RESUMEN
Background: Neurolotic sequelae after transcatheter aortic valve replacement (TAVR) can cause significant morbidity and mortality. Transcranial Doppler (TCD) imaging can show real-time high intensity transient signals (HITS), which reflect active microembolization. Although it is well known that intraprocedural microembolism occurs, it is not known if this embolic phenomenon continues in the postprocedural period. We investigated whether microemboli occur post-TAVR and whether we could determine any clinical, procedural, or echocardiographic predictors. Methods: We evaluated HITS in 51 consecutive patients undergoing unprotected TAVR with low-, intermediate-, or high-risk Society of Thoracic Surgeons score. Patients were excluded if they did not have temporal windows for insonation of the middle cerebral artery or if they were not willing to participate. Primary outcomes of HITS 24 hours post-TAVR were observed using a Philips iU22 TCD. TCD was performed at 3 time points (pre-, peri-, and post-TAVR) for each patient, before, during, and 24 hours postprocedure. Results: While no HITS were detected in any of the patients preoperatively, all patients had HITS during the procedure. Interestingly, 56.8% had HITS 24 hours post-TAVR. One patient with HITS post-TAVR had a stroke 48 hours after TAVR. Conclusion: We observed a high prevalence of microemboli 24 hours post-TAVR. None of the predictors for intraprocedural microembolism seemed to play an important role for post-TAVR microemboli.
RESUMEN
Background: Previous studies have shown that women with atrial fibrillation (AF) have a higher incidence of recurrence and non-pulmonary vein (non-PV) triggers. However, there remains an incomplete understanding of the impact of gender on AF ablation strategies and outcomes. Objective: The purpose of this study was to evaluate the impact of gender on AF ablation outcomes. Methods: We analyzed 1568 AF ablations in 1412 patients (34% female) performed at a single tertiary care center between January 2013 and July 2021. Patients were followed for at least 6 months (mean 34 months) for detection of AF recurrence, complications, and emergency department visits/hospitalizations. The effect was assessed by multivariate logistic regression analysis using propensity score matching (PSM). Results: Mean age was 64 years, and mean body mass index (BMI) was 31 kg/m2. Seventy-seven percent of patients underwent de novo ablations. Twenty-seven percent of patients had persistent AF, with a recurrence rate of 37%. There was no difference in AF recurrence when stratified by gender (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.92-1.43; P >.05) and age. After PSM gender 1:1 (criteria: age, type of AF, hypertension, diabetes mellitus, and BMI; n = 888 patients), there was no difference in AF recurrence or procedure-related complications. Having a history of persistent AF (HR 1.54; 95% CI 1.18-1.99; P = .001) predisposed to recurrence of AF. Persistent AF (HR 2.99; 95% CI 1.94-4.78; P <.001) and age >70 years (HR 1.03; 95% CI 1.02-1.05; P <.001) were associated with the need for additional substrate modification with no difference based on gender. Conclusion: There was no difference in overall safety or efficacy outcomes between genders after AF ablation.
RESUMEN
Background: There are few prospective studies assessing the benefits of rhythm control of atrial fibrillation (AF) in patients with heart failure and preserved ejection fraction (HFpEF), which accounts for 50% of all heart failure patients. Objective: Conduct a meta-analysis to assess the effects of rhythm control (ablation and/or antiarrhythmic medications) vs rate control on all-cause mortality in AF patients with HFpEF. Methods: Databases were searched for studies reporting the effect of rhythm control vs rate control on mortality in patients with HFpEF (Ovid MEDLINE, EMBASE, Scopus, Web of Science, Google Scholar, and EBSCO CINAHL). The search was not restricted to time or publication status. The primary endpoint was all-cause mortality. The minimum duration of follow-up required for inclusion was 1 year. Results: The literature search identified 1210 candidate studies; 5 studies and 16,825 patients were included. The study population had 57% men with a mean age of 71± 2.5 years. Rhythm control for AF was associated with lower all-cause mortality (odds ratio 0.735, 95% confidence interval 0.665-0.813; P < .001) as compared to rate control. Conclusion: Rhythm control for AF in patients with HFpEF was associated with decreased all-cause mortality.
