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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The current standard therapy for chronic hepatitis C (CHC) consists of a combination of pegylated IFN alpha (pegIFN␣) and ribavirin. It achieves a sustained viral clearance in only 50 -60% of patients. To learn more about molecular mechanisms underlying treatment failure, we investigated IFN-induced signaling in paired liver biopsies collected from CHC patients before and after administration of pegIFN␣. In patients with a rapid virological response to treatment, pegIFN␣ induced a strong up-regulation of IFN-stimulated genes (ISGs). As shown previously, nonresponders had high expression levels of ISGs before therapy. Analysis of posttreatment biopsies of these patients revealed that pegIFN␣ did not induce expression of ISGs above the pretreatment levels. In accordance with ISG expression data, phosphorylation, DNA binding, and nuclear localization of STAT1 indicated that the IFN signaling pathway in nonresponsive patients is preactivated and refractory to further stimulation. Some features characteristic of nonresponders were more accentuated in patients infected with HCV genotypes 1 and 4 compared with genotypes 2 and 3, providing a possible explanation for the poor response of the former group to therapy. Taken together with previous findings, our data support the concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway.Jak-STAT signaling ͉ liver ͉ viral hepatitis

Approximately 10% to 15% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in subtypes of sarcomas and astrocytomas, has rarely been reported in epithelial malignancies. However, the prevalence of ALT has not been thoroughly assessed across all cancer types. We therefore comprehensively surveyed the ALT phenotype in a broad range of human cancers. In total, two independent sets comprising 6110 primary tumors from 94 different cancer subtypes, 541 benign neoplasms, and 264 normal tissue samples were assessed by combined telomere-specific fluorescence in situ hybridization and immunofluorescence labeling for PML protein. Overall, ALT was observed in 3.73% (228/6110) of all tumor specimens, but was not observed in benign neoplasms or normal tissues. This is the first report of ALT in carcinomas arising from the bladder, cervix, endometrium, esophagus, gallbladder, kidney, liver, and lung. Additionally, this is the first report of ALT in medulloblastomas, oligodendrogliomas, meningiomas, schwannomas, and pediatric glioblastoma multiformes. Previous studies have shown associations between ALT status and prognosis in some tumor types; thus, further studies are warranted to assess the potential prognostic significance and unique biology of ALT-positive tumors. These findings may have therapeutic consequences, because ALT-positive cancers are predicted to be resistant to anti-telomerase therapies.

Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.

A B S T R A C T PurposeTo investigate the prognostic role of genomic gain for MET and epidermal growth factor receptor (EGFR) genes in surgically resected non-small-cell lung cancer (NSCLC). Patients and MethodsThis retrospective study included 447 NSCLC patients with available tumor tissue from primary lung tumor and survival data. EGFR and MET status was evaluated by fluorescent in situ hybridization (FISH) in tissue microarray sections. ResultsEGFR FISH results were obtained in 376 cases. EGFR gene amplification and high polysomy (EGFR FISHϩ) were observed in 10.4% and 32.4% of cases, respectively. EGFR FISH-positive patients had a nonsignificant shorter survival than EGFR FISH-negative patients (P ϭ .4). Activating EGFR mutations were detected in 9.7% of 144 stage I-II disease with no impact on survival. MET FISH analysis was performed in 435 cases. High MET gene copy number (mean Ն 5 copies/cell) was observed in 48 cases (METϩ, 11.1%), including 18 cases with true gene amplification (4.1%). METϩ status was associated with advanced stage (P ϭ .01), with grade 3 (P ϭ .016) and with EGFR FISHϩ result (P Ͻ .0001). No patient with activating EGFR mutation resulted METϩ. In the whole population, MET-positive patients had shorter survival than MET-negative patients (P ϭ .005). Multivariable model confirmed that MET-negative patients had a significant reduction in the risk of death than MET-positive patients (hazard ratio, 0.66; P ϭ .04). ConclusionMET increased gene copy number is an independent negative prognostic factor in surgically resected NSCLC. EGFR gene gain does not impact survival after resection.