RESUMEN
The Integrated Stress Response (ISR) is an essential homeostatic signaling network that controls the cell's biosynthetic capacity. Four ISR sensor kinases detect multiple stressors and relay this information to downstream effectors by phosphorylating a common node: the alpha subunit of the eukaryotic initiation factor eIF2. As a result, general protein synthesis is repressed while select transcripts are preferentially translated, thus remodeling the proteome and transcriptome. Mounting evidence supports a view of the ISR as a dynamic signaling network with multiple modulators and feedback regulatory features that vary across cell and tissue types. Here, we discuss updated views on ISR sensor kinase mechanisms, how the subcellular localization of ISR components impacts signaling, and highlight ISR signaling differences across cells and tissues. Finally, we consider crosstalk between the ISR and other signaling pathways as a determinant of cell health.
RESUMEN
BACKGROUND: Sudden cardiac death (SCD) after myocardial infarction (MI) is mostly caused by ventricular arrhythmias. As an arrhythmogenic substrate, infarct border zone (BZ) results in adverse electrophysiological properties. PURPOSE: To explore myocardial scar entropy (BZ, infarct core [IC], BZ + IC, expressed as IBZ) and to investigate their prognostic value combined with left ventricular (LV) strain parameters (global radial strain [GRS], global circumferential strain [GCS], global longitudinal strain [GLS]) in patients after MI. STUDY TYPE: Prospective. POPULATION: One hundred fifty-seven patients with previous MI, 26 in primary endpoint events group, 30 in secondary endpoint events group, and 43 in total endpoint events (primary + secondary). FIELD STRENGTH/SEQUENCE: 3.0 T/cine, late gadolinium enhancement (LGE). ASSESSMENT: Three-dimensional feature tracking analysis for three directions (radial, circumferential, and longitudinal), entropy and extent of infarct-related areas (BZ, IC, and IBZ), LV functional parameters. STATISTICAL TESTS: Student t-test, Mann-Whitney U, Spearman or Pearson rank correlation analysis, receiver operating characteristic curve, Kaplan-Meier event-free survival curve, and Cox proportional hazards regression were used. Results were considered statistically significant at P < 0.05. RESULTS: LGE extent and entropy of all infarct-related areas (BZ, IC, and IBZ) were significantly higher and GLS were lower in patients with endpoint events than those without. BZ and IBC entropy were further associated with LV strain in after-MI patients. In the univariable and multivariable Cox analysis, BZ entropy manifested independent association with primary endpoint events (hazard ratio: 3.859; 95% confidence interval: 2.136-6.974). Primary and secondary endpoint events prognostic value was improved by the addition of BZ entropy and GLS to the LVEF model (Delong test, Z = 2.729 for primary endpoint events; Z = 3.230 for secondary endpoint events). DATA CONCLUSION: Entropy of myocardial fibrosis was associated with LV strain. Assessment of BZ entropy and GLS improved prognostic value for endpoint events of LVEF. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.
Asunto(s)
Cicatriz , Infarto del Miocardio , Humanos , Pronóstico , Cicatriz/diagnóstico por imagen , Medios de Contraste , Estudios Prospectivos , Imagen por Resonancia Cinemagnética/métodos , Gadolinio , Imagen por Resonancia Magnética/métodos , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico por imagen , Arritmias Cardíacas , Función Ventricular Izquierda , Valor Predictivo de las Pruebas , Volumen SistólicoRESUMEN
OBJECTIVE: There is a need for prognostic biomarkers for risk assessment of small abdominal aortic aneurysm (AAA). Since CT textural analysis of tissue is a recognized feature of adverse biology and patient outcome in other diseases, we investigated it as a possible biomarker in small AAA. METHODS: Fifty consecutive patients (46-men, 4-woman, median-age 75 y, range 56-85) with small AAA (3-5.5 cm) under surveillance undergoing serial ultrasound were prospectively recruited and assessed at baseline with CT texture analysis (CTTA) and 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET). We followed forty patients (36-men, 4-woman, median-age=74 y, range 60-85, participation rate=80% for 1 year. For each axial image, CTTA using the filtration-histogram technique was carried out using a software algorithm that selectively extracts texture features of different coarseness (fine, medium and coarse) and intensity variation. Standard-deviation (SD) and kurtosis (K) at each feature-scale were measured. The maximum standardized uptake value (SUVmax) of 18F-FDG in each axial image of the AAA was also measured with corrections for blood pool 18F-FDG activity to assess AAA metabolic activity. Specificity, sensitivity, and c-statistics were calculated with 95% confidence intervals for prediction of significant AAA expansion (≥2 mm) by CTTA measures before and after adjusting for clinical variables. RESULTS: The median aneurysm expansion at 12 months was 2.0 mm, (IQR 0.0-4.0). Coarse texture SD correlated inversely with AAA SUVmax (rs=-0.456, P=0.003). Medium coarse texture K correlated significantly with future AAA expansion adjusted for baseline size (rs=0.343, P=0.030). AAA SUVmax correlated inversely with AAA expansion corrected for baseline size (rs=-0.383, P=0.015). Medium texture K was a strong predictor of significant AAA expansion (area under the Receiver-operating-characteristic (ROC) curve was 0.813) after adjusting for clinical variables. CONCLUSION: We have shown evidence that CT signal heterogeneity measurements in small aortic aneurysm may be considered as a risk stratification tool in future prospective studies to identify aneurysms at risk of significant expansion. CT textural data appears to reflect AAA metabolism measured by PET.