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AIMS: To compare outcomes of patients who underwent left atrial appendage occlusion (LAAO) for nonvalvular atrial fibrillation (NVAF) and contraindication to anticoagulants due to history of either gastrointestinal (GI) or intracranial (IC) bleeding. METHODS: Patients with NVAF that underwent LAAO for GI or IC bleeding from seven centers were included in this observational study. Baseline characteristics, procedural features, and follow-up data were collected, and compared between the two groups. The primary outcomes were incidence of ischemic and hemorrhagic events at 12-month. RESULTS: Six hundred twenty-eight patients were included, 57% with previous GI-bleeding, and 43% with previous IC-bleeding. Median CHA 2 DS 2-VASc score was 4 (interquartile range [IQRs]: 3-5) for both GI-bleeding and IC-bleeding patients, while GI-bleeding patients had a higher HAS-BLED score (4 [IQRs: 3-4] vs. 3 [IQRs]: 2-3]; p = 0.001). At 12-month follow-up, relative risk reduction for stroke was similar between the two groups. The GI-bleeding group had more hemorrhagic events compared to IC-bleeding group (any bleeding 8.4% vs. 3.2%; p = 0.012; major bleeding BARC 3-5: 4.3% vs. 1.8; p = 0.010). At multivariate analysis history of GI bleeding was an independent predictor of hemorrhagic events (adjusted HR: 2.39, 95% confidence interval: 1.02-5.63; p = 0.047). CONCLUSIONS: Outcomes after LAAO may be affected by the different indications for the procedure. In our study, GI-bleeding and IC-bleeding as indication to LAAO differ in their baseline characteristics. LAAO confirms its efficacy in ischemic risk reduction in both groups, while GI bleeding seems to be an independent predictor of bleeding recurrence at 12 months behind the antithrombotic regimen.
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Apéndice Atrial , Fibrilación Atrial , Humanos , Apéndice Atrial/diagnóstico por imagen , Resultado del Tratamiento , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Hemorragias Intracraneales/etiología , Sistema de Registros , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/terapia , LógicaRESUMEN
Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccinâ A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg2+ leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.
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Proteínas 14-3-3/química , Productos Biológicos/química , Quelantes/química , Metales/química , Descubrimiento de Drogas , Glicósidos , Humanos , Conformación Molecular , Unión ProteicaRESUMEN
The RNA-binding protein LIN28 is a regulator of miRNA let-7 biogenesis. Inhibitors of LIN28 are highly sought after given the central role that LIN28 plays in tumorigenesis and development of cancer stem cells as well as LIN28's association with poor clinical prognosis. Although LIN28 inhibitors of different scaffolds have been reported, the potential of most LIN28 inhibiting small molecules was not fully explored since very limited structure-activity relationship (SAR) studies have been performed. We previously identified trisubstituted pyrrolinones as a new class of LIN28 inhibitors disrupting the LIN28-let-7 interaction. Here, we performed extensive SAR by evaluating 95 small molecules and identified new trisubstituted pyrrolinones featuring either an N-biphenyl or N-dibenzofuran substituent, overthrowing the existing conclusion that a salicylic acid moiety is indispensable for activity. Exchange of the negatively charged salicylic acid moiety in LIN28 inhibitors with a heterocyclic substituent is beneficial for membrane permeability, leading to increased activity in a cellular assay, and will potentially reduce toxicity.
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The multidisciplinary assessment of hospitalized patients via validated scales and tools has become crucial in the early identification of sarcopenia. The objective of this study was to determine the prevalence of sarcopenia and its related factors in patients aged ≥65 years admitted to the neurological rehabilitation departments of cognitive motor disorders and functional motor rehabilitation at the IRCCS Hospital San Raffaele in Milan. Using the algorithm reported by the European Working Group on Sarcopenia in Older People (EWGSOP2), the prevalence of sarcopenia in patients was investigated from 2019-2020. Definite sarcopenia was detected in 161 of 336 recruited patients (47.9%). Age was significantly higher in sarcopenic patients than in those without sarcopenia (median 81 vs. 79 years, p < 0.001) and height, weight, and body mass index were lower (p < 0.001 for all). The malnutrition screening test (MUST) was higher but still negative in most sarcopenic patients (47.8% vs. 20.6%, p < 0.001). Patients with sarcopenia had significantly reduced life autonomy (by Barthel index, median 55 vs. 60 points, p < 0.001) and increased mental impairment (tested by MMSE and MOCA, p < 0.005 for both). In conclusion, sarcopenic patients were more cognitively impaired and less autonomous in their daily life, but the majority presented with a negative malnutrition screening test.
