Molecular profiling has led to identification of subtypes of diffuse large B-cell lymphomas (DLBCLs) differing in terms of oncogenic signaling and metabolic programs. The OxPhos-DLBCL subtype is ...characterized by enhanced mitochondrial oxidative phosphorylation. As increased oxidative metabolism leads to overproduction of potentially toxic reactive oxygen species (ROS), we sought to identify mechanisms responsible for adaptation of OxPhos cells to these conditions. Herein, we describe a mechanism involving the FOXO1-TXN-p300 redox-dependent circuit protecting OxPhos-DLBCL cells from ROS toxicity. We identify a BCL6-dependent transcriptional mechanism leading to relative TXN overexpression in OxPhos cells. We found that OxPhos cells lacking TXN were uniformly more sensitive to ROS and doxorubicin than control cells. Consistent with this, the overall survival of patients with high TXN mRNA expression, treated with doxorubicin-containing regimens, is significantly shorter than of those with low TXN mRNA expression. TXN overexpression curtails p300-mediated FOXO1 acetylation and its nuclear translocation in response to oxidative stress, thus attenuating FOXO1 transcriptional activity toward genes involved in apoptosis and cell cycle inhibition. We also demonstrate that FOXO1 knockdown in cells with silenced TXN expression markedly reduces ROS-induced apoptosis, indicating that FOXO1 is the major sensor and effector of oxidative stress in OxPhos-DLBCLs. These data highlight dynamic, context-dependent modulation of FOXO1 tumor-suppressor functions via acetylation and reveal potentially targetable vulnerabilities in these DLBCLs.
Abstract
Background
The aim of the study was to test the relationship between left atrial (LA) function parameters and the results of the pulmonary vein isolation (PVI) in patients with atrial ...fibrillation (AF).
Patients and methods
Consecutive patients undergoing first time PVI in years 2019–2021 were qualified to the study. The patients underwent radiofrequency ablation using contact-force catheters and electroanatomical system. LA pressure was measured directly just after transseptal puncture. Follow-up was based on ambulatory visits/televisits and 7-day holter monitoring (6 and 12 month after ablation). On the day of ablation all the patients underwent transesophageal and transthoracic echocardiography. The primary endpoint was any atrial tachyarrhythmia recurrence during follow-up period.
Results
A total of 210 patients were included in the study. Median of follow-up was 12 months, AF recurrence was observed in 71 patients (33.8%) after mean of 1.03 procedures per patient. In univariate Cox regression analysis several echocardiographic parameters were significant predictors of AF recurrence after catheter ablation: left and right atrial area, LA volume, average e' and average E/e' values, LA reservoir strain, LA conduit strain, LA appendage emptying velocity. AF recurrence was also predicted by mean LA pressure, age, body mass index and calculated eGFR. Interestingly, LA contraction strain and LA emptying fraction were not predictors of results of AF ablation. In multivariate Cox regression analysis (that included all parameters significant in univariate analysis) LA reservoir strain (hazard ratio (HR) 1.076, 95% confidence interval (CI) 1.014–1.141; p=0.014) and LA appendage emptying velocity (HR 0.968, 95% CI 0.947–0.988; p=0.002) were significant predictors of AF ablation results.
Conclusions
LA reservoir strain and LA appendage emptying velocity are predicting factors of AF ablation results. LA contraction strain and LA emptying function were not predictors of effective AF ablation.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Statutory Grant of Military Institute of Medicine
PDF
