The fractional shortening-velocity ratio: Validation of a new echocardiographic doppler method for identifying patients with significant aortic stenosis

AbstractPrevious studies have shown that Doppler echographic methods based on the continuity equation can accurately determine aortic valve area in patients with clinically significant aortic stenosis; nonetheless, methods based on the continuity equation are time-consuming and may not be technically possible in all subsets of patients. Thee purpose of this study was to develop and prospectively evaluate a simpler new noninvasive method for determining aortic valve area. With this new method, aortic valve area is obtained by dividing the percent fractional anteroposterior shortening at the midventriclevel by 4V2, where V is the peak instantaneous Doppler-derived How velocity across the aortic valve.In the fast part of the study, the fractional shortening-velocity ratio was used to examine a group of 25 patients evaluated retrospectively. There was a highly significant linear relation between the fractional shortening-velocity ratio (FSVR) and the aortic valve area (AVA) determined by the Gorlin formula at cardiac catheterization: FSVR = 1.1(AVA) − 0.1 (r = 0.88; significance of slope p < 0.001). Furthermore, a fractional shortening-velocity ratio <1.1 reliably identified all patients with clinically significant aortic stenosis (aortic valve area <1 cm2), whereas a fractional shortening-velocity ratio <0.8 reliably identified all patients with critical aortic stenosis (aortic valve area <0.7 cm2).This new method was then validated by prospectively applying the fractignal shortening-velocity ratio to a group of 44 patients from two separate institutions. This prospective study showed that a fractional shortening-velocity ratio <l.l had a seRR-Jitivity of 90% to 96% and a positive predictive accuracy of 90% to 92% for identifying patients with significant aortic stenosis, whereas a fractional shortening-velocity ratio <0.8 had a sensitivity of 100% and a predictive accuracy of 74% to % for identifying patients with critical aortic stenosis.In summary, the fractional shortening-velocity ratio is a new Doppler echocardiographic method that reliably identifies patients with clinically significant aortic stenosis. The simplicity of this new noninvasive method readily lends itself to routine clinical use

EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors

SUMMARY Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide1. Chemotherapies such as the topoisomerase II inhibitor (TopoIIi) etoposide effectively reduce disease in a minority of NSCLC patients2,3; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention4. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the Polycomb Repressive Complex 2 (PRC2) is well known to tri-methylate Histone H3 at lysine 27 (H3K27me3) and elicit gene silencing5. Here, we demonstrate that EZH2 inhibition (EZH2i) had differential effects on TopoIIi response of NSCLCs in vitro and in vivo. EGFR and BRG1 mutations were genetic biomarkers that predicted enhanced sensitivity to TopoIIi in response to EZH2i. BRG1 loss-of-function mutant tumors responded to EZH2i with increased S phase, anaphase bridging, apoptosis, and TopoIIi sensitivity. Conversely, EGFR and BRG1 wild-type tumors up-regulated BRG1 in response to EZH2i and ultimately became more resistant to TopoIIi. EGFR gain-of-function mutant tumors were also sensitive to dual EZH2i and TopoIIi, due to genetic antagonism between EGFR and BRG1. These findings suggest an exciting opportunity for precision medicine in the genetically complex disease of NSCLC