Enhanced tumor homing of pathogen-mimicking liposomes driven by R848 stimulation: A new platform for synergistic oncology therapy

Although multifarious tumor-targeting modifications of nanoparticulate systems have been attempted in joint efforts by our predecessors, it remains challenging for nanomedicine to traverse physiological barriers involving blood vessels, tissues, and cell barriers to thereafter demonstrate excellent antitumor effects. To further overcome these inherent obstacles, we designed and prepared mycoplasma membrane (MM)-fused liposomes (LPs) with the goal of employing circulating neutrophils with the advantage of inflammatory cytokine-guided autonomous tumor localization to transport nanoparticles. We also utilized in vivo neutrophil activation induced by the liposomal form of the immune activator resiquimod (LPs-R848). Fused LPs preparations retained mycoplasma pathogen characteristics and achieved rapid recognition and endocytosis by activated neutrophils stimulated by LPs-R848. The enhanced neutrophil infiltration in homing of the inflammatory tumor microenvironment allowed more nanoparticles to be delivered into solid tumors. Facilitated by the formation of neutrophil extracellular traps (NETs), podophyllotoxin (POD)-loaded MM-fused LPs (MM-LPs-POD) were concomitantly released from neutrophils and subsequently engulfed by tumor cells during inflammation. MM-LPs-POD displayed superior suppression efficacy of tumor growth and lung metastasis in a 4T1 breast tumor model. Overall, such a strategy of pathogen-mimicking nanoparticles hijacking neutrophils in situ combined with enhanced neutrophil infiltration indeed elevates the potential of chemotherapeutics for tumor targeting therapy.     

Surface-engineered liposomes for dual-drug delivery targeting strategy against methicillin-resistant Staphylococcus aureus (MRSA)

This study focused on the encapsulation of vancomycin(VAN) into liposomes coated with a red blood cell membrane with a targeting ligand, daptomycin–polyethylene glycol–1,2-distearoyl-sn-glycero-3-phosphoethanolamine, formed by conjugation of DAPT and Nhydroxysuccinimidyl-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine.This formulation is capable of providing controlled and targeted drug delivery to the bacterial cytoplasm. We performed MALDI-TOF, NMR and FTIR analyses to conf...     

Cluster phenotypes in a non-idiopathic pulmonary fibrosis fibrotic interstitial lung diseases cohort in Singapore

BackgroundNon-idiopathic pulmonary fibrosis fibrosing interstitial lung diseases (F-ILDs) may demonstrate a progressive disease trajectory similar to idiopathic pulmonary fibrosis (IPF). We aimed to identify novel F-ILD phenotypes in a multi-ethnic South-East Asian population.MethodsF-ILD subjects (n=201) were analysed using unsupervised hierarchical cluster analysis and their outcomes compared against IPF (n=86).ResultsFour clusters were identified. Cluster 1 (n=53, 26.4%) comprised older Chinese males with high body mass index (BMI) and comorbidity burden, higher baseline forced vital capacity (FVC) percentage predicted and lower diffusing capacity of the lung for carbon monoxide (DLCO) percentage predicted. They had similar mortality to IPF. Cluster 2 (n=67, 33.3%) had younger female non-smokers with low comorbidity burden, groundglass changes on high-resolution chest computed tomography (HRCT) and a positive anti-nuclear antibody (ANA) titre ≥1:160. They had lower baseline FVC and higher DLCO, low mortality and slower lung function decline. Cluster 3 (n=42, 20.9%) consisted male smokers with low comorbidity burden, emphysema on HRCT and high baseline lung function. They had low mortality and slow lung function decline. Cluster 4 (n=39, 19.4%) was the highest risk and comprised of mainly Indians with high BMI. They had the highest proportion of ischemic heart disease (IHD) and previous pulmonary tuberculosis. Subjects had the lowest baseline lung function, highest mortality, and fastest lung function decline. Survival differences across clusters remained significant following adjustment for treatment.ConclusionsWe identified four distinct F-ILD clinical phenotypes with varying disease trajectories. This demonstrates heterogeneity in F-ILD and the need for complementary approaches for classification and prognostication beyond ATS/ERS guideline diagnosis.     

骨组织工程研究现状与趋势

骨组织工程是目前的研究热点,作者从组织工程研究的主要构成要素,即种子细胞、细胞载体支架、组织构建三个方面对骨组织工程研究的现状和存在的挑战进行了回顾和展望,旨在分析当前研究成果与骨组织工程的最终临床应用之间的差距,为尽快缩短这一距离提供可行的设想。     

