Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

卵巢上皮性癌组织中Gab1与PD L1蛋白表达与临床病理特征及预后的相关性

【摘要】 目的 探讨卵巢上皮性癌组织中Gab1与程序性死亡配体 1（PD L1）的表达情况,并分析Gab1、PD L1蛋白与卵巢上皮性癌患者临床病理特征及预后的相关性。方法 选取我院2008年5月~2014年5月收治的86例卵巢上皮性癌患者作为研究对象,采用回顾性分析法分析其临床及随访资料,收集86份癌组织标本（观察组）及86份癌旁正常组织标本（对照组）,所有组织标本均行Gab1与PD L1蛋白检测,并根据其资料及检测结果记录所有患者年龄、体质量指数等一般临床资料及肿瘤情况、Gab1与PD L1蛋白水平及预后等。结果 观察组中Gab1及 PD L1蛋白的表达水平均显著高于对照组（P＜0.05）;随着卵巢上皮性癌患者临床分期更高、分化程度越低及出现淋巴结转移时其Gab1及 PD L1蛋白的阳性表达率也显著增高（P＜0.05）;Gab1阴性和阳性患者其3年总生存率分别为7273%和4286%,而 PD L1阴性和阳性患者其3年总生存率分别为7368%和4583%（P＜0.05）;经非条件单因素Cox 比例风险回归模型显示不同临床分期、分化程度、是否出现淋巴结转移以及Gab1和 PD L1不同表达的卵巢上皮性癌患者间其预后生存时间均存在差异（P＜0.05）;经多因素Cox 比例风险回归模型分析显示临床分期Ⅲ~Ⅳ期、低分化、出现淋巴结转移以及Gab1和 PD L1阳性均为影响卵巢上皮性癌患者预后的独立危险因素（P＜0.05）。结论 Gab1和 PD L1蛋白在卵巢上皮性癌组织中均高表达,随着病情加重其阳性表达率更高,且其阳性表达联合临床分期Ⅲ~Ⅳ期、低分化和出现淋巴结转移均为影响卵巢上皮性癌患者预后生存的独立危险因素,故可将其作为临床上评估卵巢上皮性癌患者病情进展和预后的有效指标。     

基于无线刺激与遥测系统的心房颤动动物模型

目的探索一种可控、可靠、安全的心房颤动(简称房颤)动物模型的建立方法。方法自主设计并制作一种基于Microchip公司的PIC18(Peripheral Interface Controller,外围接口控制器)系列单片机和TI公司的RF(Radio Frequency,射频)无线收发芯片CC1101 CC1101(Chipcon公司)的植入式遥测刺激器,植入比格犬背部,记录电极留置腹侧皮下,刺激电极缝合于左心耳上,在犬清醒自由的条件下,通过计算机专用心电软件连续监测体表II导联心电信号,并发放间歇(刺激1 s,暂停2 s)高频(频率30 Hz)阈上(强度2 mA,脉宽5 ms)刺激,若间歇期内出现房颤,则人为干预中止刺激,若转为窦性心律,则继续刺激。结果植入式遥测刺激器在体外可稳定工作(包括采集模拟心电信号和发放刺激)30天,植入犬体内刺激3天后可诱导出房颤,持续时间最长达8 h。结论应用植入式遥测刺激器是建立房颤动物模型的可行性方法之一。     

Caspase-8 as a therapeutic target in cancer

Caspase-8 is an apical caspase which initiates programmed cell death following death receptor ligation. This central role in apoptosis has prompted significant clinical interest in regulating caspase-8 expression and proteolytic activity. However, caspase-8 has also been found to play a number of non-apoptotic roles in cells, such as promoting activation NF-κB signaling, regulating autophagy and altering endosomal trafficking, and enhancing cellular adhesion and migration. Therefore, depending upon the specific cellular context, caspase-8 may either potentiate or suppress tumor malignancy. Accordingly, a marked heterogeneity exists in the expression patterns of caspase-8 among different tumor types. Therapeutics have been developed which can increase caspase-8 expression, yet it remains unclear whether this approach will be beneficial in all cases. Care is warranted, and the role of caspase-8 should be addressed on a case by case basis.     

恶性黑素瘤免疫检查点抑制疗法研究进展

【摘要】 免疫检查点抑制剂在过去几年中已成为许多恶性黑素瘤患者的重要治疗选择，其旨在恢复并促进效应T细胞特异性识别和杀伤肿瘤细胞的功能，系统性增强全身的抗肿瘤免疫反应，对于手术切除后具有高复发风险或处于疾病晚期（不可切除或存在转移）的患者都是较好的治疗选择。目前免疫检查点抑制的主要目标是程序性死亡受体 1与细胞毒性T淋巴细胞相关抗原4，它们分别是中枢和外周免疫耐受的两个关键受体。本文主要讨论不同免疫检查点抑制剂的临床效应、可能存在的药物反应性预测标志物与相关不良反应。     

