A manual synchronous low energy shock impedance as a predictor of successful defibrillation testing during subcutaneous ICD implantation.

BACKGROUND: Guidelines recommend defibrillation testing (DFT) during subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation. Implant position, patient characteristics and device factors, such as shock impedance, influence defibrillation success. To evaluate the shock impedance, a manual synchronous 10J shock (low energy synchronous shock [LESS]) can be delivered, without the need to induce ventricular fibrillation (VF). OBJECTIVE: To compare LESS and DFT impedance values and to evaluate the diagnostic accuracy of LESS impedance for predicting a successful DFT during S-ICD implantation. METHODS: Consecutive S-ICD implantations were included. Shock impedances were compared by paired t-tests. Univariate analysis was performed to investigate factors associated with successful DFT. A prediction model of successful DFT based on LESS impedance was assessed by logistic regression. Receiver operating characteristic (ROC) curve, area under the ROC curve and the Hosmer-Lemeshow tests were used to evaluate the accuracy of LESS impedance. RESULTS: Sixty patients were included (52 ± 14 years; 69% male). LESS and DFT impedance values were highly correlated (r2 = 0.97, p < .01). Patients with a failed first shock had higher body mass index (BMI) (30 ± 3 vs. 25.7 ± 4.3, p = .014), higher mean LESS (120 ± 35Ω vs. 86. ± 23Ω, p = .0013) and DFT impedance (122 ± 33Ω vs. 87 ± 24Ω, p = .0013). ROC analysis showed that LESS impedance had a good diagnostic performance in predicting a successful conversion test (AUC 84% [95% CI: 0.72-0.92]) with a cutoff value of <94Ω to identify a successful DFT (sensitivity 71%, specificity 73%). CONCLUSION: LESS impedance values without the need to induce VF can intraoperatively predict a successful DFT.

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma.

Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly co-expressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph-based statistics. Using the Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-glycan, mevalonate and sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.

New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study.

BACKGROUND AND AIMS: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. METHODS: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. RESULTS: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. CONCLUSIONS: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.