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BaCKgRoUND aND aIMS: Older patients with obesity/ type II diabetes mellitus frequently present with advanced NASH. Whether this is due to specific molecular pathways that accelerate fibrosis during aging is unknown. Activation of the Src homology 2 domain-containing collagen-related (Shc) proteins and redox stress have been recognized in aging; however, their link to NASH has not been explored. appRoaCH aND ReSUltS: Shc expression increased in livers of older patients with NASH, as assessed by real time quantitative PCR (RT-qPCR) or western blots. Fibrosis, Shc expression, markers of senescence, and nicotinamide adenine dinucleotide phosphate, reduced form oxidases (NOXs) were studied in young/old mice on fast food diet (FFD). To inhibit Shc in old mice, lentiviral (LV)-short hairpin Shc versus control-LV were used during FFD. For hepatocyte-specific effects, floxed (fl/fl) Shc mice on FFD were injected with adeno-associated virus 8-thyroxine-binding globulin-Cre-recombinase versus control. Fibrosis was accelerated in older mice on FFD, and Shc inhibition by LV in older mice or hepatocyte-specific deletion resulted in significantly improved inflammation, reduction in senescence markers in older mice, lipid peroxidation, and fibrosis. To study NOX2 activation, the interaction of p47 phox (NOX2 regulatory subunit) and p52Shc was evaluated by proximity ligation and coimmunoprecipitations. Palmitate-induced p52Shc binding to p47 phox , activating the NOX2 complex, more so at an older age. Kinetics of binding were assessed in Src homology 2 domain (SH2) or phosphotyrosine-binding (PTB) domain deletion mutants by biolayer interferometry, revealing the role of SH2 and the PTB domains. Lastly, an in silico model of p52Shc/p47 phox interaction using RosettaDock was generated. CoNClUSIoNS: Accelerated fibrosis in the aged is modulated by p52Shc/NOX2. We show a pathway for direct activation of the phagocytic NOX2 in hepatocytes by p52Shc binding and activating the p47 phox subunit that results in redox stress and accelerated fibrosis in the aged. (Hepatology 2020;72:1204-1218). N ASH and associated cirrhosis are the leading causes of liver-related mortality in the United States and worldwide. (1) The incidence of NASH rises strikingly with age, contributing significantly to elder mortality. (2) Older patients are often excluded from liver transplantation because of comorbidities and the age limit for transplantation; therefore, a significant increase in NASH-related mortality is expected because NASH has no approved medical treatment. Most of the preclinical data in NASH/fibrosis research is derived from experiments employing young mice. In clinical trials, however, the target population is usually middle-aged or elderly. To

Type 2 diabetes mellitus (T2DM) is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development, and increased stiffness is known to promote HCC progression in cirrhotic conditions. T2DM is characterized by an accumulation of advanced glycation end products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here, we find that in patients and animal models AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signaling promote HCC induction, while inhibiting AGEs production, reconstituting the clearance receptor AGER1, or breaking AGE-mediated collagen crosslinks reduce viscoelasticity and HCC growth. Matrix analysis and computational modeling demonstrate that lower interconnectivity of AGEs-bundled collagen matrix, marked by shorter fiber length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through integrin β1–Tensin 1–YAP mechanotransduction pathway. These results reveal for the first time that AGEs-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can drive cancer progression in vivo, independent of stiffness.

Objectives: Type II endoleaks (T2EL) are common after endovascular repair of abdominal aortic aneurysms. Although optimal technique and material to treat T2EL are ill-defined, embolization with ethylene vinyl alcohol copolymer (Onyx) has been suggested as an effective strategy. Owing to limited data supporting use and high cost, we sought to analyze outcomes of Onyx embolization for T2EL.Methods: We performed a retrospective review of patients treated for T2EL using Onyx embolization agent from 2009 to 2018. All pre-and post-Onyx intervention computed tomography scans were analyzed for diameter and volume changes with three-dimensional reconstruction software. The primary outcomes were change in maximum abdominal aortic aneurysm diameter and volume. Secondary outcomes included additional interventions, rupture, and mortality.Results: We identified 85 patients (86% men; mean age, 77.6 6 5.1 years) who underwent 112 Onyx interventions. Average time to first Onyx intervention after endovascular repair of abdominal aortic aneurysm was 3.3 6 2.6 years, and the average sac growth was 6.3 6 6.7 mm. Patients underwent 1.3 Onyx interventions using a mean of 4.9 6 4.7 mL for treatment. Three complications occurred (Onyx extravasation, colon ischemia, and access site hematoma). Mean follow-up was 2.5 6 2.1 years after initial Onyx treatment. At the most recent follow-up, sac shrinkage of greater than 5 mm was seen in 19% and sac stabilization was seen in 47%. Sac growth of greater than 5 mm was seen in 34% of patients following the first Onyx intervention. Results were similar when sac volume was analyzed. Eleven percent of the patients required additional interventions to treat separate endoleaks. Four patients experienced a rupture (three had active T1ELs). Rupture-free survival was 95% at 5 years, and overall survival was 58% at 5 years.Conclusions: Onyx for embolization of T2EL resulted in sac shrinkage or stabilization in 66% of patients. 34% had continued sac growth despite intervention. Given its high cost and similar outcomes to other embolization strategies in the literature, Onyx may not be a cost-effective method for T2EL management.Objectives: Abdominal aortic aneurysms (AAA) after endovascular aortic repair (EVAR), are routinely monitored for change in sac size and the presence of endoleaks. Recent data suggest that lack of sac regression at one year is associated with long-term mortality. However, sac behavior may change with extended follow-up. The aim of this study was to evaluate sac size change after EVAR over an extended period of time, and study association of sac behavior with mortality.Methods: Clinical data and imaging of consecutive patients undergoing EVAR for infrarenal AAA between 2000 and 2018 were reviewed retrospectively. Those with saccular and isolated internal iliac artery aneurysm indications were excluded. Maximal aneurysm diameter on axial imaging was measured on computed tomography angiography preoperatively, followed by postoperative intervals of 1 to 6 months, 1 year and 3 years. Patie...