PINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage.

PINK1 is a causative gene for Parkinson's disease and the corresponding protein has been identified as a master regulator of mitophagy-the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson's disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the pro-apoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1-Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases

Rationale and Design of the PARTHENOPE Trial: A Two-by-Two Factorial Comparison of Polymer-Free vs. Biodegradable-Polymer Drug-Eluting Stents and Personalized vs. Standard Duration of Dual Antiplatelet Therapy in All-Comers Undergoing PCI.

BACKGROUND Over the past few decades, percutaneous coronary intervention (PCI) has undergone significant advancements as a result of the combination of device-based and drug-based therapies. These iterations have led to the development of polymer-free drug-eluting stents. However, there is a scarcity of data regarding their clinical performance. Furthermore, while various risk scores have been proposed to determine the optimal duration of dual antiplatelet therapy (DAPT), none of them have undergone prospective validation within the context of randomized trials. DESIGN The PARTHENOPE trial is a phase IV, prospective, randomized, multicenter, investigator-initiated, assessor-blind study being conducted at 13 centers in Italy (NCT04135989). It includes 2,107 all-comers patients with minimal exclusion criteria, randomly assigned in a 2-by-2 design to receive either the Cre8 amphilimus-eluting stent or the SYNERGY everolimus-eluting stent, along with either a personalized or standard duration of DAPT. Personalized DAPT duration is determined by the DAPT score, which accounts for both bleeding and ischemic risks. Patients with a DAPT score <2 (indicating higher bleeding than ischemic risk) receive DAPT for 3 or 6 months for chronic or acute coronary syndrome, respectively, while patients with a DAPT score ≥2 (indicating higher ischemic than bleeding risk) receive DAPT for 24 months. Patients in the standard DAPT group receive DAPT for 12 months. The trial aims to establish the non-inferiority between stents with respect to a device-oriented composite endpoint of cardiovascular death, target-vessel myocardial infarction, or clinically-driven target-lesion revascularization at 12 months after PCI. Additionally, the trial aims to demonstrate the superiority of personalized DAPT compared to a standard approach with respect to a net clinical composite of all-cause death, any myocardial infarction, stroke, urgent target-vessel revascularization, or type 2 to 5 bleeding according to the Bleeding Academic Research Consortium criteria at 24-months after PCI. SUMMARY The PARTHENOPE trial is the largest randomized trial investigating the efficacy and safety of a polymer-free DES with a reservoir technology for drug-release and the first trial evaluating a personalized duration of DAPT based on the DAPT score. The study results will provide novel insights into the optimizing the use of drug-eluting stents and DAPT in patients undergoing PCI

PINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage

PINK1 is a causative gene for Parkinson&rsquo;s disease and the corresponding protein has been identified as a master regulator of mitophagy&mdash;the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson&rsquo;s disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the pro-apoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1&ndash;Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases

Dual antiplatelet therapy duration after percutaneous coronary intervention in high bleeding risk: a meta-analysis of randomized trials.

AIMS The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients at high bleeding risk (HBR) is still debated. The current study, using the totality of existing evidence, evaluated the impact of an abbreviated DAPT regimen in HBR patients. METHODS AND RESULTS A systematic review and meta-analysis was performed to search randomized clinical trials comparing abbreviated [i.e. very-short (1 month) or short (3 months)] with standard (≥6 months) DAPT in HBR patients without indication for oral anticoagulation. A total of 11 trials, including 9006 HBR patients, were included. Abbreviated DAPT reduced major or clinically relevant non-major bleeding [risk ratio (RR): 0.76, 95% confidence interval (CI): 0.61-0.94; I2 = 28%], major bleeding (RR: 0.80, 95% CI: 0.64-0.99, I2 = 0%), and cardiovascular mortality (RR: 0.79, 95% CI: 0.65-0.95, I2 = 0%) compared with standard DAPT. No difference in all-cause mortality, major adverse cardiovascular events, myocardial infarction, or stent thrombosis was observed. Results were consistent, irrespective of HBR definition and clinical presentation. CONCLUSION In HBR patients undergoing PCI, a 1- or 3-month abbreviated DAPT regimen was associated with lower bleeding and cardiovascular mortality, without increasing ischaemic events, compared with a ≥6-month DAPT regimen. STUDY REGISTRATION PROSPERO registration number CRD42021284004

P2Y12 Inhibitor or Aspirin Monotherapy for Secondary Prevention of Coronary Events.

