Fungal infections in solid organ transplantation: An update on diagnosis and treatment

Invasive fungal infections constitute an important cause of morbidity and mortality in solid organ transplantation recipients. Since solid organ transplantation is an effective therapy for many patients with end-stage organ failure, prevention and treatment of fungal infections are of vital importance. Diagnosis and management of these infections, however, remain difficult due to the variety of clinical symptoms in addition to the lack of accurate diagnostic methods. The use of fungal biomarkers can lead to an increased diagnostic accuracy, resulting in improved clinical outcomes. The evidence for optimal prophylactic approaches remains inconclusive, which results in considerable variation in the administration of prophylaxis. The implementation of a standard protocol for prophylaxis remains difficult as previous treatment regimens, which can alter the distribution of different pathogens, affect the outcome of antifungal susceptibility testing. Furthermore, the increasing use of antifungals also contributes to incremental costs and the risk of development of drug resistance. This review will highlight risk factors, clinical manifestations and timing of fungal infections and will focus predominately on the current evidence for diagnosis and management of fungal infections.     

Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis

BackgroundCystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR.MethodsThis multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport.ResultsIn the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was ?3.0 mV (?6.6; 0.6) at day 15, ?4.1 mV (?7.8; ?0.4, p = .04) at day 26 (end of treatment) and ? 3.7 mV (?8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile.ConclusionsIn F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity.     

新型肝癌组织的体外三维培养模型

目的:利用肝癌组织进行体外的三维（three-dimension，3D）组织块培养，通过添加PD98059和霍乱毒素（cholera toxin，CT）优化培养条件，建立一种高活性的肝癌组织体外培养模型。方法:收集中山大学肿瘤防治中心肝胆科的肝癌组织标本，经清洗、冻存、复苏等处理后分为对照组、PD组、CT组、PD+CT组，同时进行体外的二维（two-dimension，2D）和三维培养。各组组织采用DNA断裂的原位末端标记法（TUNEL）检测组织细胞凋亡情况，qRT-PCR检测BCL-2、BID、Caspase 3、Cyclin D1、CDK2、ELK-1、C-FOS、C-MYC、C-JUN等相关基因的mRNA表达水平，免疫荧光染色检测BCL-2和cleaved caspase-3蛋白表达情况，筛选并确定最优的体外培养方法。结果:3D培养组的组织细胞凋亡均少于2D培养组；PD98059通过上调BCL-2蛋白的表达，下调cleaved caspase-3蛋白的表达，激活MEK/ERK下游基因，从而减少体外培养的组织细胞凋亡，增强其抗凋亡能力；霍乱毒素通过上调Cyclin D1、CDK2的基因表达，促进其增殖。结论:我们开发了一种新型肝癌组织的体外三维培养模型，它可以作为进一步的药物试验和人源性异种移植(PDX)模型的工具。