Citations

Abstract Background: Chronic inflammation is implicated in pancreatic cancer carcinogenesis. Advanced glycation end-products (AGEs), which are rich in cooked red meat and cigarette smoke, can perpetuate inflammation by binding to the receptor for advanced glycation end products (AGER, also known as RAGE). We hypothesized that genetic variation of the AGEs/AGER pathway affects pancreatic cancer risk by modulating chronic inflammation. Methods: We conducted a two-stage case-control study to examine the association between 96 single nucleotide polymorphisms (SNPs) in 21 genes (GLO1, MSR1, PINK1, KIF17, AGPAT1, AKR1B1, DDOST, CD36, SCARB1, AGER, APP, HMGB1, S100A8, S100B, S100P, S100A12, MMP9, ADAM10, PPARG, NOTCH4, and PDGF) of the AGEs/AGER pathway and risk of pancreatic cancer. The discovery study was conducted in 672 pancreatic cancer cases and 1361 controls ascertained from the Women’s Health Initiative (WHI) Study matched on age, race/ethnicity and study arm. The validation study was conducted in a PANC4 pooled hospital-based case-control study of 1,034 women cases and 989 women controls. A pooled analysis of 1706 cases and 2350 controls was also performed. SNP data were obtained or imputed from the previously performed GWASs. Pancreatic cancer risk was calculated as odds ratios (ORs) and 95% confidence intervals (Cis) using logistic regression models adjusting for age, race/ethnicity, body mass index (BMI), type 2 diabetes, and smoking using an additive genetic model. The potential interaction between individual SNP and red meat intake and cigarette smoking was examined. A false discovery rate (FDR) adjusted q value < 0.20 was considered statistically significant in the pooled analyses. We also conducted logistic-Kernel machine (LKM) test to examine the association between sets of SNP and risk of pancreatic cancer in the pooled dataset. Results: We identified 11 SNPs with raw P values < 0.10 in the discovery stage in the WHI study. However, none of the SNPs was validated in the validation and pooled dataset. The LKM test showed that sets of SNPs in CD36 (P = 9.3E-10), GLO1(P =2.0E-7), and DDOST (P = 2.5E-4) were significantly associated with pancreatic cancer risk. We found an interaction effect between the GLO1 SNP rs6932648 and smoking status (never versus ever) in the WHI study (P for interaction = 0.01) and the pooled dataset (P for interaction = 0.049). In the pooled dataset, the variant T allele of rs6932648 (MAF = 0.12) was associated with increased risk of pancreatic cancer among ever smokers (additive OR = 1.26, 95% CI: 1.02-1.55), but not among never smokers (additive OR = 0.94, 95% CI: 0.78-1.14), compared with the C allele. Summary and Conclusion: We did not observe significant association between any of 96 single SNP and pancreatic cancer risk. However, we found combined set of SNPs in the GLO1, DDOST, and CD36 genes were associated with risk of pancreatic cancer. GLO SNP rs6932648 may modify the association between smoking and risk of pancreatic cancer. GLO1, DDOST, and CD36 are involved in detoxification or clearance of AGEs compounds. Further investigation of AGEs and receptors systems in pancreatic cancer is warranted. Citation Format: Guochong Jia, Kathryn Royse, Hongwei Tang, Donghui Li, Liang Chen, Lesley Tinker, Gloria Petersen, Alison Klein, Peter Richardson, Donna White, Haleh Sangi-Haghapeykar, Hashem B. El-Serag, Li Jiao. Genetic variations in the AGEs/AGER pathway and risk of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2017-LB-160

AbstractObjectivesWe assessed the effectiveness and safety of cryoballoon ablation (CBA) in the Chinese population with paroxysmal atrial fibrillation (AF) with a 1‐year follow‐up and determined the association of early recurrence of atrial tachyarrhythmias (ERAT) with late recurrence (LR).MethodsA total of 114 patients (age 61 ± 10 years, 78 males) with paroxysmal AF who underwent CBA were consecutively enrolled. After procedures, patients were observed for 3 days with continuous electrocardiogram monitoring in the hospital with routine follow‐up visits at 3 months, 6 months, and 1 year. Documented atrial tachyarrhythmia >30 seconds was defined as recurrence. ERAT was defined as any recurrence during the first 3 months, and LR was recurrence between 3 and 12 months.ResultsWith the first 3 months as blanking period, 76% of patients were free of LR at 12 months. Five patients (4%) experienced complications, including phrenic nerve palsy, stroke, and groin complications. Forty‐five percent of patients had ERAT in the first 3 months and 31% of patients had ERAT in the first 3 days. Patients with ERAT had higher LR rate (LRR) than those without ERAT (43% vs 8%, P < 0.001). The LRR of patients with ERAT only in the first 3 days was lower than those with ERAT both in the first 3 days and in 4–90 days (29% vs 64%, P = 0.036).ConclusionsCBA was an effective and safe treatment option for paroxysmal AF. Patients with ERAT had higher LRR after CBA of AF. The time when ERAT occurred had an impact on LRR.

Background: Hydrogen peroxide (H2O2)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. Methods: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H2O2 (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Gö 6983 (1 μM), was applied to test the involvement of PKC. Results: H2O2 perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H2O2-induced afterdepolarizations. Additional application of Gö 6983 with H2O2 effectively suppressed H2O2-induced afterdepolarizations. H2O2 increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H2O2 also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H2O2-induced enhancement of Ito. Conclusions: H2O2 induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.

On‐board magnetic resonance (MR) image guidance during radiation therapy offers the potential for more accurate treatment delivery. To utilize the real‐time image information, a crucial prerequisite is the ability to successfully segment and track regions of interest (ROI). The purpose of this work is to evaluate the performance of different segmentation algorithms using motion images (4 frames per second) acquired using a MR image‐guided radiotherapy (MR‐IGRT) system. Manual contours of the kidney, bladder, duodenum, and a liver tumor by an experienced radiation oncologist were used as the ground truth for performance evaluation. Besides the manual segmentation, images were automatically segmented using thresholding, fuzzy k‐means (FKM), k‐harmonic means (KHM), and reaction‐diffusion level set evolution (RD‐LSE) algorithms, as well as the tissue tracking algorithm provided by the ViewRay treatment planning and delivery system (VR‐TPDS). The performance of the five algorithms was evaluated quantitatively by comparing with the manual segmentation using the Dice coefficient and target registration error (TRE) measured as the distance between the centroid of the manual ROI and the centroid of the automatically segmented ROI. All methods were able to successfully segment the bladder and the kidney, but only FKM, KHM, and VR‐TPDS were able to segment the liver tumor and the duodenum. The performance of the thresholding, FKM, KHM, and RD‐LSE algorithms degraded as the local image contrast decreased, whereas the performance of the VP‐TPDS method was nearly independent of local image contrast due to the reference registration algorithm. For segmenting high‐contrast images (i.e., kidney), the thresholding method provided the best speed ( ) with a satisfying accuracy ( ). When the image contrast was low, the VR‐TPDS method had the best automatic contour. Results suggest an image quality determination procedure before segmentation and a combination of different methods for optimal segmentation with the on‐board MR‐IGRT system. PACS number(s): 87.57.nm, 87.57.N‐, 87.61.Tg

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 −7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 −8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.