RESUMEN
BACKGROUND: Biomarkers of atrial dysfunction or "cardiopathy" are associated with embolic stroke risk. However, it is unclear if this risk is mediated by undiagnosed paroxysmal atrial fibrillation or flutter (AF). We aim to determine whether atrial cardiopathy biomarkers predict AF on continuous heart-rhythm monitoring after embolic stroke of undetermined source (ESUS). METHODS: This was a single-center retrospective study including all patients with ESUS undergoing 30 days of ambulatory heart-rhythm monitoring to look for AF between January 1, 2013 and December 31, 2015. We reviewed medical records for clinical, radiographic, and cardiac variables. The primary outcome was a new diagnosis of AF detected during heart-rhythm monitoring. The primary predictors were atrial biomarkers: left atrial diameter on echocardiography, P-wave terminal force in electrocardiogram (ECG) lead V1, and P wave - R wave (PR) interval on ECG. A multiple logistic regression model was used to assess the relationship between atrial biomarkers and AF detection. RESULTS: Among 196 eligible patients, 23 (11.7%) were diagnosed with AF. In unadjusted analyses, patients with AF were older (72.4 years versus 61.4 years, P < .001) and had larger left atrial diameter (39.2 mm versus 35.7 mm, P = .03). In a multivariable model, the only predictor of AF was age ≥ 60 years (odds ratio, 3.0; 95% CI, 1.06-8.5; P = .04). CONCLUSION: Atrial biomarkers were weakly associated with AF after ESUS. This suggests that previously reported associations between these markers and stroke may reflect independent cardiac pathways leading to stroke. Prospective studies are needed to investigate these mechanisms.
Asunto(s)
Atención Ambulatoria/métodos , Fibrilación Atrial/complicaciones , Aleteo Atrial/complicaciones , Función del Atrio Derecho , Electrocardiografía Ambulatoria , Atrios Cardíacos/fisiopatología , Frecuencia Cardíaca , Embolia Intracraneal/etiología , Accidente Cerebrovascular/etiología , Telemetría/métodos , Función Ventricular Izquierda , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/fisiopatología , Aleteo Atrial/diagnóstico , Aleteo Atrial/fisiopatología , Ecocardiografía , Femenino , Atrios Cardíacos/diagnóstico por imagen , Humanos , Embolia Intracraneal/diagnóstico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnósticoRESUMEN
PURPOSE: Mantle cell lymphoma (MCL) has one of the poorest prognoses of the non-Hodgkin's lymphomas, and novel therapeutic approaches are needed. We wished to determine whether Nutlin-3, a novel small-molecule murine double minute 2 (MDM2) antagonist that efficiently activates TP53, might be effective in inducing cell death in MCL. EXPERIMENTAL DESIGN: MCL cell lines with known TP53 status were treated with Nutlin-3, and biological and biochemical consequences were studied. Synergies with the prototypic genotoxic agent doxorubicin and the novel proteasome inhibitor bortezomib were assessed. RESULTS: Nutlin-3 resulted in a reduction in cell proliferation/viability (IC50 < 10 micromol/L), an increase in the apoptotic fraction, and cell cycle arrest in wild-type (wt) TP53 Z-138 and Granta 519 cells. These effects were accompanied by TP53 accumulation and induction of TP53-dependent proteins p21, MDM2, Puma, and Noxa. Cell cycle arrest was characterized by suppression of S phase and an increase in the G0-G1 and G2-M fractions and accompanied by suppression of total and phosphorylated retinoblastoma protein and a decrease in G2-M-associated proteins cyclin B and CDC2. The combination of Nutlin-3 with doxorubicin or bortezomib was synergistic in wt-TP53 MCL cells. Nutlin-3 also induced cell cycle arrest and reduced cell viability in the mutant TP53 MINO cells but at a significantly higher IC50 (22.5 micromol/L). These effects were associated with induction of the TP53 homologue p73, slight increases in p21 and Noxa, and caspase activation. Nutlin-3 and bortezomib synergistically inhibited cell growth of MINO. CONCLUSION: These findings suggest that the MDM2 antagonist Nutlin-3 may be an effective agent in the treatment of MCL with or without wt-TP53.
Asunto(s)
Imidazoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Ácidos Borónicos/administración & dosificación , Bortezomib , Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Humanos , Imidazoles/administración & dosificación , Linfoma de Células del Manto/patología , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Fosfohidrolasa PTEN/metabolismo , Piperazinas/administración & dosificación , Proteínas Proto-Oncogénicas/metabolismo , Pirazinas/administración & dosificación , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
To assess the role of interferon regulatory factor (IRF) 8 in B-cell development and lymphomagenesis, we studied its expression in reactive lymphoid tissues, its relationship to other B-cell transcription factors, and its expression in a series of 232 B-cell tumors and 30 cell lines representing a variety of B-cell developmental stages. We found that although IRF8 was detectable in most reactive B-cells, its expression levels differed with developmental stage. Germinal center B cells contained the highest levels of IRF8, with lower levels seen in mantle and marginal zone B cells and none in plasma cells. IRF8 was coexpressed with PAX-5, Pu.1, and B-cell lymphoma (BCL)-6, and similar to BCL-6, was absent from the small population of IRF4-positive germinal center B cells thought to be committed to postgerminal center developmental programs. Similarly, IRF8 was most strongly expressed in lymphomas of germinal center origin with lower levels present in mantle cell lymphomas, chronic lymphocytic leukemia, and marginal zone lymphomas, and no expression observed in plasmacytic/plasmablastic neoplasms. The reciprocal expression pattern with IRF4 in reactive tissues was generally maintained in lymphomas with some exceptions. These results suggest an important role for IRF8 during germinal center B-cell development and in related lymphomas, and provide a new diagnostic marker helpful in distinguishing B-cell non-Hodgkin lymphoma subtypes.