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BACKGROUND: Multicenter ventricular tachycardia (VT) ablation studies have shown poorer outcomes compared with single-center experiences. This difference could be related to heterogeneous mapping and ablation strategies. OBJECTIVES: This study evaluated a homogenous simplified catheter ablation strategy for different substrates and compared the results with those of a single referral center. METHODS: This was a multicenter prospective VT ablation registry of patients with the following 4 causes of VT: previous myocardial infarction; previous myocarditis; arrhythmogenic right ventricular dysplasia; or idiopathic dilated cardiomyopathy. The procedural protocol included precise mapping and ablation steps with the combined endpoint of late potential (LP) abolition and noninducibility of VT. The long-term primary efficacy endpoint was freedom from VT. RESULTS: A total of 309 patients were enrolled. LPs were present in 70% of patients and were abolished in 83%. At the end of the procedure 74% of LPs were noninducible. The primary combined endpoint of LP abolition and noninducibility was achieved in 64% of patients with LPs at baseline. Freedom from VT at 12 months was observed in 67% of patients. In the overall study group, VT inducibility was the only predictor of freedom from VT (P = 0.013). In patients with LPs, the VT recurrence rate was lower both for patients with complete LP abolition (P = 0.040) and for patients meeting the composite endpoint (P = 0.035). CONCLUSIONS: A standardized VT mapping and ablation technique reproduced the procedural outcomes of a single referral center in a multicenter prospective study. LP abolition and noninducibility were effective in reducing VT recurrences in patients with 4 causes of cardiomyopathy. (Ventricular Tachycardia Ablation Registry; NCT03649022).
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Ablación por Catéter , Taquicardia Ventricular , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Taquicardia Ventricular/epidemiología , Taquicardia Ventricular/cirugía , Taquicardia Ventricular/etiología , Lipopolisacáridos , Ablación por Catéter/efectos adversos , Ablación por Catéter/métodos , Sistema de RegistrosRESUMEN
The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.
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Glucocorticoides , Receptores de Glucocorticoides , Glucocorticoides/metabolismo , Receptores de Glucocorticoides/metabolismo , Proteínas 14-3-3/metabolismo , Regulación de la Expresión Génica , Sitios de Unión , Esteroides , DexametasonaRESUMEN
Protein-protein interactions (PPIs) remain poorly explored targets for the treatment of Alzheimer's disease. The interaction of 14-3-3 proteins with Tau was shown to be linked to Tau pathology. This PPI is therefore seen as a potential target for Alzheimer's disease. When Tau is phosphorylated by PKA (Tau-PKA), several phosphorylation sites are generated, including two known 14-3-3 binding sites, surrounding the phosphorylated serines 214 and 324 of Tau. The crystal structures of 14-3-3 in complex with peptides surrounding these Tau phosphosites show that both these motifs are anchored in the amphipathic binding groove of 14-3-3. However, in the absence of structural data with the full-length Tau protein, the stoichiometry of the complex or the interface and affinity of the partners is still unclear. In this work, we addressed these points, using a broad range of biophysical techniques. The interaction of the long and disordered Tau-PKA protein with 14-3-3σ is restricted to two short sequences, containing phosphorylated serines, which bind in the amphipathic binding groove of 14-3-3σ. Phosphorylation of Tau is fundamental for the formation of this stable complex, and the affinity of the Tau-PKA/14-3-3σ interaction is in the 1-10 micromolar range. Each monomer of the 14-3-3σ dimer binds one of two different phosphorylated peptides of Tau-PKA, suggesting a 14-3-3/Tau-PKA stoichiometry of 2 : 1, confirmed by analytical ultracentrifugation. These results contribute to a better understanding of this PPI and provide useful insights for drug discovery projects aiming at the modulation of this interaction.
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Proteínas 14-3-3/metabolismo , Enfermedad de Alzheimer/metabolismo , Multimerización de Proteína , Proteínas tau/metabolismo , Proteínas 14-3-3/química , Proteínas 14-3-3/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Sitios de Unión , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Exorribonucleasas/química , Exorribonucleasas/genética , Exorribonucleasas/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Mutación , Fosforilación , Unión Proteica , Conformación Proteica , Serina/química , Serina/metabolismo , Resonancia por Plasmón de Superficie , Proteínas tau/química , Proteínas tau/genéticaRESUMEN
BACKGROUND: after transvenous lead extraction (TLE) of cardiac implantable electric devices (CIEDs), some patients may not benefit from device reimplantation. This study sought to analyse predictors and long-term outcome of patients after TLE with vs. without reimplantation in a high-volume centre. METHODS: all patients undergoing TLE at our centre between January 2010 and November 2015 were included into this analysis. RESULTS: a total of 223 patients (median age 70 years, 22.0% female) were included into the study. Cardiac resynchronization therapy-defibrillator (CRT-D) was the most common device (40.4%) followed by pacemaker (PM) (31.4%), implantable cardioverter-defibrillator (ICD) (26.9%), and cardiac resynchronization therapy-PM (CRT-P) (1.4%). TLE was performed due to infection (55.6%), malfunction (35.9%), system upgrade (6.7%) or other causes (1.8%). In 14.8%, no reimplantation was performed after TLE. At a median follow-up of 41 months, no preventable arrhythmia-related events were documented in the no-reimplantation group, but 11.8% received a new CIED after 17-84 months. While there was no difference in short-term survival, five-year survival was significantly lower in the no-reimplantation group (78.3% vs. 94.7%, p = 0.014). CONCLUSIONS: in patients undergoing TLE, a re-evaluation of the indication for reimplantation is safe and effective. Reimplantation was not related to preventable arrhythmia events, but all-cause survival was lower.