尔茨海默病（CDR=1分）及中重度阿尔茨海默病患（CDR ≥ 2分）者各40例，并选择健康体检志愿者40例为对照组，采用酶联免疫吸附测定法（ELISA）检测尿液中AD7c-NTP含量，采用循环酶法测定血浆Hcy的含量，通过绘制ROC曲线，分析二者联合检测对AD的诊断准确性。结果 3组受试者尿AD7c-NTP含量比较，差异有统计学意义（P<0.05）；组间比较差异均有统计学意义（P<0.05）。根据ROC曲线，当尿AD7c-NTP为1.745 ng/mL时，对应的灵敏度和特异度之和最大。3组受试者血浆Hcy的含量比较，差异有统计学意义（P<0.05）；组间比较差异均有统计学意义（P<0.01）。根据ROC曲线，当血浆HCY为15.05 μmol/L时，对应的灵敏度和特异度之和最大。当二者进行联合检测时，ROC曲线下面积为0.891，大于各项单独检测。结论 AD患者尿AD7c-NTP含量及血浆HCY含量均增高；尿液AD7c-NTP含量及血浆HCY含量可作为辅助AD诊断的生物标记物；二者联合检测可提高AD诊断的准确性。