TET1 is a 5-methylcytosine dioxygenase and its DNA demethylating activity has been implicated in pluripotency and reprogramming. However, the precise role of TET1 in DNA methylation regulation outside of developmental reprogramming is still unclear. Here, we show that overexpression of the TET1 catalytic domain but not full length TET1 (TET1-FL) induces massive global DNA demethylation in differentiated cells. Genome-wide mapping reveals that 5-hydroxymethylcytosine production by TET1-FL is inhibited as DNA methylation increases, which can be explained by the preferential binding of TET1-FL to unmethylated CpG islands (CGIs) through its CXXC domain. TET1-FL specifically accumulates 5-hydroxymethylcytosine at the edges of hypomethylated CGIs, while knockdown of endogenous TET1 induces methylation spreading from methylated edges into hypomethylated CGIs. We also found that gene expression changes after TET1-FL overexpression are relatively small and independent of its dioxygenase function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically prevents aberrant methylation spreading into CGIs in differentiated cells.

No abstract

Along with its established activities in ECM degradation, CatS plays novel roles in TGF-β1 signalling, myofibroblast trans-differentiation, and ECM protein synthesis, thereby regulating scar formation in the infarcted myocardium and preserving LV function after experimental MI.

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Background: Patients with atrial fibrillation (AF) and left atrial (LA) enlargement may develop functional, normal leaflet motion mitral regurgitation (MR) without left ventricular (LV) remodeling. Mitral annular dynamics and LV mechanics are important for preserving normal mitral valve function. The aim of this study was to assess the annular and LV dynamics in patients with AF and functional MR. Methods: Twenty-one patients with AF with moderate or more MR (AFMR+ group), 46 matched patients with AF with no or mild MR (AFMRÀ group), and 19 normal patients were retrospectively studied. Mitral annular dynamics were quantitatively assessed using three-dimensional echocardiography. Systolic LV global longitudinal strain (GLS), global circumferential strain, and LA strain were measured using two-dimensional speckle-tracking echocardiography. Results: The normal annulus displayed presystolic followed by systolic contraction and increase in saddle shape (P < .01 for all). Presystolic annular dynamics were abolished in both groups of patients with AF (P > .05 vs normal). In contrast, systolic and total annular dynamics during the cardiac cycle were preserved in AFMRÀ patients (P > .10 vs normal) but impaired in AFMR+ patients (P < .05 vs normal and AFMRÀ). LV GLS (P < .0001) and LA strain (P = .02), but not LV global circumferential strain (P = .97), were impaired in AFMR+ compared with AFMRÀ patients despite comparable LA and LV volumes. MR severity correlated with systolic annular contraction (r = 0.64, P < .0001), saddle deepening (r = 0.53, P = .003), and LV GLS (r = 0.46, P < .0001). Multivariate analysis identified that impaired systolic contraction (odds ratio, 2.18; P = .001) and saddle deepening (odds ratio, 2.68; P = .04) were independently associated with MR. Excluding annular dynamics from the model, less negative LV GLS, but not LA strain, became associated with MR (odds ratio, 1.93; P < .0001). Conclusions: In patients with AF and absent LA contraction, the normal predominantly ''atriogenic'' annular dynamics become ''ventriculogenic.'' Isolated LA enlargement is insufficient to cause important MR without coexisting abnormal LV mechanics and annular dynamics during systole. ''Atrial'' functional MR may not be purely an atrial disorder.

No abstract

Tea consumption is associated with a decreased risk of stroke, particularly ischemic stroke. More well-designed, rigorously conducted studies are needed in order to make confident conclusions about the association between tea consumption and stroke subtypes.

4507 Background: Chinese patients (pts) account for more than 50% of hepatocellular carcinoma (HCC) cases in the world and have special features in etiology, biological behavior, treatment strategy and prognosis. The aim of this study was to evaluate the efficacy and safety of apatinib, an inhibitor targeting vascular endothelial growth factor receptor-2, in Chinese pts with pretreated advanced HCC. Methods: In this randomized, placebo-controlled, double-blind, phase 3 trial done in 31 sites in China, pts with HCC who had received at least one line of systemic therapy (including sorafenib and oxaliplatin-based chemotherapy, which is another first-line standard-of-care in China) and had Child-Pugh liver function class A or B ≤7 points were enrolled. The pts were randomly assigned (2:1) to receive 750 mg apatinib orally once daily or placebo and stratified by ECOG performance status (0 or 1), previous sorafenib treatment (yes or no), and extrahepatic spread and/or macrovascular invasion (yes or no) in 28-day treatment cycles. The primary endpoint was overall survival (OS). Results: Between Apr 01, 2014 and May 03, 2017, 393 pts were randomized and received at least one dose of study treatment (261 in apatinib arm and 132 in placebo arm). The median OS was significantly longer with apatinib than that with placebo (8.7 months [95% CI 7.5-9.8] vs 6.8 months [95% CI 5.7-9.1]; hazard ratio 0.785 [95% CI 0.617-0.998]; p=0.0476). Pts in the apatinib arm also had prolonged median progression free survival (PFS) compared with those in the placebo arm (4.5 months [95% CI 3.9-4.7] vs 1.9 months [95% CI 1.9-2.0]; hazard ratio 0.471 [95% CI 0.369-0.601]; p˂0.0001). The objective response rate was 10.7% (95% CI 7.2-15.1) with apatinib versus 1.5% (95% CI 0.2-5.4) with placebo. Treatment-related adverse events (TRAEs) were reported in 250 (97.3%) pts in the apatinib arm and 92 (70.8%) pts in the placebo arm. The most common TRAEs of grade 3 and 4 were hypertension (71 [27.6%] pts in the apatinib arm vs 3 [2.3%] pts in the placebo arm), hand-foot syndrome (46 [17.9%] vs 0), decreased platelet count (34 [13.2%] vs 1 [0.8%]), and decreased neutrophil count (27 [10.5%] vs 0). 24 (9.3%) pts with apatinib and 13 (10.0%) pts with placebo died due to adverse events, and none were deemed treatment-related by investigators. Conclusions: Apatinib significantly prolonged OS and PFS in Chinese pts with pretreated advanced HCC, and was well tolerated with a manageable safety profile. Clinical trial information: NCT02329860 .