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.     

Knowledge about the impact of age on fertility: a brief review

Delayed childbearing is currently a major challenge in reproductive medicine as increased age has an important impact on successful conception, both in natural and in assisted reproduction. There is a lack of knowledge about the impact of age on fertility, even in highly educated populations. A number of initiatives have been taken to increase fertility awareness. Health care providers have been encouraged to talk with patients about their reproductive life plan (RLP) for almost a decade based on recommendations from the Centres for Disease Control and Prevention. This concept has been explored successfully in Swedish contraception counselling. A growing number of online interventions aim to raise fertility awareness. These websites or interactive tools provide relevant information for individuals and couples as they consider whether they want children, when they should have them, and how many they may wish to have. These interventions are important, because research depicts that knowledge helps people in their decision-making process. With new fertility preservations such as egg freezing now available, additional education is needed to be sure that women and couples are well informed about the cost and low success rates of this intervention.     

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6 months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC_0–24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.     

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。     

开胸术后肋间神经冷冻治疗对术后切口镇痛疗效的临床研究(附30例分析)

目的:探讨开胸术后肋间神经冷冻治疗对术后切口镇痛的临床疗效。方法:对2005年1月~2010年12月30例开胸术后肋间神经冷冻治疗(冷冻组)与同期收治的开胸术后静脉镇痛组(对照组)进行临床分析。冷冻组采用北京库蓝公司JT-1型冷冻手术治疗机在关胸前对切口所在肋间及上下各一肋间和放置胸管所在肋间神经根部进行冷冻,并以视觉模拟评分法观察两组术后切口疼痛情况。结果:冷冻组术后72 h内视觉模拟评分法(VAS)评分与对照组比较差异有统计学意义(P<0.01),冷冻组镇痛效果明显优于对照组。结论:肋间神经冷冻治疗是防治开胸术后切口疼痛的一种安全、有效的方法之一。