Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.
This study aimed to evaluate the accuracy of the HOSPITAL Score (Haemoglobin level at discharge, Oncology at discharge, Sodium level at discharge, Procedure during hospitalization, Index admission, number of hospital admissions, Length of stay) LACE index (Length of stay, Acute/emergent admission, Charlson comorbidy index score, Emerency department visits in previous 6 months) and LACE+ index in predicting 30-day readmission in patients with diastolic dysfunction. Heart failure remains one of the most common hospital readmissions in adults, leading to significant morbidity and mortality. Different models have been used to predict 30-day hospital readmissions. All adult medical patients discharged from the SIU School of Medicine Hospitalist service from 12 June 2016 to 12 June 2018 with an International Classification of Disease, 10th Revision, Clinical Modification diagnosis of diastolic heart failure were studied retrospectively to evaluate the performance of the HOSPITAL Score, LACE index and LACE+ index readmission risk prediction tools in this patient population. Of the 730 patient discharges with a diagnosis of heart failure with preserved ejection fraction (HFpEF), 692 discharges met the inclusion criteria. Of these discharges, 189 (27%) were readmitted to the same hospital within 30 days. A receiver operating characteristic evaluation showed C-statistic values to be 0.595 (95% CI 0.549 to 0.641) for the HOSPITAL Score, 0.551 (95% CI 0.503 to 0.598) for the LACE index and 0.568 (95% CI 0.522 to 0.615) for the LACE+ index, indicating poor specificity in predicting 30-day readmission. The result of this study demonstrates that the HOSPITAL Score, LACE index and LACE+ index are not effective predictors of 30-day readmission for patients with HFpEF. Further analysis and development of new prediction models are needed to better estimate the 30-day readmission rates in this patient population.
Background: Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation but the recurrence rate remains relatively high in persistent patients with AF. Therefore, posterior wall isolation (PWI) in addition to PVI has been proposed to increase freedom from AF.Objective: To evaluate the success of adjunctive PWI in persistent AF. Methods:We searched electronic database using specific terms. The primary outcomes are recurrence rate of AF and recurrence of atrial arrhythmias. The secondary outcomes were atrial flutter/tachycardia (AFL/AT), procedure time, fluoroscopy time, and procedure related complications. Estimated risk ratios (RRs) and 95% confidence intervals (CIs) were evaluated.Results: Six studies were included (1334 patients with persistent AF). Adjunctive PWI resulted in a significant reduction in the recurrence rate of AF compared with patients who had PVI only (19.8% vs 29.1%; RR, 0.64; 95% CI, 0.42-0.97; P < .04; I 2 = 76%). There was a significant reduction in the recurrence rate of all atrial arrhythmia (30.8% vs 41.1%; RR, 0.75; 95% CI, 0.60-0.94; P < .01; I 2 = 60%). Compared with PVI only, adjunctive PWI did not increase the rate of AFL or AT (11.6% vs 13.9%; RR, 0.85; 95% CI, 0.54-1.32; P < .46; I 2 = 47%) or the rate of procedure related complications (4.6% vs 3.6%; RR, 1.25; 95% CI, 0.72-2.17; P < .44; I 2 = 0%). Conclusion:In patients with persistent AF, adjunctive PWI was associated with decreased recurrence of AF and atrial arrhythmias compared with PVI alone without an increased risk of AFL or AT or procedure related complications. K E Y W O R D Satrial fibrillation, atrial flutter, meta-analysis, posterior wall isolation, pulmonary vein isolation 1 | BACKGROUND Atrial fibrillation (AF) is the most common arrhythmia, with a prevalence of 0.5% to 1% of the population, 1 and is expected to rise even more over the next decades. 2 Historically management of AF has been geared toward rate control, or rhythm control with antiarrhythmic drugs. Over the last two decades, catheter ablation has emerged as an alternative for rhythm control with medications and is now a recognized first line therapy for the treatment of AF in select populations. This is emphasized for instance in the recent American College of Cardiology updated guidelines, which states that catheter ablation may be used in selected patients with symptomatic AF and heart failure with low ejection fraction based on data to support reduced hospitalization and potentially even reduce mortality. 3
Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P ¼ 2.30 Â 10 À11 , OR ¼ 1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r 2 ¼ 0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (b ¼ 0.26, P ¼ 0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region $6 kb upstream of DIS3. Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.
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