👤 Isabelle Nault

Individuals with atrial fibrillation (AF) are at increased risk of stroke, cognitive impairment and dementia. Observational studies suggest that anticoagulation may reduce the risk of cognitive decline in patients with AF and elevated thromboembolic risk, implicating subclinical cerebral emboli as a potential mechanistic link. Whether anticoagulation prevents cognitive deterioration in patients with AF at low risk of stroke remains uncertain. Here we conducted a multicenter, double-blind, placebo-controlled trial in which participants with AF and low thromboembolic risk (CHA Show less

The aryl hydrocarbon receptor is a ligand-activated transcription factor known for mediating the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. TCDD induces nonalcoholic fatty liver disease (NAFLD)-like pathologies including simple steatosis that can progress to steatohepatitis with fibrosis and bile duct proliferation in male mice. Dose-dependent progression of steatosis to steatohepatitis with fibrosis by TCDD has been associated with metabolic reprogramming, including the disruption of amino acid metabolism. Here, we used targeted metabolomic analysis to reveal dose-dependent changes in the level of ten serum and eleven hepatic amino acids in mice upon treatment with TCDD. Bulk RNA-seq and protein analysis showed TCDD repressed CPS1, OTS, ASS1, ASL, and GLUL, all of which are associated with the urea cycle and glutamine biosynthesis. Urea and glutamine are end products of the detoxification and excretion of ammonia, a toxic byproduct of amino acid catabolism. Furthermore, we found that the catalytic activity of OTC, a rate-limiting step in the urea cycle was also dose dependently repressed. These results are consistent with an increase in circulating ammonia. Collectively, the repression of the urea and glutamate-glutamine cycles increased circulating ammonia levels and the toxicity of TCDD. Show less

To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty-one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole-exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT-rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced-stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1-G6 transcriptomic classification and the molecular prognostic 5-gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5-gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty-two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies. Show less

Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype. 657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing. We identified 296 IHCA (45%), 81% of them were mutated in either Recurrent chromosomal alterations involving Show less

Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. Adcy9-inactivated ( Adcy9 Adcy9 Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone. Show less

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmet medical need in this field. Show less

Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy. Show less

Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV-related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features. Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing HBS and HBX genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied. HBX revealed frequent non-sense, frameshift and deletions in tumours, suggesting an HBX inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, TP53 mutations were associated with shorter survival only in HBV-related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (HBX, TP53, IRF2, AXIN1 and CTNNB1). Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients. Show less

In patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF), radiofrequency catheter ablation (RFCA) represents a promising option. However, the predictors of RFCA efficacy remain largely unknown. We assessed the outcome of a multicentre HCM cohort following RFCA for symptomatic AF refractory to medical therapy. Sixty-one patients (age 54 +/- 13 years; time from AF onset 5.7 +/- 5.5 years) with paroxysmal (n = 35; 57%), recent persistent (n = 15; 25%), or long-standing persistent AF (n = 11; 18%) were enrolled. A scheme with pulmonary vein isolation plus linear lesions was employed. Of the 61 patients, 32 (52%) required redo procedures. Antiarrhythmic therapy was maintained in 22 (54%). At the end of a 29 +/- 16 months follow-up, 41 patients (67%) were in sinus rhythm, including 17 of the 19 patients aged < or = 50 years, with marked improvement in New York Heart Association (NYHA) functional class (1.2 +/- 0.5 vs. 1.9 +/- 0.7 at baseline; P < 0.001). In the remaining 20 patients (33%), with AF recurrence, there was less marked, but still significant, improvement following RFCA (NYHA class 1.8 +/- 0.7 vs. 2.3 +/- 0.7 at baseline; P = 0.002). Independent predictors of AF recurrence were increased left atrium volume [hazard ratio (HR) per unit increase 1.009, 95% confidence interval (CI) 1.001-1.018; P = 0.037] and NYHA functional class (HR 2.24, 95% CI 1.16-4.35; P = 0.016). Among 11 genotyped HCM patients (6 with MYBPC3, 2 with MYH7, 1 with MYL2 and 2 with multiple mutations), RFCA success rate was comparable with that of the overall cohort (n = 8; 73%). RFCA was successful in restoring long-term sinus rhythm and improving symptomatic status in most HCM patients with refractory AF, including the subset with proven sarcomere gene mutations, although redo procedures were often necessary. Younger HCM patients with small atrial size and mild symptoms proved to be the best RFCA candidates, likely due to lesser degrees of atrial remodelling. Show less