RNA Biomarker Release with Ultrasound and Phase-Change Nanodroplets

Microbubbles driven by ultrasound are capable of permeabilizing cell membranes and allowing biomarkers or therapeutics to exit from or enter cancer cells, respectively. Unfortunately, the relatively large size of microbubbles prevents extravasation. Lipid-based perfluorobutane microbubbles can be made seven-fold smaller by pressurization, creating 430-nm nanodroplets. The present study compares microbubbles and nanodroplets with respect to their ability to enhance miR-21 and mammaglobin mRNA release from cultured ZR-75-1 cells. Mammaglobin mRNA and miR-21 release increased with escalating concentrations of nanodroplets up to, respectively, 25- and 42-fold with 2% nanodroplets (v/v), compared with pre-ultrasound levels, whereas cell viability decreased to 62.4%. Sonication of ZR-75-1 cells incubated with microbubbles or nanodroplets caused relatively similar levels of cell death and miR-21 release, suggesting that nanodroplets are similar to microbubbles in enhancing cell permeability, but may be more advantageous because of their smaller size, which may allow extravasation through leaky tumor vasculature.     

Effect of oral administration of lipids with 67% medium chain triglycerides on glucose homeostasis in preterm neonates

Since hypoglycemic responses to medium chain triglycerides (MCT) have been reported in adults we studied the effect of an acute oral load of lipids (2,8 g/kg) with 67% MCT on glucose homeostasis in 21 preterm infants in comparison to 14 age-matched control preterm infants. A hyperglycemic response from (mean ± SEM) 57 ± 1.1 to 74 ± 2.5 at 30 min (p < 0.01) and to 80.5 ± 2.5 mg/dl at 60 min (p < 0.01) was observed after administration of the lipids whereas no change in plasma glucose concentration was observed in the control group. After administration of the lipids there was no change in the concentration of insulin and glucagon in plasma. An intravenous glucose tolerance test (1 g/kg) was similar in the control group and 60 min after administration of the lipids. After administration of the lipids free fatty acid concentration remained unchanged while a significant decrease from 304 ± 56 to 199 ± 28 μEq/l was observed in 60 min in the control group. At 60 min β-hydroxybutyrate concentration was higher after lipid administration (630 ± 86 μmol/l) than in the control group (436 ± 66 μmole/l) (p < 0.05). A more rapid decrease in blood lactate concentration was found after lipid administration than in the control group while no change in plasma alanine concentration was observed in either groups. In five additional preterm infants, plasma glucose concentration increased from 56 ± 0.6 to 75 ± 0.9 mg/dl (p < 0.01) 60 minutes after gastric administration of glycerol (0.3 g/kg). These data show that in preterm infants, a lipid load with 67% TCM produces a hyperglycemic response through gluconeogenesis without changing the peripheral rate of glucose disappearance.     

Advances in pharmacotherapy for the treatment of allergic rhinitis; MP29-02 (a novel formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) fills the gaps

Introduction: Effective pharmacologic treatment exists for most patients suffering from allergic rhinitis (AR). However, both in clinical trials and in real-life studies, many patients are dissatisfied with treatment. Physicians often use multiple therapies, in an attempt to improve symptom control, often with limited evidence of success. Novel treatment options are needed and must consider unmet medical needs.

Areas covered: This article reviews the clinical data for a new AR treatment. MP29-02 (Dymista®, Meda, Solna, Sweden) contains azelastine hydrochloride (AZE) and fluticasone propionate (FP), in a novel formulation and delivered in an improved device as a single nasal spray. It has shown superior efficacy in AR patients than either commercially available AZE or FP monotherapy for both nasal and ocular symptom relief, regardless of disease severity. MP29-02 also provided more effective and rapid symptom relief than either AZE or FP monotherapy delivered in the MP29-02 formulation and device. However, the effect was less than that observed versus commercial comparators, suggesting the impact of formulation and device on clinical efficacy.

Expert opinion: MP29-02 simplifies AR management, surpassing the efficacy of gold standard treatment, intranasal corticosteroids (INS), for the first time. It is indicated for the treatment of moderate-to-severe seasonal allergic rhinitis and perennial allergic rhinitis when monotherapy with either intranasal antihistamine or INS is NOT considered sufficient. Most patients present with moderate/severe disease, with evidence of current or previous treatment insufficiency. MP29-02 should be the treatment of choice for these patients.     