Association of serine/threonine kinase 11 mutations and response to programmed cell death 1 inhibitors in metastatic gastric cancer

Programmed cell death 1 (PD-1) inhibitors have shown therapeutic efficacy in metastatic gastric cancer (mGC). However, no predictive biomarkers have been established in mGC. Inactivating mutations in serine/threonine kinase 11 (STK11) are associated with poor response to PD-1 inhibitors in KRAS-mutant lung adenocarcinoma. Therefore, we hypothesized that STK11 inactivating mutations would be associated with inferior clinical response to PD-1 inhibitors in mGC. We analyzed 59 mGC patients who had been treated with PD-1 inhibitors and whose tumors had been analyzed by targeted high-throughput sequencing. STK11 mutations were identified in 30 (50.8%) patients, and were all missense mutations. Three patients (5.1%) had STK11 gene amplification and mutation, simultaneously. Patients with STK11 mutations had prolonged overall survival (median: 19.0 vs 11.6 months, p = 0.15), and progression-free survival (4.2 vs 1.9 months, p = 0.06) when treated with PD-1 inhibitors, but these differences were not statistically significant. Patients with STK11 inactivating mutations without STK11 gene amplification had significantly prolonged progression-free survival compared to patients with wild type STK11 or STK11 gene amplification (4.8 vs 1.0 months, p = 0.04). However, in multivariate Cox regression analysis with high microsatellite instability (MSI-H), the number of tumor mutations, PD Ligand-1 (PD-L1)+, Epstein-Barr virus positivity (EBV)+, and type of PD-1 inhibitor used (pembrolizumab vs nivolumab), only MSI-H and PD-L1+ were significantly associated with longer progression-free survival. In mGC, the presence of STK11 mutation was not predictive of the response to PD-1 inhibitors. Instead, patients with MSI-H or PD-L1+ tumors displayed superior clinical responses to PD-1 inhibitors.     

卵巢浆液性腺癌肿瘤微环境中CD8~+TILs密度及PD-L1的表达与临床意义

目的:研究卵巢浆液性腺癌肿瘤微环境中CD8~+肿瘤浸润淋巴细胞(TILs)密度及癌细胞程序性死亡配体-1(PD-L1)的表达情况与临床意义。方法:收集2004年7月至2010年12月于上海交通大学医学院附属仁济医院行肿瘤细胞减灭术的116例卵巢浆液性腺癌患者组织标本,免疫组化检测肿瘤组织CD8~+TILs密度及癌细胞PD-L1表达情况;Spearman相关性分析癌细胞PD-L1表达水平与癌巢及间质CD8~+TILs数目的关系;采用乘积极限法进行基于癌巢CD8~+TILs密度及肿瘤细胞PD-L1表达的单因素生存分析。结果:卵巢浆液性腺癌PD-L1高表达的比例为70.69%(82/116)。癌细胞PD-L1表达强度与癌巢内的CD8~+TILs数目呈显著负相关(P=0.024),而与间质内的CD8~+TILs数目无相关性(P=0.117)。癌巢CD8~+TILs高密度组患者的中位生存时间(64月)显著高于低密度组(43月),差异有统计学意义(P0.05);乘积极限法的亚组分析显示肿瘤微环境中癌细胞PD-L1低表达癌巢CD8~+TILs高密度组患者的预后较好。结论:卵巢浆液性腺癌肿瘤微环境中癌巢CD8~+TILs密度及癌细胞PD-L1表达水平与患者预后密切相关,重视肿瘤微环境的免疫分型有助于评估患者预后及筛选合适患者实施抗PD-1/PD-L1免疫治疗。     

Increased Cell Death and Reduced Neural Crest Cell Numbers in Ethanol-Exposed Embryos: Partial Basis for the Fetal Alcohol Syndrome Phenotype

Fetal alcohol syndrome (FAS) is characterized by growth retardation, craniofacial malformations, and heart and neural defects; the cellular and molecular mechanism(s) responsible for ethanol's teratogenicity remains unknown. Although the phenotype suggests that prenatal ethanol exposure perturbs neural crest cell development, direct proof that these cells are an in utero target is still lacking. Previous research suggested that cranial neural crest cells are eliminated by ethanol-induced apoptosis. We tested this hypothesis using a chick embryo model of FAS. A single dose of ethanol, chosen to achieve a concentration of 35–42 mg/dl, was injected in ovo at gastrulation and resulted in growth retardation, craniofacial foreshortening, and disrupted hindbrain segmentation. Ethanol exposure enhanced cell death within areas populated by cranial neural crest cells, particularly in the hindbrain and craniofacial mesenchyme. In contrast, control embryos had limited cell death within these regions. Subsequent immunolabeling with neural crest cell-specific antibody revealed that ethanol treatment resulted in fewer neural crest cell numbers, whereas neural crest migration patterns were unaffected by ethanol. These results suggest that prenatal ethanol exposure leads to loss of cranial neural crest cells. Such a loss could result, in part, in the phenotype characteristic of FAS.