Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Association of right bundle branch block or intraventricular conduction delay with recurrence of atrial fibrillation after catheter ablation

Abstract Background The association between bundle branch block (BBB) and recurrence of atrial fibrillation (AF) after catheter ablation is unclear. The aim of this study was to determine whether AF combined with BBB is associated with AF recurrence after catheter ablation. Methods A total of 477 consecutive AF patients who underwent catheter ablation were included. The AF patients were divided into three groups according to BBB: AF without BBB (n = 427), AF with right bundle branch block (AF with RBBB) (n = 16), and AF with intraventricular conduction delay (AF with IVCD) (n = 34). Results Of the 477 AF patients (mean age 57 years, 81% men, median CHA2DS2‐VASc score of 1), 16 (3.4%) patients had RBBB, and 34 (7.1%) patients had IVCD. During a mean follow‐up of 15.2 ± 6.7 months, 119 patients (24.9%) had recurrence of AF. Of these, 111 (26%) patients were in the AF without BBB group, with 2 (12.5%) and 6 (17.6%) patients in the RBBB and IVCD groups, respectively. The Kaplan–Meier estimate of the rate of recurrent AF was not significantly different among the three groups (p = .39). Multivariable analysis showed that persistent AF (HR 1.7, 95% CI 1.15–2.50, p = .007), chronic kidney disease (HR 2.94, 95% CI 1.20–7.17, p = .01), and left atrial diameter (HR 1.04, 95% CI 1.009–1.082, p = .01) were significantly associated with AF recurrence. Conclusion AF with BBB was not significantly associated with the recurrence of AF after catheter ablation in middle‐aged patients with low‐risk cardiovascular profile

Initial Experience with Left Bundle Branch Area Pacing with Conventional Stylet-Driven Extendable Screw-In Leads and New Pre-Shaped Delivery Sheaths

Until recently, left bundle branch area pacing (LBBAp) has mostly been performed using lumen-less fixed screw leads. There are limited data on LBBAp with conventional style-driven extendable screw-in (SDES) leads, particularly data performed by operators with no previous experience with LBBAp procedures. In total, 42 consecutive patients undergoing LBBAp using SDES leads and newly designed delivery sheaths (LBBAp group) were compared with those treated with conventional right ventricular pacing (RVp) for atrioventricular block (RVp group, n = 84) using propensity score matching (1:2 ratio). The LBBAp was successful in 83% (35/42) of patients, with satisfactory pacing thresholds (0.8 &plusmn; 0.2 V at 0.4 ms). In the LBBAp group, the mean paced-QRS duration obtained during RV apical pacing (173 &plusmn; 18 ms) was significantly reduced by LBBAp (116 &plusmn; 14 ms, p &lt; 0.001). Compared with the RVp group, the LBBAp group showed more physiological pacing, suggested by a much narrower paced-QRS duration (116 &plusmn; 14 vs. 151 &plusmn; 21 ms, p &lt; 0.001). The pacing threshold was comparable in both groups. The LBBAp group revealed stable pacing thresholds for 6.8 &plusmn; 4.8 months post-implant and no serious complications including lead dislodgement or septal perforation. The novel approach of LBBAp using SDES leads and the new dedicated pre-shaped delivery sheaths was effectively and safely performed, even by inexperienced operators with LBBAp procedures

Orthodromic and Antidromic Snare Techniques for Left Ventricular Lead Implantation in Cardiac Resynchronization Therapy

The snare technique can be used to overcome unsuitable cardiac venous anatomies for left ventricular (LV) lead implantation in cardiac resynchronization therapy (CRT) procedures. However, limited data exist regarding performance of the snare technique. We classified 262 patients undergoing CRT procedure into the snare (n = 20) or conventional group (n = 242) according to the LV lead implantation method. We compared the safety, efficacy, and composite outcome (all-cause death and heart failure readmission) at 3 years post-implant between the snare and conventional groups. In the snare group, all LV leads were implanted safely using orthodromic (n = 15) or antidromic (n = 5) techniques, and no immediate complications occurred including vessel perforation, tamponade, and lead dislodgement. During follow-up, LV lead threshold and impedance remained stable without requiring lead revision in the snare group. There were no significant between-group differences regarding LV ejection fraction increase (12 ± 13% vs. 12 ± 13%, p = 0.929) and LV end-systolic volume reduction (18 ± 48% vs. 28 ± 31%, p = 0.501). Both groups exhibited comparable CRT-response rates (62.5% vs. 60.6%, p = 1.000). The risk of primary outcome was not significantly different between the two groups (25.9% vs. 30.9%, p = 0.817). In patients who failed conventional LV lead implantation for CRT, the snare technique could be a safe and effective solution to overcome difficult coronary venous anatomy

