Dysregulation of mRNA translation is a frequent feature of neoplasia. Many oncogenes and tumour suppressors affect the translation machinery, making aberrant translation a widespread characteristic of tumour cells, independent of the genetic make-up of the cancer. Therefore, therapeutic agents that target components of the protein synthesis apparatus hold promise as novel anticancer drugs that can overcome intra-tumour heterogeneity. In this Review, we discuss the role of translation in cancer, with a particular focus on the eIF4F (eukaryotic translation initiation factor 4F) complex, and provide an overview of recent efforts aiming to 'translate' these results to the clinic.

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The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non-US Food and Drug Administration-approved, bovine-derived, gelatin-based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin-based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340-580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56-1.74 mmol/L) and produced bile (61 mL; 14-146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP-preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1-3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1-1.56] versus 1.1 [1-1.3]; P = 0.5) and bilirubin (1.5; 1-7.7 mg/dL versus 2.78; 0.4-15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0-8 versus 0-23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8-17 versus 7-89 days; P = 0.23). Major complications (Dindo-Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration-approved Steen solution will avoid a potential regulatory barrier in North America. Liver Transplantation 22 1501-1508 2016 AASLD.

Active-site mTOR inhibitors (asTORi) hold great promise for targeting dysregulated mTOR signaling in cancer. Because of the multifaceted nature of mTORC1 signaling, identification of reliable biomarkers for the sensitivity of tumors to asTORi is imperative for their clinical implementation. Here, we show that cancer cells acquire resistance to asTORi by downregulating eukaryotic translation initiation factor (eIF4E)-binding proteins (4E-BPs-EIF4EBP1, EIF4EBP2). Loss of 4E-BPs or overexpression of eIF4E renders neoplastic growth and translation of tumor-promoting mRNAs refractory to mTOR inhibition. Conversely, moderate depletion of eIF4E augments the anti-neoplastic effects of asTORi. The anti-proliferative effect of asTORi in vitro and in vivo is therefore significantly influenced by perturbations in eIF4E/4E-BP stoichiometry, whereby an increase in the eIF4E/4E-BP ratio dramatically limits the sensitivity of cancer cells to asTORi. We propose that the eIF4E/4E-BP ratio, rather than their individual protein levels or solely their phosphorylation status, should be considered as a paramount predictive marker for forecasting the clinical therapeutic response to mTOR inhibitors. Cancer Res; 72(24); 6468-76. Ó2012 AACR.

Machine learning (ML) utilizes artificial intelligence to generate predictive models efficiently and more effectively than conventional methods through detection of hidden patterns within large data sets. With this in mind, there are several areas within hepatology where these methods can be applied. In this review, we examine the literature pertaining to machine learning in hepatology and liver transplant medicine. We provide an overview of the strengths and limitations of ML tools and their potential applications to both clinical and molecular data in hepatology. ML has been applied to various types of data in liver disease research, including clinical, demographic, molecular, radiological, and pathological data. We anticipate that use of ML tools to generate predictive algorithms will change the face of clinical practice in hepatology and transplantation. This review will provide readers with the opportunity to learn about the ML tools available and potential applications to questions of interest in hepatology.

The mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical role in cellular metabolism, growth and proliferation, and has been evaluated as a target for therapy in various malignancies. The mTOR pathway is a major tumor-initiating pathway in hepatocellular carcinoma, with upregulation seen in up to 50% of (HCC) tumors. Metformin, which represses mTOR signaling by activating AMPK, has been shown to decrease liver carcinogenesis in population studies. mTOR inhibitors such as everolimus have been evaluated as adjunctive chemotherapy with some success, although efficacy has been limited by the lack of complete mTOR pathway inhibition. The active site mTOR inhibitors hold greater promise, given that they offer complete mTOR suppression. There is also evidence of mTOR pathway activation in cholangiocarcinoma, although its biological significance in initiating and promoting tumor progression remains ambiguous. This review article provides an overview of the complex biochemistry behind the mTOR pathway and its role in carcinogenesis, especially as it pertains to hepatic malignancies.

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Nonalcoholic fatty liver disease (NAFLD) can occur de novo in patients undergoing liver transplantation (LT) for indications other than NAFLD, and it has been increasingly recognized as a complication in the post‐LT setting. This study aims to better characterize de novo NAFLD after LT by identifying risk factors for its development, describing incidence and extent of fibrosis, assessing the diagnostic utility of noninvasive serum fibrosis algorithms, and comparing survival to those without NAFLD. This was a retrospective single‐center analysis of de novo NAFLD in a post‐LT cohort. Those whose primary indication for LT was nonalcoholic steatohepatitis (NASH) were excluded. Risk factors were analyzed by univariate and multivariate analyses. De novo NAFLD and fibrosis were assessed on posttransplant liver biopsies, and noninvasive fibrosis scores were calculated from concomitant blood tests. After applying the exclusion criteria, 430 for‐cause post‐LT biopsies were evaluated; 33.3% (n = 143) had evidence of de novo steatosis and/or NASH at a median of 3.0 years after transplant. On multivariate analysis, body mass index (BMI; odds ratio [OR], 1.12; P < 0.001), diabetes mellitus (OR, 3.01; P = 0.002), hepatitis C virus (OR, 4.61; P < 0.001), weight gain (OR, 1.03; P = 0.007), and sirolimus use (OR, 3.11; P = 0.02) were predictive of de novo NAFLD after LT. Significant fibrosis (≥F2) was present in almost 40% of the cohort. Noninvasive serum fibrosis scores were not useful diagnostic tests. There was no significant difference in the short‐term or longterm survival of patients who developed de novo NAFLD. In conclusion, diabetes, BMI, weight gain after LT, and sirolimus‐based immunosuppression, in keeping with insulin resistance, were the only modifiable factors associated with development of de novo NAFLD. A significant proportion of patients with de novo NAFLD had fibrosis and given the limited utility of noninvasive serum fibrosis algorithms, alternative noninvasive tools are required to screen for fibrosis in this population. There was no significant difference in the short‐term or longterm survival of patients who developed de novo NAFLD.