Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region

Acute Effects of Dual-chamber Pacing on the Left Ventricular Systolic Function and Relaxation in Patients with Advanced AV Block and Sick Sinus Syndrome

Abnormal activation of the ventricles via right ventricular apical pacing deteriorates cardiac function, which may explain the increased mortality of patients with congestive heart failure receiving permanent pacemakers. We hypothesized that pacing at alternative sites may cause less detrimental effects on the cardiac function. Methods: Five symptomatic patients with either advanced AV block (n = 4) or sick sinus syndrome with normal left ventricular (LV) function (n = 1) were studied. During cardiac catheterization, LV pressure was recorded with a high-fidelity catheter-tipped transducer. Baseline rhythms were sinus rhythm or VVI pacing. Sequential VDD pacing with variable AV intervals was performed at the right ventricular apex (RVA), right ventricular septum (RVS), right ventricular outflow tract (RVOT) and coronary sinus (CS). LV systolic function was assessed by calculating dP/dtmax and LV diastolic function was indexed by calculating the exponential isovolumic relaxation constant (Tau). Percentage changes (mean ± SE) from baseline to pacing were measured. Results: RVA pacing reduced dP/dtmax (-0.8 ± 8.4%) and prolonged Tau (7.0 ± 5.6%); RVS pacing enhanced dP/dtmax (20.7 ± 15.3%) and shortened Tau (-10.4 ± 9%); RVOT pacing reduced dP/dtmax (-8.0 ± 20.0%) and shortened Tau (-6.0 ± 12.2%); CS pacing reduced dP/dtmax (-11.7 ± 13.0%) and prolonged Tau (10.5 ± 11.9%). Our results demonstrated that different pacing sites have different effects on LV contractility and relaxation in patients with normal LV function. Conclusion: Since pacing at the RVS preferably increased LV dP/dtmax and shortened Tau, it may be a better alternative than the RVA

Influence of Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism, B Vitamins and Other Factors on Plasma Homocysteine and Risk of Thromboembolic Disease in Chinese

Thromboembolic disease is a major cause of morbidity and mortality in many countries. Our previous study found that Chinese subjects carried the same polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene as described in Western studies. The aim of the present study was to determine the influence of MTHFR polymorphism, B vitamins and other factors on plasma homocysteine (Hcy) levels and risk of thromboembolic disease in Chinese. Methods: One hundred and six subjects were enrolled into the study. They were categorized into 4 groups: healthy individuals (n = 42); those with diabetes mellitus (n = 20); those with deep vein thrombosis (DVT) (n = 11); and those with coronary artery disease (CAD) (n = 33). Plasma levels of folic acid, vitamins B6 and B12, Hcy, and fasting blood sugar were measured; total cholesterol, triglycerides, complete blood count, and 677 C?T mutation in MTHFR were determined. Results: Plasma Hcy was lowest in the healthy subjects, higher in diabetics, followed by patients with DVT, and highest in patients with CAD (p < 0.001, ANOVA). MTHFR C677T polymorphism was the common factor affecting plasma logHcy levels in all 4 groups of subjects. Triglycerides affected plasma logHcy in the CAD patients. For the 4 groups as a whole, MTHFR polymorphism, triglycerides, and vitamin B12 were the most significant factors influencing plasma Hcy. Conclusion: We suggest that high plasma Hcy is an important risk factor for CAD. Other factors including MTHFR polymorphism, vitamin B12, triglycerides, total cholesterol, and gender might affect Hcy levels in different diseases and conditions

Guidelines for the use and interpretation of assays for monitoring autophagy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field