Liver FoxO1 overexpression is positively associated with the degree of liver injury in cirrhotic patients.

Objectives: Chronic liver disease and related complications, cirrhosis and hepatocellular carcinoma, are associated with high mortality. Curative treatments, partial hepatectomy or liver transplantation, have limited applicability in patients with cirrhosis due to the poor liver regenerative capacity. Thus, we need to find new diagnostic and therapeutic alternatives, to block the disease progression and to improve the survival of patients. In this context, preclinical studies have demonstrated the key role of the protein kinase B (Akt) in liver dysfunction, but the status of Akt and its targets in patients with chronic hepatopathy remains unknown. Aims: To determine the activation status of the Akt pathway and their association with liver functionality in cirrhotic patients. Methods: This retrospective study includes liver tissue samples from 36 hepatectomized patients with (n=27) and without (n=9) cirrhosis. Multiplex analysis of proteins involved in the Akt/mTOR pathway was performed using a Luminex panel and Western blot. Conventional liver function tests were determined in serum before resection surgery. Results: Akt and forkhead box protein O1 (FoxO1) are overexpressed in the liver of cirrhotic patients: (2.1 vs. 1.0 densitometric relative units (DRU); p<0.01, and 9.5 vs. 4.4 DRU; p<0.01, respectively). FoxO1 showed the best correlation with markers of liver injury (aspartate aminotransferase (ASAT): r=0.51, p<0.05; alanine aminotransferase (ALAT): r=0.49, p<0.05), and was the only enzyme in the Akt pathway identified as an independent predictor of ASAT and ALAT levels. Conclusions: The intrahepatic expression of FoxO1 could have clinical utility as a potential prognostic marker for patients with advanced liver disease.

Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome.

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and pan-chromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition.

BACKGROUND & AIMS: Studies in experimental models of cirrhosis showed that anti-angiogenic treatments may be effective for the treatment of liver fibrosis. In this context, angiopoietins are potential therapeutic targets as they are involved in the maintenance and stabilization of newly formed blood vessels. In addition, angiopoietin-2 is expressed in fibrotic livers and its inhibition in tumours results in vessel stability. Therefore, our study was aimed to assess the therapeutic utility of inhibiting angiopoietin-2. METHODS: Circulating levels of angiopoietin-1 and angiopoietin-2 were quantified by ELISA in CCl4 -treated rats and in patients with cirrhosis. In vivo blockade of angiopoietin-2 in rats with liver fibrosis was performed with a chemically programmed antibody, CVX-060. RESULTS: High levels of angiopoietin-2 were found in the systemic and suprahepatic circulation of cirrhotic patients and the ratio angiopoietin-1/angiopoietin-2 inversely correlated with prognostic models for alcoholic liver disease. Chronic treatment of CCl4 -treated rats with CVX-060 was associated with a significant decrease in inflammatory infiltrate, normalization of the hepatic microvasculature and reduction in VCAM-1 vascular expression. The anti-angiopoietin-2 treatment was also associated with less liver fibrosis and with lower levels of circulating transaminases. CVX-060 treatment was not associated with either vascular pruning in healthy tissue or compensatory overexpression of VEGF. CONCLUSIONS: Inhibition of angiopoietin-2 is an effective and safe treatment for liver fibrosis in CCl4 -treated rats, acting mainly through the induction of vessel normalization and the attenuation of hepatic inflammatory infiltrate. Therefore, inhibition of angiopoietin-2 offers a therapeutic alternative for liver fibrosis.