Dinuclear silver and gold bisNHC complexes as drug candidates for cancer therapy.

We report four dinuclear silver(I) and gold(I) complexes containing two different bidentate N-heterocyclic carbene ligands (bisNHC). One of these complexes 4, shows strong and selective anticancer activity against the human ovarian cancer cell line A2780. Mechanistically, 4 enhances the oxidative stress by stimulating reactive oxygen species production and inhibiting the scavenging activity of thioredoxin reductase. Our findings provide evidence that tuning ligand and electronic properties of metal-NHC complexes can modulate their reactivity and selectivity and it may result in potential novel anticancer drugs.

Identification of a Plasma MicroRNA Profile Associated With Venous Thrombosis.

OBJECTIVE: Venous thrombosis (VT) is a complex condition with a highly heritable genetic component that predisposes one to its development. Certain microRNAs (miRNAs) might be used as biomarkers of VT, but few studies have examined miRNA expression in this respect. The aim of the present work was to identify a plasma miRNA profile associated with VT. Approach and Results: miRNAs were analyzed by quantitative polymerase chain reaction in plasma samples from members of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) population (n=935). A discovery phase involving the screening of 752 miRNAs from a subset of 104 GAIT-2 subjects was followed by an internal validation phase in which the selected miRNAs were quantified in the whole GAIT-2 population. In the discovery phase, 16 miRNAs were selected, including 9 associated with VT and 7 that correlated with an intermediate phenotype of VT. In the next phase, 4 miRNAs were validated as differentially expressed (false discovery rate, <0.1) in VT: hsa-miR-126-3p, hsa-miR-885-5p, hsa-miR-194-5p, and hsa-miR-192-5p. The 4 miRNAs each returned a significant (P<0.05) odds ratio for VT (range of 1.3-1.8). A risk model including the 4 miRNAs, age, and sex returned an area under the receiver operating characteristic curve of 0.77. Moreover, all 4 miRNAs showed significant correlations with intermediate phenotypes of VT (eg, protein S and factor VII). The targets of the miRNAs in the blood coagulation pathway and their interactions are also discussed. CONCLUSIONS: The present results suggest a 4-miRNA plasma profile associated with VT is of potential use in predicting the risk of this condition.

Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk.

Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes involved in the regulation of cfDNA levels using data from the Genetic Analysis of Idiopathic Thrombophilia (GAIT-2) Project.Imputed genotypes, whole blood RNA-Seq data, and plasma cfDNA quantification were available for 935 of the GAIT-2 participants from 35 families with idiopathic thrombophilia. We performed heritability and GWAS analysis for cfDNA. The heritability of cfDNA was 0.26 (p = 3.7 × 10-6), while the GWAS identified a significant association (rs1687391, p = 3.55 × 10-10) near the ORM1 gene, on chromosome 9. An eQTL (expression quantitative trait loci) analysis revealed a significant association between the lead GWAS variant and the expression of ORM1 in whole blood (p = 6.14 × 10-9). Additionally, ORM1 expression correlated with levels of cfDNA (p = 4.38 × 10-4). Finally, genetic correlation analysis between cfDNA and thrombosis identified a suggestive association (ρ g = 0.43, p = 0.089).All in all, we show evidence of the role of ORM1 in regulating cfDNA levels in plasma, which might contribute to the susceptibility to thrombosis through mechanisms of immunothrombosis.

Expression of microRNAs in human platelet-poor plasma: analysis of the factors affecting their expression and association with proximal genetic variants.

To translate circulating microRNAs (miRNAs) into the clinic, a deeper understanding of the factors affecting their expression is needed. In this study, we explored the features affecting the expression of miRNAs and their genetic regulation using the expression data of 103 miRNAs obtained by qPCR in the platelet-poor plasma of 104 subjects. The principal components (PCs) of the expression of the miRNAs were associated with technical and biological features (e.g., synthetic controls or sex) and with blood cell counts. Also, the associations with proximal genetics variants were analysed. We found that haemolysis marker (dCt hsa-miR-23a-3p-hsa-miR-451a) was correlated strongly (ß = 0.84, p = 2.07x10-29) with the second PC, which explained 10.1% of the overall variability. Thus, we identified haemolysis as a source of variability for miRNA expression even in mild hemolyzed samples (haemolysis marker dCt <5). In addition to hsa-miR-23a-3p and hsa-miR-451a, the miRNAs most stable and most susceptible to haemolysis were identified. Then, we discovered that the expression of miRNAs in platelet-poor plasma was not biased by any blood cell count, and thus, our results supported their role as biomarkers of tissue-specific conditions. Finally, we identified 1,323 genetic variants that corresponded to 158 miRNA expression quantitative trait loci for 14 miRNAs (FDR <0.2), which were enriched in promoter regions (p = 0.03). This enrichment corresponded to a range of specific tissues (e.g., breast or fat) although not to blood tissue, supporting the concept that the expression of circulating miRNAs is under the genetic control of different tissues.