Bc13-dependent stabilization of CtBP1 is crucial for the inhibition of apoptosis and tumor progression in breast cancer

B-cell lymphoma 3 (Bcl3) is a proto-oncogene upregulated in a wide range of cancers, including breast cancer Although Bcl3 is known to promote cell proliferation and inhibit apoptosis, the molecular mechanisms underlying the proto-oncogenic function of Bcl3 have not been completely elucidated To gain insight into the oncogenic role of Bcl3, we applied a proteomic approach, which led to the identification of C-terminal binding protein 1 (CtBP1) as a binding partner of Bcl3 A PXDLS/R motif embedded in Bcl3 was found to mediate the interaction between Bcl3 and CtBP1, which caused the stabilization of CtBP1 by blocking proteasome-dependent degradation. Apoptotic stimuli-induced degradation of CtBP1 was significantly abolished by the upregulation of Bcl3, leading to the sustained repression of pro-apoptotic gene expression and subsequent inhibition of apoptosis. Intriguingly, a strong positive correlation between the protein levels of Bcl3 and CtBP1 was detected in breast cancer patient samples Our study reveals a novel combinatorial role for Bcl3 and CtBP1, providing an explanation for the acquisition of resistance to apoptosis in cancer cells, which is a major requirement for cancer development.Keutgens A, 2010, MOL CELL BIOL, V30, P4006, DOI 10.1128/MCB.01600-09Ahmed SU, 2009, PLOS ONE, V4, DOI 10.1371/journal.pone.0007305Carmody RJ, 2007, SCIENCE, V317, P675, DOI 10.1126/science.1142953O`Neil BH, 2007, ONCOLOGY-BASEL, V72, P97, DOI 10.1159/000111116Wang SY, 2006, J BIOL CHEM, V281, P34810, DOI 10.1074/jbc.M607484200Paliwal S, 2006, MOL CELL BIOL, V26, P2360, DOI 10.1128/MCB.26.6.2360-2372.2006Kashatus D, 2006, GENE DEV, V20, P225, DOI 10.1101/gad.1352206Corazzari M, 2005, BIOCHEM BIOPH RES CO, V331, P810, DOI 10.1016/j.bbrc.2005.03.184Kim JH, 2005, NATURE, V434, P921, DOI 10.1038/nature03452Zhang QH, 2005, P NATL ACAD SCI USA, V102, P2802, DOI 10.1073/pnas.0409373102Thornburg NJ, 2003, CANCER RES, V63, P8293Zhang OH, 2003, CELL, V115, P177Grooteclaes M, 2003, P NATL ACAD SCI USA, V100, P4568, DOI 10.1073/pnas.0830998100Natsume T, 2002, ANAL CHEM, V74, P4725, DOI 10.1021/ac020018nChinnadurai G, 2002, MOL CELL, V9, P213Johnstone RW, 2002, CELL, V108, P153Grooteclaes ML, 2000, ONCOGENE, V19, P3823Cogswell PC, 2000, ONCOGENE, V19, P1123Hanahan D, 2000, CELL, V100, P57OHNO H, 1990, CELL, V60, P991SUBRAMANIAN T, 1989, ONCOGENE, V4, P415

Identification of Single-Atom Ni Site Active toward Electrochemical CO₂ Conversion to CO

Electrocatalytic conversion of CO2 into value-added products offers a new paradigm for a sustainable carbon economy. For active CO2 electrolysis, the single-atom Ni catalyst has been proposed as promising from experiments, but an idealized Ni-N-4 site shows an unfavorable energetics from theory, leading to many debates on the chemical nature responsible for high activity. To resolve this conundrum, here we investigated CO2 electrolysis of Ni sites with well-defined coordination, tetraphenylporphyrin (N-4-TPP) and 21-oxatetraphenylporphyrin (N3O-TPP). Advanced spectroscopic and computational studies revealed that the broken ligand-field symmetry is the key for active CO2 electrolysis, which subordinates an increase in the Ni redox potential yielding Ni-I. Along with their importance in activity, ligand-field symmetry and strength are directly related to the stability of the Ni center. This suggests the next quest for an activity-stability map in the domain of ligand-field strength, toward a rational ligand-field engineering of single-atom Ni catalysts for efficient CO2 electrolysis.11Nsciescopu