BACKGROUND Aspirin is the only antiplatelet agent with a Class I recommendation for long-term prevention of cardiovascular events in patients with coronary artery disease (CAD). There is inconsistent evidence on how it compares with alternative antiplatelet agents. OBJECTIVES This study compared P2Y12 inhibitor monotherapy vs aspirin in patients with CAD. METHODS We conducted a patient-level meta-analysis of randomized trials comparing P2Y12 inhibitor monotherapy vs aspirin monotherapy for the prevention of cardiovascular events in patients with established CAD. The primary outcome was the composite of cardiovascular death, myocardial infarction, and stroke. Prespecified key secondary outcomes were major bleeding and net adverse clinical events (the composite of the primary outcome and major bleeding). Data were pooled in a 1-step meta-analysis. RESULTS Patient-level data were obtained from 7 trials. Overall, 24,325 participants were available for analysis, including 12,178 patients assigned to receive P2Y12 inhibitor monotherapy (clopidogrel in 7,545 [62.0%], ticagrelor in 4,633 [38.0%]) and 12,147 assigned to receive aspirin. Risk of the primary outcome was lower with P2Y12 inhibitor monotherapy compared with aspirin over 2 years (HR: 0.88; 95% CI: 0.79-0.97; P = 0.012), mainly owing to less myocardial infarction (HR: 0.77; 95% CI: 0.66-0.90; P < 0.001). Major bleeding was similar (HR: 0.87; 95% CI: 0.70-1.09; P = 0.23) and net adverse clinical events were lower (HR: 0.89; 95% CI: 0.81-0.98; P = 0.020) with P2Y12 inhibitors. The treatment effect was consistent across prespecified subgroups and types of P2Y12 inhibitors. CONCLUSIONS Given its superior efficacy and similar overall safety, P2Y12 inhibitor monotherapy might be preferred over aspirin monotherapy for long-term secondary prevention in patients with established CAD. (P2Y12 Inhibitor or Aspirin Monotherapy as Secondary Prevention in Patients With Coronary Artery Disease: An Individual Patient Data Meta-Analysis of Randomized Trials [PANTHER collaborative initiative]; CRD42021290774)

Biolimus-eluting vs. other limus-eluting stents in NSTE-ACS: A pooled analysis of GLASSY and TWILIGHT

BACKGROUND: Biodegradable polymer biolimus-eluting stents (BP-BES) may be associated with better outcomes in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) compared to other current-generation limus-eluting stents (LES). AIMS: To compare BP-BES with other current-generation LES in ACS patients undergoing PCI. METHODS: We pooled individual data of Non-ST-segment elevation (NSTE)-ACS patients from two large randomized controlled trials (GLASSY and TWILIGHT). The BP-BES groups consisted mostly of GLASSY patients, while the control group (other current-generation LES) included exclusively TWILIGHT patients. The primary outcome was major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, or stent thrombosis; the key secondary outcome was target-vessel failure (TVF). To account for trial design differences, outcomes were assessed at 3 months (short-term) and between 3 and 12 months (long-term) after PCI and subsequently pooled to estimate the 12-month hazards. RESULTS: Of 7107 and 6053 NSTE-ACS patients included in the short- and long-term analysis, 32.7% and 36.5% received a BP-BES, respectively. Risk of MACE associated with BP-BES versus other LES was similar at short-term (1.1% vs 1.3%, adjusted HR 0.86, 95%CI 0.53-1.38), lower at long-term (1.7% vs 3.1%, adjusted HR 0.49, 95%CI 0.34-0.72), and lower in the entire 12-month period (pooled adjusted HR 0.61, 95%CI 0.45-0.82). The cumulative 12-month risk of TVF was reduced with BP-BES (adjusted HR 0.52, 95%CI 0.38-0.70). CONCLUSION: BP-BES was associated with lower 12-month risks of MACE and TVF compared to other current generation LES among NSTE-ACS patients treated with abbreviated or standard ticagrelor-based DAPT. These non-randomized findings are hypothesis-generating. CONDENSED ABSTRACT: Differences in clinical outcomes may exist between biodegradable polymer biolimus-eluting stents (BP-BES) and other current-generation limus-eluting stent (LES) in patients with acute coronary syndrome (ACS). We pooled individual data of about 7000 Non-ST-segment elevation ACS patients undergoing PCI and treated with ticagrelor with or without aspirin from two large randomized controlled trials (GLASSY and TWILIGHT). BP-BES patients derived very largely from GLASSY and other LES patients from TWILIGHT. In this population, BP-BES compared to other current generation LES, were associated with a lower 12-month risk of major adverse cardiovascular events and target-vessel failure