高压氧对脓毒症大鼠膈肌损伤的保护作用

目的 观察高压氧(hyperbaric oxygen,HBO)对大鼠脓毒症时膈肌损伤的保护作用.方法 SPF级成年雄性SD大鼠30只,随机分为假手术组、脓毒症组及HBO治疗组,每组10只.其中假手术组在给予水合氯醛麻醉成功后,从正中线剪开大鼠腹部,然后缝合伤口.脓毒症组和HBO组在麻醉成功后.使用盲肠结扎穿刺(CLP)模型,将大鼠制成脓毒症动物模型,并且HBO组在术后立即行HBO治疗.所有大鼠在术后16 h处死,取左侧膈肌检测肌条收缩力,右侧膈肌检测超氧化物歧化酶(SOD)、丙二醛(MDA)含量,膈肌肌细胞凋亡率及病理切片.结果 脓毒症组与假手术组比较,MDA含量、膈肌肌细胞凋亡率明显上升,SOD含量及肌条收缩力明显下降,2组比较差异有统计学意义(P<0.01).给予HBO治疗后,MDA含量、膈肌细胞凋亡率及肌条收缩力较脓毒症组明显恢复,SOD含量也明显上升,2组比较差异有统计学意义(P<0.01).结论 HBO可有效抑制氧自由基生成,减轻氧化应激反应,对膈肌的结构与功能起保护作用,减轻脓毒症膈肌损伤的程度.     

iTRAQ串联质谱筛选尾吊小鼠感染空间诱变大肠杆菌后脾脏差异表达蛋白

目的应用同重同位素标记相对与绝对定量技术(iTRAQ),联合液相色谱串联质谱(LC-MS/MS),检测经空间诱变大肠杆菌(T1-13)感染尾吊模拟失重小鼠后,其脾脏组织中的差异蛋白,并探讨其生物学意义。方法 C57BL/6小鼠尾吊模拟失重后以空间诱变大肠杆菌灌胃建立感染模型,采用iTRAQ结合LC-MS/MS技术筛选脾脏组织差异表达蛋白,并对差异蛋白进行GO、pathway富集分析和STRING蛋白互作分析。结果共鉴定出2589个蛋白,尾吊组与对照组相比筛选出378个差异表达蛋白。尾吊染菌后与对照组相比,共筛选出452个差异表达蛋白,STRING蛋白互作网络中有286个差异蛋白间存在相互作用,这些差异蛋白经KEGG分析共得到32条存在显著性的通路,主要为氧化磷酸化通路,代谢通路、蛋白消化和吸收通路、蛋白酶体通路。结论成功筛选出了模拟失重后空间诱变大肠杆菌感染脾脏组织差异表达蛋白,这些差异蛋白可能通过调控代谢通路、不同环境下微生物代谢、颉氨酸/亮氨酸/异亮氨酸降解、溶酶体、碳代谢、吞噬体、丙酸代谢、蛋白酶体参与失重条件下免疫和炎症反应的发生。     

The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.KEY WORDS: Osteosarcoma, Fibroblast activation protein alpha, Growth, Pulmonary metastasis, Vinblastine prodrug, AXL, β-Catenin     

青年急性心肌梗死患者冠状动脉造影正常的临床分析

目的:探讨青年急性心肌梗死(AM I)患者冠状动脉(冠脉)造影正常的发生率,并分析其临床特点。方法:回顾分析我院1995年5月~2004年10月收治的436例AM I患者冠脉造影结果及有关冠心病的危险因素。结果:本组436例中,冠脉造影异常402例(异常组),正常34例,其中青年AM I患者冠脉造影正常8例(正常组),提示青年冠脉造影正常者多无心绞痛、高血压病、糖尿病病史及血酯异常,但大量吸烟者居多。结论:在冠脉造影正常的青年AM I中,冠脉痉挛在心肌梗死的发病中可能起着十分重要的作用,急性血栓形成伴血栓自溶亦是其病理改变之一。     

长骨液在下肢骨延长中的疗效观察

目的:观察“长骨液”对下肢骨延长术后的治疗效果。方法:56例患者分为长骨液组和对照组进行配对对照观察。于术后第3天开始口服长骨液。观察骨延长区新骨生长情况、肢体伤后肿胀及并发症发生的情况。结果:①对照组平均骨延长愈合指数为41.797±3.5862(d/cm),治疗组平均骨延长愈合指数为36.291±2.8969(d/cm)(P<0.01)。②治疗组的46例病例平均骨延长愈合指数为37.121±2.2176(d/cm),明显低于国内报道指数。结论:“长骨液”有明显促进骨延长区新骨再生与成熟及减少并发症的作用。     

Aggregate Geometrical Features and Their Influence on the Surface Properties of Asphalt Pavement

Aggregate geometrical features directly affect asphalt pavement surface properties, which further affect the resistance to skidding of a road surface. In order to establish a relationship between the aggregate geometrical features and pavement surface properties, this paper employs an aggregate geometric characteristic evaluation system (AGCES) to describe the form property, angularity, and surface texture of aggregate particles. The geometrical feature parameters of 15 different aggregates were examined by AGCES and the corresponding surface properties of asphalt pavement prepared from the mentioned aggregates were evaluated by sand patch method, 2-Dimension Image-based Texture Analysis Method (2D-ITAM) and Walking Friction Tester (WFT), respectively. The relationships between the pavement surface property parameters and the aggregate geometric characteristic parameters studied were developed by the Levenberg-Marquarat and universal global optimization (LM-UGO). The results show that the calculated geometric characteristic parameters are in agreement with traditional manual measurement results. The pavement surface properties are significantly influenced by aggregate angularity and aggregate surface texture. Regression relationships were established to predict pavement surface properties from the aggregate geometrical features.