凋亡抑制蛋白XIAP和促凋亡因子Smac在胰腺癌化疗抵抗中的作用

目的探讨x-相关凋亡抑制蛋白（XIAP）和促凋亡因子Smac在胰腺癌细胞化疗抵抗中的作用，以及转染胞浆表达型Smac基因靶向下凋XIAP对化疗药物诱导的胰腺癌细胞凋亡的影响。方法应用流式细胞术检测顺铂、5-FU介导的Panc-1、BXPC-3的凋亡率及胞浆染色分析细胞XIAP表达变化，Western blot分析XIAP、Smac、Caspase-3表达水平；构建pEGFP-NI／Smac真核表达载体并转染胰腺癌Panc-1细胞，流式细胞术检测转染Smac基因前后Panc-1细胞的凋亡敏感性。结果与BXPC-3细胞相比，Panc-1对顺铂或5-FU介导的凋亡具有较强抵抗性，Western blot分析显示Panc-1细胞高表达XIAP，在化疗药物作用下化疗敏感细胞BXPC-3胞浆内XIAP水平下降明显多于Panc-1细胞，而且凋亡的BXPC-3细胞释放入胞浆内的成熟Smac蛋白水平明显高于Panc-1细胞。转染胞浆表达型Smac基因至化疗抵抗Panc-1细胞，可明显下调其XIAP表达水平，促进效应Caspase-3分子活化，显著提高顺铂、5-FU诱导的细胞凋亡率。结论胰腺癌细胞XIAP的表达水平下调与其化疗敏感性有关，XIAP是克服化疗抵抗的重要靶分子，而上调Smac活性蛋白的胞浆表达作为一种有效调节信号，通过拮抗XIAP的凋亡抑制作用协同化疗药物促进胰腺癌细胞凋亡。     

Inhibitor of apoptosis proteins as targets for anticancer therapy

Cell death by apoptosis plays a critical role in regulating the subtle balance between cell death and proliferation to maintain tissue homeostasis. Accordingly, tipping the balance in either direction may cause human disease. Too little cell death may promote tumor formation and progression. In addition, killing of cancer cells by current therapies is largely due to induction of apoptosis in tumor cells. Since a hallmark of human cancers is their resistance to apoptosis, there is a demand to develop novel strategies that restore the apoptotic machinery in order to overcome cancer resistance. Inhibitor of apoptosis proteins (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases. Elevated levels of IAPs are found in many human cancers and have been associated with poor prognosis. Recent insights into the role of IAPs have provided the basis for various exciting developments that aim to modulate the expression or function of IAPs in human cancers. Targeting IAPs (e.g., by antisense approaches or small-molecule inhibitors) presents a promising novel approach to either directly trigger apoptosis or to potentiate the efficacy of cytotoxic therapies in cancer cells. Thus, inhibition of IAPs such as X chromosome-linked IAP may prove to be a successful strategy to overcome apoptosis resistance of human cancers that deserves further exploitation.     

Cost-effectiveness of maternal immunization against neonatal invasive Group B Streptococcus in the Netherlands

BackgroundNeonatal invasive Group B Streptococcus (GBS) infection causes considerable disease burden in the Netherlands. Intrapartum antibiotic prophylaxis (IAP) prevents early-onset disease (EOD), but has no effect on late-onset disease (LOD). A potential maternal GBS vaccine could prevent both EOD and LOD by conferring immunity in neonates.ObjectiveExplore under which circumstances maternal vaccination against GBS would be cost-effective as an addition to, or replacement for the current risk factor-based IAP prevention strategy in the Netherlands.MethodsWe assessed the maximum cost-effective price per dose of a trivalent (serotypes Ia, Ib, and III) and hexavalent (additional serotypes II, IV, and V) GBS vaccine in addition to, or as a replacement for IAP. To project the prevented costs and disease burden, a decision tree model was developed to reflect neonatal GBS disease and long-term health outcomes among a cohort based on 169,836 live births in the Netherlands in 2017.ResultsUnder base-case conditions, maternal immunization with a trivalent vaccine would gain 186 QALYs and prevent more than €3.1 million in health care costs when implemented in addition to IAP. Immunization implemented as a replacement for IAP would gain 88 QALYs compared to the current prevention strategy, prevent €1.5 million in health care costs, and avoid potentially ~ 30,000 IAP administrations. The base-case results correspond to a maximum price of €58 per dose (vaccine + administration costs; using a threshold of €20,000/QALY). Expanding the serotype coverage to a hexavalent vaccine would only have a limited additional impact on the cost-effectiveness in the Netherlands.ConclusionsA maternal GBS vaccine could be cost-effective when implemented in addition to the current risk factor-based IAP prevention strategy in the Netherlands. Discontinuation of IAP would save costs and prevent antibiotic use, however, is projected to lead to a lower health gain compared to vaccination in addition to IAP.     

Multifaceted targeting in cancer: the recent cell death players meet the usual oncogene suspects

Recent complicated advances towards the blueprinting of the altered molecular networks that lie behind cancer development have paved the way for targeted therapy in cancer. This directed a significant part of the research community to the development of specialized targeted agents, many of which are already available or in clinical trials. The prospect of patient-tailored therapeutic strategies, although very close to becoming a reality also raises the level of complexity of the therapeutic approach. This review summarizes the functions, in vivo expression patterns and aberrations of factors presently targeted or representing potential targets by therapeutic agents, focusing on those implicated in death receptor-induced apoptosis. The authors overview the regulation of these factors and death receptor-induced apoptosis by classical oncogenes (e.g., RAS, MYC, HER2) and their effectors/regulators, most of which are also being targeted. In addition, the importance of orthologic systemic approaches in future patient-tailored therapies are discussed.     

