MicroRNA-365 regulates human cardiac action potential duration.

Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Here, we aim to identify microRNAs that regulate the human cardiac action potential and ask whether their manipulation allows for therapeutic modulation of action potential abnormalities. Quantitative analysis of the microRNA targetomes in human cardiac myocytes identifies miR-365 as a primary microRNA to regulate repolarizing ion channels. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes. Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Whole-cell patch-clamp experiments confirm miR-365-dependent regulation of repolarizing ionic current Iks. Finally, refractory period measurements in human myocardial slices substantiate the regulatory effect of miR-365 on action potential in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac action potential duration by targeting key factors of cardiac repolarization.

HES1 mRNA expression is associated with survival in sinonasal squamous cell carcinoma.

OBJECTIVE: In squamous cell carcinoma of the pharynx and larynx, NOTCH1 downstream signaling has been shown to be activated. The NOTCH1 signaling pathway has not been examined in detail for sinonasal squamous cell carcinomas (SNSCCs). The aim of this study was to evaluate NOTCH1 signaling by mRNA expression analysis and to examine the occurrence of NOTCH1 mutations in SNSCC. STUDY DESIGN: In a retrospective study, we analyzed tissues from 44 SNSCCs and 56 head and neck squamous cell carcinomas (HNSCCs) at other locations. Expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 mRNA were measured by using quantitative real-time polymerase chain reaction (q-rtPCR). In SNSCC, NOTCH1 mutations were evaluated with sequencing of seven selected exons. RESULTS: Expression of NOTCH1, HEY1, and JAG1 at the mRNA level were significantly higher in tumor tissue compared with normal tissue. In SNSCC, the subgroup of patients with high expression (5th quintile) of HES1 mRNA was associated with better survival (P = .04); however these patients with high expression of HES1 mRNA had also a more favorable tumor stage and grade and more unfavorable resections representing potential confounders. CONCLUSIONS: Key components of NOTCH1 are upregulated at the mRNA level in HNSCCs. The mechanism, clinical significance, and potential therapeutic options should therefore be further evaluated.