RESUMEN
Protein kinases are attractive therapeutic targets because their dysregulation underlies many diseases, including cancer. The high conservation of the kinase domain and the evolution of drug resistance, however, pose major challenges to the development of specific kinase inhibitors. We recently discovered selective Src kinase inhibitors from a DNA-templated macrocycle library. Here, we reveal the structural basis for how these inhibitors retain activity against a disease-relevant, drug-resistant kinase mutant, while maintaining Src specificity. We find that these macrocycles display a degree of modularity: two of their three variable groups interact with sites on the kinase that confer selectivity, while the third group interacts with the universally conserved catalytic lysine and thereby retains the ability to inhibit the "gatekeeper" kinase mutant. We also show that these macrocycles inhibit migration of MDA-MB-231 breast tumor cells. Our findings establish intracellular kinase inhibition by peptidic macrocycles, and inform the development of potent and specific kinase inhibitors.
Asunto(s)
Compuestos Macrocíclicos/farmacología , Oligopéptidos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Compuestos Macrocíclicos/química , Modelos Moleculares , Estructura Molecular , Oligopéptidos/química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Familia-src Quinasas/metabolismoRESUMEN
The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase that is found in all metazoans, and is ubiquitously expressed in mammalian tissues. The Abl tyrosine kinase plays important roles in the regulation of mammalian cell physiology. Abl-like kinases have been identified in the genomes of unicellular choanoflagellates, the closest relatives to the Metazoa, and in related unicellular organisms. Here, we have carried out the first characterization of a premetazoan Abl kinase, MbAbl2, from the choanoflagellate Monosiga brevicollis. The enzyme possesses SH3, SH2, and kinase domains in a similar arrangement to its mammalian counterparts, and is an active tyrosine kinase. MbAbl2 lacks the N-terminal myristoylation and cap sequences that are critical regulators of mammalian Abl kinase activity, and we show that MbAbl2 is constitutively active. When expressed in mammalian cells, MbAbl2 strongly phosphorylates cellular proteins on tyrosine, and transforms cells much more potently than mammalian Abl kinase. Thus, MbAbl2 appears to lack the autoinhibitory mechanism that tightly constrains the activity of mammalian Abl kinases, suggesting that this regulatory apparatus arose more recently in metazoan evolution.
Asunto(s)
Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-abl/metabolismo , Secuencia de Aminoácidos , Animales , Coanoflagelados/enzimología , Coanoflagelados/genética , Evolución Molecular , Genes Protozoarios , Genes abl , Células HEK293 , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Células 3T3 NIH , Fosforilación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-abl/química , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de AminoácidoRESUMEN
Despite significant evidence to the contrary, the view that phosphatases are "nonspecific" still pervades the field. Systems biology approaches to defining how signal transduction pathways are integrated at the level of whole organisms also often downplay the contribution of phosphatases, defining them as "erasers" that serve merely to restore the system to its basal state. Here, we present a study that counteracts the idea of "nonspecific phosphatases." We have characterized two structurally similar and functionally related kinases, BRK and SRC, which are regulated by combinations of activating autophosphorylation and inhibitory C-terminal sites of tyrosine phosphorylation. We demonstrated specificity at the level of the kinases in that SRMS phosphorylated the C terminus of BRK, but not SRC; in contrast, CSK is the kinase responsible for C-terminal phosphorylation of SRC, but not BRK. For the phosphatases, we observed that RNAi-mediated suppression of PTP1B resulted in opposing effects on the activity of BRK and SRC and have defined the mechanisms underlying this specificity. PTP1B inhibited BRK by directly dephosphorylating the Tyr-342 autophosphorylation site. In contrast, PTP1B potentiated SRC activity, but not by dephosphorylating SRC itself directly; instead, PTP1B regulated the interaction between CBP/PAG and CSK. SRC associated with, and phosphorylated, the transmembrane protein CBP/PAG at Tyr-317, resulting in CSK recruitment. We identified PAG as a substrate of PTP1B, and dephosphorylation abolished recruitment of the inhibitory kinase CSK. Overall, these findings illustrate how the combinatorial effects of PTKs and PTPs may be integrated to regulate signaling, with both classes of enzymes displaying exquisite specificity.
Asunto(s)
Neoplasias de la Mama/enzimología , Proteínas de Neoplasias/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Familia-src Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Secuencias de Aminoácidos , Animales , Neoplasias de la Mama/genética , Proteína Tirosina Quinasa CSK , Femenino , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Familia-src Quinasas/química , Familia-src Quinasas/genéticaRESUMEN
Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties.
Asunto(s)
Aminas/farmacología , Diseño de Fármacos , Etanolaminas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Aminas/síntesis química , Aminas/química , Relación Dosis-Respuesta a Droga , Etanolaminas/síntesis química , Etanolaminas/química , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.