Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

A Set of miRNAs, Their Gene and Protein Targets and Stromal Genes Distinguish Early from Late Onset ER Positive Breast Cancer.

UNLABELLED:Breast cancer (BC) in young adult patients (YA) has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in middle aged patients (MA). We proposed that differentially expressed miRNAs could regulate genes and proteins underlying aggressive phenotypes of breast tumors in YA patients when compared to those arising in MA patients. OBJECTIVE:Using integrated expression analyses of miRs, their mRNA and protein targets and stromal gene expression, we aimed to identify differentially expressed profiles between tumors from YA-BC and MA-BC. METHODOLOGY AND RESULTS:Samples of ER+ invasive ductal breast carcinomas, divided into two groups: YA-BC (35 years or less) or MA-BC (50-65 years) were evaluated. Screening for BRCA1/2 status according to the BOADICEA program indicated low risk of patients being carriers of these mutations. Aggressive characteristics were more evident in YA-BC versus MA-BC. Performing qPCR, we identified eight miRs differentially expressed (miR-9, 18b, 33b, 106a, 106b, 210, 518a-3p and miR-372) between YA-BC and MA-BC tumors with high confidence statement, which were associated with aggressive clinicopathological characteristics. The expression profiles by microarray identified 602 predicted target genes associated to proliferation, cell cycle and development biological functions. Performing RPPA, 24 target proteins differed between both groups and 21 were interconnected within a network protein-protein interactions associated with proliferation, development and metabolism pathways over represented in YA-BC. Combination of eight mRNA targets or the combination of eight target proteins defined indicators able to classify individual samples into YA-BC or MA-BC groups. Fibroblast-enriched stroma expression profile analysis resulted in 308 stromal genes differentially expressed between YA-BC and MA-BC. CONCLUSION:We defined a set of differentially expressed miRNAs, their mRNAs and protein targets and stromal genes that distinguish early onset from late onset ER positive breast cancers which may be involved with tumor aggressiveness of YA-BC

Clinicopathological characteristics of tumors in YA-BC versus MA-BC groups.

<p>Clinicopathological characteristics of tumors in YA-BC versus MA-BC groups.</p

Sample classifications based on genes.

<p>Four index pairs of genes as potential classifiers of samples (circles) into the right side of cut-off mark corresponding to YA-BC group, and to the left side corresponding to MA-BC.</p

Association between miRs and tumors clinicopathological characteristics.

<p>Association between miRs and tumors clinicopathological characteristics.</p

Association between proteins and mRNA expression levels.

<p>Association between proteins and mRNA expression levels.</p

Protein-protein interaction and miRs network.

<p>This network represent over and under expression miRs (not fulfilled and fulfilled triangle respectively) in the YA-BC tumors interacting with their protein targets (circles). The inversely or coordinately regulation of proteins by miRs were represented by red or black edges respectively. The strong, or less strong protein-protein interactions based on databases, were represented by thicker or thinner blue edges respectively.</p