Best Core Stabilization for Anticipatory Postural Adjustment and Falls in Hemiparetic Stroke

Objectives

To compare the effects of conventional core stabilization and dynamic neuromuscular stabilization (DNS) on anticipatory postural adjustment (APA) time, balance performance, and fear of falls in chronic hemiparetic stroke.

Changes in spatial QRS-T angle and QTc interval in patients with traumatic brain injury with or without intra-abdominal hypertension

Introduction

Traumatic brain injury (TBI) affects cardiac electrical function, and several extra-cerebral factors, including intra-abdominal pressure (IAP), might further modulate this brain-heart interaction. The purpose of this study was to investigate the impact of TBI, and of increased IAP during TBI, on cardiac electrical function as measured by vectorcardiographic (VCG) variables.

Survivin在妇科肿瘤中的研究与应用

Survivin是迄今为止发现的最强的凋亡抑制因子,也是凋亡抑制因子基因家族成员中最小的一个.Survivin组织分布有明显特征性,在胚胎组织及恶性肿瘤中表达丰富而在除了胎盘,胸腺外的正常分化成熟组织及癌旁组织无表达.该文就Survivin分子生物学结构、组织分布、生物学功能及与妇科常见肿瘤关系的研究进展与临床应用作以综述.     

无创机械通气不同吸气压力对慢性阻塞性肺疾病急性加重期患者腹内压的影响

目的 探讨不同吸气压力(IPAP)对慢性阻塞性肺疾病急性加重期(AECOPD)无创正压机械通气患者腹内压(IAP)的影响.方法 选取60例AECOPD无创正压机械通气患者,行机械通气前测量患者IAP值,行无创正压机械通气后,按照正压机械通气不同吸气压力将患者随机分为三组:10～ 14 cm H2O(A组),15 ～19 cm H2O(B组),20～25 cm H2O(C组);每组各20例患者,分别于调整吸气压力后2h、第1～7天每天同一时间点监测患者IAP.结果 与A组、B组比较,C组患者IAP差异有统计学意义(P＜0.05);A组与B组比较差异无统计学意义(P＞0.05).同一组不同监测时间点比较,通气后2h及通气后第1天与其他时间点比较差异有统计学意义(P＜0.05).结论 对于AECOPD无创正压机械通气患者,随着吸气压力水平的升高,患者IAP有升高趋势,并且在早期较明显.因此,在无创正压机械通气早期,监测患者IAP可能有益于为患者选择适合的吸气压力支持水平.     

胰腺癌围手术期IAP和T淋巴细胞rDNA转录活性的动态观察

探讨胰腺癌患者围手术期血清免疫抑制酸性蛋白(IAP)和T淋巴细胞rDNA转录活性的变化及其临床意义。分别用单向免疫扩散法和核仁形成区相关蛋白银染技术测定58例胰腺癌患者手术前后血清IAP和外周血T淋巴细胞rDNA转录活性的改变，并与健康对照组比较分析。结果显示，胰腺癌组治疗前血清IAP增高，外周血T淋巴细胞rDNA转录活性降低，与对照组比较有显著性差异(P＜0．01)；且与淋巴结转移和肿瘤临床TNM分期有明显相关性。行根治性手术组(32例)术后血清IAP显著性降低(P＜0．01)，外周血T淋巴细胞rDNA转录活性显著性增高(P＜0．01)；而姑息性手术组(26例)血清IAP和外周血T淋巴细胞rDNA转录活性则无显著性变化(P＞0．05)。提示胰腺癌患者血清IAP和T淋巴细胞rDNA转录活性的变化与肿瘤的浸润转移和病程有关，检测胰腺癌患者血清IAP和T淋巴细胞rDNA转录活性的变化，有助于评估患者的治疗效果和预后。     

Inhibitors of apoptosis proteins in prostate cancer cell lines

BACKGROUND: The caspases are the central executioners of apoptosis. The inhibitors of apoptosis proteins (IAPs) are a family of recently described caspase inhibitors. We hypothesised that tumor resistance to apoptosis could be due in part to IAP expression. METHODS: The expression of NAIP, cIAP-1, cIAP-2, XIAP, and survivin was investigated in the prostate cancer cell lines LNCaP, PC3, and DU145. RNase protection assays and Western blotting were used to assess RNA and protein expression. Apoptotic susceptibility was determined using etoposide and assessed by propidium iodide (PI) DNA incorporation using flow cytometry. RESULTS: DU145 and PC3 cells were more resistant to apoptosis than LNCaP cells. All the IAPs were identified in the cell lines with variation in IAP expression between different cell types. Immunohistochemistry demonstrated cIAP-1 expression in PC3 cells was nuclear, while the expression of cIAP-2 and XIAP was perinuclear. Growing LNCaP cells in charcoal-stripped or androgen-supplemented medium resulted in no alteration in IAP expression. CONCLUSIONS: This study characterises the expression of IAP in three of the most commonly used prostate cancer cells. IAP may make an important contribution to apoptotic resistance in patients with prostate cancer.