Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Analysis of Base Excision Repair proteins in A549 lung cancer cell line upon induction of cancer cell senescence by genotoxicants treatments

Senescence is a cellular process characterized by an irreversible arrest of the cell cycle following various stressors potentially harmful to cells, such as DNA damage, oxidative stress, or oncogene expression. The p53-p21CIP1 and p16-Rb pathways were activated in response to these stimuli and promote cell cycle arrest. One of the most important hallmarks of senescence is the "senescence-associated secretory phenotype" (SASP), in which chemokines, cytokines, and proteases are secreted in an autocrine and paracrine manner. Among cytokines, IL-6 and IL-8 are mainly involved in regulating the tissue microenvironment. Several studies have shown that cellular senescence is related to tumor progression and chemoresistance. When damaged DNA is not properly repaired, cell clearance leads to a chronic pro-inflammatory state. The Base Excision Repair pathway (BER), specifically the protein Apurinic/Apyrimidinic endodeoxyribonuclease 1 (APE1), has been shown to be involved in the induction of intrinsic cell senescence. Currently, involvement of BER in extrinsic cancer cell senescence is still unknown. In recent years, a new pharmacological strategy has been developed to selectively eliminate senescent cells by using senolytic compounds. In the present work, we investigated a possible involvement of BER enzymes in the onset of extrinsic cell senescence of A549 cancer cells. To this end, we first established a model of extrinsic cancer cell senescence by using cisplatin (CDDP) and doxorubicin (DOXO) as genotoxic agents. We analysed the expression of the majority of the BER enzymes: APE1, XRCC-1, POL-β, POL-δ. We found that APE1 was downregulated in a proteasomal-dependent manner during the onset of cancer cell senescence, whereas no significant changes were detected for the other BER enzymes. Of interest, APE1 controls the expression of miRNAs involved in cell senescence. We observed that miR regulated by APE1, i.e., miR-130b, which regulates the expression of p21CIP1, is downregulated in line with APE1 expression, leading to upregulation of its target p21CIP1 and promotion of the senescence process. Moreover, APE1 contributed to the onset of senescence by inducing SASP factors (IL-6 and IL-8) in the early phase of the process. Interestingly, treatment of senescent cells with APE1 inhibitors sensitizes cancer cells to CDDP treatment. These data suggest that APE1 is involved in the early stages of senescence through induction of SASP factors and deregulation of miRNAs. We also demonstrated the senolytic activity of APE1 inhibitors. Overall, this work suggests that APE1 plays a role in the development of extrinsic cell senescence through several mechanisms and that inhibition of APE1 activity could be a promising target for the development of new senolytic agents

‘The role of novel oral anticoagulants in patients undergoing cryoballoon ablation for atrial fibrillation’

Aim: Peri-procedural thromboembolic (TE) and hemorrhagic events are complications of major concern for patients undergoing cryoballoon (CB) ablation for atrial fibrillation (AF). While peri-procedural anticoagulation management could decrease the incidence of these complications, data on CB ablation are scarce. The role of novel oral anticoagulants (NOACs) has not been thoroughly tested in this population. Methods: In the present study, we sought to assess acute peri-procedural complications in patients undergoing CB ablation for AF under different anticoagulation regimens; anticoagulation administration was performed according to the CHA2DS2-VASc score guidelines. To the best of our knowledge, this is the first study that compares 1) uninterrupted warfarin, 2) bridging therapy with low molecular weight heparin (LMWH), 3) aspirin and 4) NOACs in this subgroup of patients. Results: NOACs were as effective as uninterrupted warfarin in terms of bleeding complications and TE events. Surprisingly, the aspirin group had more hemorrhagic complications than both the warfarin and NOACs groups. Conclusion: In the current study, the use of NOACs was an effective and safe approach in CB ablation

Atrial fibrillation outcomes: changing the paradigm.

LetterResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

Phrenic nerve paralysis during cryoballoon ablation for atrial fibrillation: a comparison between the first- and second-generation balloon.

