RESUMO
Endoreplication, duplication of the nuclear genome without cell division, occurs in disease to drive morphologic growth, cell fate, and function. Despite its criticality, the metabolic underpinnings of disease-induced endoreplication and its link to morphologic growth are unknown. Heart disease is characterized by endoreplication preceding cardiac hypertrophy. We identify ATP synthase as a central control node and determinant of cardiac endoreplication and hypertrophy by rechanneling free mitochondrial ADP to methylenetetrahydrofolate dehydrogenase 1 L (MTHFD1L), a mitochondrial localized rate-limiting enzyme of formate and de novo nucleotide biosynthesis. Concomitant activation of the adenosine monophosphateactivated protein kinase (AMPK)retinoblastoma protein (Rb)-E2F axis co-opts metabolic products of MTHFD1L function to support DNA endoreplication and pathologic growth. Gain- and loss-of-function studies in genetic and surgical mouse heart disease models and correlation in individuals confirm direct coupling of deregulated energetics with endoreplication and pathologic overgrowth. Together, we identify cardiometabolic endoreplication as a hitherto unknown mechanism dictating pathologic growth progression in the failing myocardium.
Assuntos
Endorreduplicação , Cardiopatias , Animais , Ciclo Celular , Divisão Celular , Replicação do DNA , CamundongosRESUMO
BACKGROUND: This quantitative meta-analysis was conducted to provide an indirect comparison of the diagnostic value of computed tomography (CT) with positron emission tomography (PET)/CT for differentiating benign and malignant solitary pulmonary nodules (SPNs). METHODS: PubMed, Embase, and the Cochrane Library were searched to identify eligible studies throughout November 2018, which differentiated benign and malignant SPNs using CT or PET/CT. The summary sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) were calculated using bivariate generalized linear mixed model and random-effects model. The diagnostic value of CT with PET/CT was indirectly evaluated using the ratio for diagnostic parameters. RESULTS: The sensitivity, specificity, PLR, NLR, DOR, and AUC for CT were 0.94 [95% confidence interval (CI): 0.87-0.97], 0.73 (95% CI: 0.64-0.80), 3.45 (95% CI: 2.60-4.58), 0.09 (95% CI: 0.04-0.17), 32.01 (95% CI: 15.10-67.86), and 0.89 (95% CI: 0.86-0.91), respectively. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC for PET/CT were 0.89 (95% CI: 0.85-0.92), 0.78 (95% CI: 0.66-0.86), 3.97 (95% CI: 2.57-6.13), 0.15 (95% CI: 0.10-0.20), 24.04 (95% CI: 12.71-45.48), and 0.91 (95% CI: 0.89-0.94), respectively. No significant differences were observed between CT and PET/CT for sensitivity, specificity, PLR, NLR, DOR, and AUC. CONCLUSIONS: This study used both CT and PET/CT with a moderate-to-high diagnostic value for differentiating benign and malignant SPNs and showed no significant differences in diagnostic parameters between CT and PET/CT.