👤 Ikram U Haq

The effects of disease-causing MYBPC3 or MYH7 genetic variants on atrial myopathy, atrial fibrillation (AF) clinical course, and catheter ablation efficacy remain unclear. The aim of this study was to characterize the atrial substrate of patients with MYBPC3- or MYH7-mediated hypertrophic cardiomyopathy (HCM) and its impact on catheter ablation outcomes. A retrospective single-center study of patients with HCM who underwent genetic testing and catheter ablation for AF was performed. Patients with MYBPC3- or MYH7-mediated HCM formed the gene-positive cohort; those without disease-causative genetic variants formed the control cohort. High-density electroanatomical mapping was performed using a 3-dimensional mapping system, followed by radiofrequency ablation. Twelve patients were included in the gene-positive cohort (mean age 55.6 ± 9.9 years, 83% men, 50% MYBPC3, 50% MYH7, mean ejection fraction 59.3% ± 13.7%, mean left atrial [LA] volume index 51.7 ± 13.1 mL/m Patients with MYBPC3- or MYH7-mediated HCM undergoing AF ablation have appreciably more low-amplitude LA signals, suggestive of fibrosis. However, catheter ablation remains an effective rhythm-control strategy. Show less

Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients. Show less

A 280 kilobase (kb) contig was isolated from mouse genomic P1 and cosmid libraries, using as probes human cDNA and genomic DNA fragments that map in the interval between the second component of complement and tumor necrosis factor genes of the HLA complex. The clone contig demonstrates synteny of eleven mouse genes that are homologous to genes initially mapped within the human major histocompatibility complex. These include the mouse homologs of BAT2 (HLA-B-associated transcript 2) through BAT9 and also three HSP70-related genes. Five P1 clones form a contig of 240 kb that spans from BAT9 through BAT3. Twelve cosmid clones are arranged in three contigs that confirm most of the structure of the P1 contig and link the mouse BAT3 homolog to the BAT2 homolog approximately 15 kb farther telomeric. Polymorphic DNA markers within the cloned region were used to map the cleft palate susceptibility-1 (Cps-1) locus to the interval between Hsp70.1 and BAT6 (valyl-tRNA synthetase). This refines the location of the Cps-1 locus to a 45 kb region contained in the H2-124 P1 insert. Show less