低氧对SH-SY5Y细胞miR-124及BACE1蛋白表达的影响

目的研究低氧对培养细胞miR-124及β-淀粉样前体蛋白裂解酶1(BACE1)蛋白表达的影响。方法培养人神经母细胞瘤细胞(SH-SY5Y),分为对照组、氧-糖剥夺组、Aβ1-42处理组、过表达或抑制miR-124组,用实时定量PCR方法检测miR-124表达,Western blot法检测BACE1蛋白表达。结果氧-糖剥夺处理48 h,细胞内miR-124表达水平明显下降,仅为对照组的46.9%(P0.05),BAE1蛋白表达水平与较对照组增高36%(P0.01);转染miR-124过表达组组细胞内miR-124表达水平较对照组增高245倍(P0.01),为miR-124过表达对照组的219倍(P0.01),BACE1蛋白表达水平较对照组下降了29%(P0.05),较miR-124过表达对照组下降25%(P0.05)。转染miR-124抑制剂组miR-124表达水平下降至对照组的45.4%(P0.05),至miR-124抑制对照组的48%(P0.05),BACE1表达水平较对照组升高21%(P0.05),较miR-124抑制对照组升高40.3%(P0.01);细胞经Aβ1-42处理24 h,miR-124表达水平较对照组下降52%(P0.05),BACE1蛋白表达水平较对照组增高51%(P0.05)。结论低氧通过降低SH-SY5Y细胞miR-124表达进而升高BAEC1蛋白表达,且可能在阿尔茨海默病(Alzheimer's disease,AD)早期发病中发挥作用。     

大鼠肝脏发育成熟及癌变时miR-100的表达

目的：探讨microRNA-100(miR-100)在大鼠肝脏发育成熟和癌变时的表达。方法取新生SD乳鼠、成年SD大鼠肝组织以及经连续喂饲2-乙酰氨基芴加部分肝切除术(2-AAF/PH)诱导的SD大鼠肝癌组织,分别采用实时荧光定量PCR及FISH技术检测miR-100的表达。结果同新生SD乳鼠相比,miR-100在成年SD大鼠肝组织中表达明显升高( P<0．05)。大鼠肝脏癌变组织的miR-100表达较成年大鼠肝组织明显下降( P<0．05),接近于新生SD乳鼠miR-100的表达水平。结论 miR-100可作为SD大鼠肝脏发育成熟的标志,其表达降低可能与肿瘤形成有关。     

Distinct microRNA expression profiles in acute myeloid leukemia with common translocations

MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.     

Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN

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miR-34a通过靶向抗凋亡基因Survivin抑制皮肤鳞状细胞癌增殖的研究

[摘要]　目的　研究miR-34a在皮肤鳞状细胞癌(SCC)中的表达及对肿瘤细胞增殖、抗凋亡的调控作用及机制。　方法　采用实时定量PCR检测46例SCC病人肿瘤组织及15例正常皮肤组织中miR-34a及Survivin的表达;将miR-34a mimic转染进皮肤鳞状细胞癌A431细胞系,探讨miR-34a对SCC细胞增殖、Survivin表达的影响;评估miR-34a及Survivin表达对SCC预后的生物诊断价值。 　结果　　（1）低分化SCC患者miR-34a显著低于高分化组,而Survivin则显著高于高分化组（P均<0.05）。与正常皮肤比较,SCC病人的miR-34a显著降低,而Survivin表达则显著提高,P值分别为0.0013及<0.0001,差异均有极显著性意义。（2）与未转染组相比,miR-34a mimic可以显著抑制A431细胞增殖（P<0.05）;同时显著降低Survivin蛋白表达（P<0.01）。（3）高miR-34a表达的SCC患者生存率显著高于低表达者,P=0.020567;高Survivin表达的SCC患者生存率则显著低于高表达者,P=0.008198。　结论　　miR-34a可通过对Survivin表达调控影响SCC细胞增殖,同时它也可作为一个很好的生物学诊断指标为评估SCC病人预后提供参考。