Phrenic nerve palsy (PNP) is the most frequently observed complication during cryoballoon ablation (CB; Arctic Front, Medtronic, MN) occurring in roughly 7%-9% of the cases. The new second-generation cryoballoon ablation Arctic Front Advance (CB-A) (Arctic Front) has recently been launched in the market.Journal Articleinfo:eu-repo/semantics/publishe

Asymptomatic Brugada Syndrome: Clinical Characterization and Long-Term Prognosis

Background - Among Brugada syndrome patients, asymptomatic individuals are considered to be at the lowest risk. Nevertheless, arrhythmic events and sudden cardiac death are not negligible. Literature focused on this specific group of patients is sparse. The purpose of this study is to investigate the clinical characteristics, management, and long-term prognosis of asymptomatic Brugada syndrome patients. Methods and Results - Patients presenting with spontaneous or drug-induced Brugada type I ECG and no symptoms at our institution were considered eligible. A total of 363 consecutive patients (200 men, 55.1%; mean age, 40.9±17.2 years; 41 [11.3%] with spontaneous type I ECG) were included. Electrophysiological study was performed in 321 (88.4%) patients, and ventricular arrhythmias were induced in 32 (10%) patients. An implantable cardioverter defibrillator was implanted in 61 (16.8%) patients. After a mean follow-up time of 73.2±58.9 months, 9 arrhythmic events occurred, accounting for an annual incidence rate of 0.5%. Event-free survival was 99.0% at 1 year, 96.2% at 5 years, and 95.4% at 10 and 15 years. Univariate analysis identified as risk factors: electrophysiological study inducibility (hazard ratio, 11.4; P<0.01), spontaneous type I (hazard ratio, 4.0; P=0.04), and previous sinus node dysfunction (hazard ratio, 8.0; 95% confidence interval, 1.0-63.9; P=0.05). At the multivariate analysis, only inducibility remained significant (hazard ratio, 9.1; P<0.01) Conclusions - Arrhythmic events in asymptomatic Brugada syndrome patients are not insignificant. Ventricular arrhythmia inducibility, spontaneous type I ECG, and presence of sinus node dysfunction might be considered as risk factors and used to drive long-term management.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Prognostic Value of Programmed Electrical Stimulation in Brugada Syndrome

Background - The prognostic value of electrophysiological investigations in individuals with Brugada syndrome remains controversial. Different groups have published contradictory data. Long-term follow-up is needed to clarify this issue. Methods and Results - Patients presenting with spontaneous or drug-induced Brugada type I ECG and in whom programmed electric stimulation was performed at our institution were considered eligible for this study. A total of 403 consecutive patients (235 males, 58.2%; mean age, 43.2±16.2 years) were included. Ventricular arrhythmias during programmed electric stimulation were induced in 73 (18.1%) patients. After a mean follow-up time of 74.3±57.3 months (median 57.3), 25 arrhythmic events occurred (16 in the inducible group and 9 in the noninducible). Ventricular arrhythmias inducibility presented a hazard ratio for events of 8.3 (95% confidence interval, 3.6-19.4), P<0.01. Conclusions - Programmed ventricular stimulation of the heart is a good predictor of outcome in individuals with Brugada syndrome. It might be of special value to guide further management when performed in asymptomatic individuals. The overall accuracy of the test makes it a suitable screening tool to reassure noninducible asymptomatic individualsSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Repeat procedure using radiofrequency energy for recurrence of atrial fibrillation after initial cryoballoon ablation: a 2-year follow-up.

The ideal energy source needed to perform 're-isolation' of the pulmonary veins (PVs) during a repeat procedure for recurrence of paroxysmal atrial fibrillation (AF) has not been established yet. In this study we analysed the outcome of repeat procedure using radiofrequency (RF) energy after initial cryoballoon (CB) ablation at 2-year follow-up.Journal Articleinfo:eu-repo/semantics/publishe

Mitochondrial AKAP1 supports mTOR pathway and tumor growth

Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy