Citations

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4–dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation–dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1 + LSECs promote the recruitment of CD63 + monocyte–derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

ObjectivesTo prospectively evaluate the diagnostic performance of 3‐dimensional (3D) shear wave elastography (SWE) for assessing thyroid nodules.MethodsA total of 176 surgically or cytologically confirmed thyroid nodules (63 malignant and 113 benign) in 176 patients who had undergone conventional ultrasound (US), 2‐dimensional (2D) SWE, and 3D SWE examinations were included in this study. Quantitative elasticity values (mean elasticity, maximum elasticity, and standard deviation of elasticity of a large region of interest and mean elasticity of a 2‐mm region of interest) were measured on 2D and 3D SWE. Diagnostic performances of conventional US, 2D SWE, and 3D SWE were assessed. The role of 2D and 3D SWE in reducing unnecessary fine‐needle aspiration (FNA) for nodules with low suspicion was also evaluated.ResultsThe diagnostic performances in terms of the area under the receiver operating characteristic curve were 0.612 for conventional US, 0.836 for 2D SWE (P < .001 in comparison with conventional US), and 0.839 for 3D SWE (P < .001 in comparison with conventional US). The mean elasticity achieved the highest diagnostic performance in 2D SWE, whereas the standard deviation of elasticity achieved the highest performance in 3D SWE, although no significant difference was found between them (P > .05). Three‐dimensional SWE increased the specificity in comparison with 2D SWE (88.5% versus 82.3%; P = .039). For the 37 nodules with low suspicion on conventional US imaging, 2D SWE was able to avoid unnecessary FNA in 77.1% (27 of 35) of benign nodules, and 3D SWE further increased the number to 88.6% (31 of 35).ConclusionsThree‐dimensional SWE is a useful tool for predicting thyroid nodule malignancy and reducing unnecessary FNA procedures in thyroid nodules with low suspicion of malignancy.