Ticagrelor Monotherapy Versus Dual-Antiplatelet Therapy After PCI : an Individual Patient-Level Meta-Analysis

OBJECTIVES The aim of this study was to compare ticagrelor monotherapy with dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents. BACKGROUND The role of abbreviated DAPT followed by an oral P2Y12 inhibitor after PCI remains uncertain. METHODS Two randomized trials, including 14,628 patients undergoing PCI, comparing ticagrelor monotherapy with standard DAPT on centrally adjudicated endpoints were identified, and individual patient data were analyzed using 1-step fixed-effect models. The protocol was registered in PROSPERO (CRD42019143120). The primary outcomes were the composite of Bleeding Academic Research Consortium type 3 or 5 bleeding tested for superiority and, if met, the composite of all-cause death, myocardial infarction, or stroke at 1 year, tested for noninferiority against a margin of 1.25 on a hazard ratio (HR) scale. RESULTS Bleeding Academic Research Consortium type 3 or 5 bleeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%, respectively; HR: 0.56; 95% confidence interval [CI]: 0.41 to 0.75; p < 0.001). The composite of all-cause death, myocardial infarction, or stroke occurred in 231 patients (3.2%) with ticagrelor and in 254 patients (3.5%) with DAPT (HR: 0.92; 95% CI: 0.76 to 1.10; p < 0.001 for noninferiority). Ticagrelor was associated with lower risk for all-cause (HR: 0.71; 95% CI: 0.52 to 0.96; p = 0.027) and cardiovascular (HR: 0.68; 95% CI: 0.47 to 0.99; p = 0.044) mortality. Rates of myocardial infarction (2.01% vs. 2.05%; p = 0.88), stent thrombosis (0.29% vs. 0.38%; p = 0.32), and stroke (0.47% vs. 0.36%; p = 0.30) were similar. CONCLUSIONS Ticagrelor monotherapy was associated with a lower risk for major bleeding compared with standard DAPT, without a concomitant increase in ischemic events

Parry Romberg syndrome with a wide range of ocular manifestations: a case report

BACKGROUND: Parry-Romberg syndrome (PRS) is a rare disorder characterized by unilateral facial atrophy affecting the skin, subcutaneous tissue, muscles, and sometimes extending to the osteocartilaginous structures. Ocular involvement is relatively rare. CASE PRESENTATION: We present a case of a 23-year-old female caucasian patient with Parry Romberg syndrome and extensive ocular involvement: enophthalmos, uveitis, iris atrophy. Ultrasound biomicroscopy (UBM) demonstrated hypotrophy of the ciliary body. The ciliary body atrophy has been previously reported just once and can be an explanation for the hypotony, frequently present in these patients. CONCLUSIONS: Parry Romberg syndrome is a rare multidisciplinary disease. Our case presents a full spectrum of ocular manifestations. The pathogenesis of hypotonia is discussed