IntroductionNAFLD is characterized by an excessive accumulation of fat in the liver. The most severe form of NAFLD, NASH, often progresses to liver cancer (1-3). Tracking with the increasing prevalence of general obesity, 30% of the US population is now estimated to have NAFLD, and 25% of these individuals will develop NASH (1, 3). Currently, there are no effective therapies to prevent the incidence and progression of NAFLD or NASH (4). This makes clarification of the detailed mechanisms of disease progression using appropriate animal models that much more urgent.Insulin signaling begins with the binding of insulin to the insulin receptor (IR). This then phosphorylates insulin receptor substrates (IRSs) and subsequently triggers the recruitment of PI3K and the activation of AKT (5-9). Deletion of IRS1 and IRS2 in the mouse liver reduces AKT activity and gives rise to insulin resistance (10). Excessive AKT activation leads to the development of NAFLD by promoting the maturation of the transcription factor SREBP1c (11,12). In its mature form, SREBP1c contributes to the induction of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), which are key enzymes in de novo lipogenesis (13). Phosphatase and tensin homolog (PTEN) is a negative regulator of AKT signaling, and several human cancers are associated with mutations or downregulation of the PTEN gene (14-16). Liver-specific PTEN-knockout mice progressively develop NAFLD, NASH, and HCC (17, 18) as a result of increased AKT signaling (19).The Hippo signaling pathway has been implicated in the suppression of tissue regeneration, the proliferation of stem cells, and the development of cancer by inhibiting the oncogenic activity of the transcriptional coactivators YAP and TAZ (20,21). In mice, liverspecific knockout of the Hippo pathway components MST1/2, SAV1, or NF2 induces the expansion of hepatic progenitor cells via YAP/TAZ activation and leads eventually to the development of liver cancer (HCC, cholangiocarcinoma [CC], or both) (22)(23)(24)(25). Despite its importance in tumorigenesis, the role of Hippo signaling in the metabolic dysregulation that precedes the development of liver cancer remains unclear.Previous studies have suggested that YAP regulates components of the AKT pathway (i.e., PI3K, PTEN, and AKT) and that the Drosophila Hippo ortholog MST1 binds and inhibits AKT directly (26)(27)(28)(29). Increased YAP expression in human liver tumors is associated with high levels of p- AKT (30,31). This suggests that crosstalk between the Hippo and AKT pathways may be important in the maintenance of functional liver homeostasis. The molecular coordination of these 2 pathways in liver tumorigenesis, however, has not been revealed. Using several mouse models, we now show Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transc...

The malignancy rate of AUS/FLUS nodules in our study cohort was higher than previously reported. Nodules with suspicious features on ultrasound had a higher malignancy rate than did those with indeterminate features on ultrasound. The malignancy rate differed according to histologic subcategory; therefore, management of AUS/FLUS nodules should be tailored according to histologic subcategory.

In this study, we evaluated the association between thyroid echogenicity on ultrasonography (US) and thyroid function in pediatric and adolescent Hashimoto's thyroiditis (HT) patients. In 86 pediatric and adolescent HT patients, the association between echogenicity and thyroid function and microsomal autoantibody status was evaluated. Among patients with overt hypothyroidism, 89.2% (33/37) showed a US grade of 3 or 4. All of the patients at grade 4 presented with overt hypothyroidism. In contrast, 97.8% (44/49) of the patients with subclinical hypothyroidism or euthyroidism showed grades 1 or 2. Patients with increased thyroid-stimulating hormone titer also tended to have increased US grades ( P < .001). In contrast, free thyroxine levels were significantly decreased with increasing US grade ( P < .001). In conclusion, patients with higher US grades had decreased thyroid function ( P < .001).