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INTRODUCTION: The anterior approach (AA), whether or not associated with the liver hanging maneuver (LHM), has been advocated to improve survival and postoperative outcomes in HCC patients undergoing major liver resection. This systematic review and meta-analysis of randomized controlled trials aims to explore intra/perioperative and long-term survival outcomes of AA ± LHM compared to CA regardless of tumor histology. METHODS: The study was conducted according to the Cochrane recommendations searching the PubMed, Scopus, and EMBASE databases until January 27, 2024 (PROSPERO ID: CRD42024507060). Only English-language RCTs were included. The primary outcome, expressed as hazard ratio (HR) and 95 % confidence intervals (CI), was the overall and disease-free survival. Random effects models were developed to assess heterogeneity. The risk of bias in included studies was assessed with the RoB 2 tool. The certainty of evidence was assessed following GRADE recommendations. RESULTS: Six RCTs, for a total of 736 patients were included. A significant survival benefit was highlighted for patients undergoing AA ± LHM in terms of overall (HR: 0.65; 95 % CI: 0.62-0.68; p < 0.0001) and disease-free survival (HR: 0.65; 95 % CI: 0.63-0.68; p < 0.0001). AA ± LHM was associated with a longer duration of surgery (WMD: 29.5 min; 95 % CI: 17.72-41.27; p = 0.004), and a lower intraoperative blood loss (WMD: 24.3; 95 % CI: 31.1 to -17.5; p = 0.0014). No difference was detected for other postoperative outcomes. The risk of bias was low. CONCLUSION: AA ± LHM provides better survival outcomes compared to CA. Furthermore, AA ± LHM is related to a modest reduction in intraoperative blood loss, at the price of a slightly longer duration of hepatectomy. Regarding other postoperative outcomes, the two techniques appear comparable.
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The Organic Cation Transporter Novel 1 (OCTN1), also known as SLC22A4, is widely expressed in various human tissues, and involved in numerous physiological and pathological processes remains. It facilitates the transport of organic cations, zwitterions, with selectivity for positively charged solutes. Ergothioneine, an antioxidant compound, and acetylcholine (Ach) are among its substrates. Given the lack of experimentally solved structures of this protein, this study aimed at generating a reliable 3D model of OCTN1 to shed light on its substrate-binding preferences and the role of sodium in substrate recognition and transport. A chimeric model was built by grafting the large extracellular loop 1 (EL1) from an AlphaFold-generated model onto a homology model. Molecular dynamics simulations revealed domain-specific mobility, with EL1 exhibiting the highest impact on overall stability. Molecular docking simulations identified cytarabine and verapamil as highest affinity ligands, consistent with their known inhibitory effects on OCTN1. Furthermore, MM/GBSA analysis allowed the categorization of substrates into weak, good, and strong binders, with molecular weight strongly correlating with binding affinity to the recognition site. Key recognition residues, including Tyr211, Glu381, and Arg469, were identified through interaction analysis. Ach demonstrated a low interaction energy, supporting the hypothesis of its one-directional transport towards to outside of the membrane. Regarding the role of sodium, our model suggested the involvement of Glu381 in sodium binding. Molecular dynamics simulations of systems at increasing levels of Na+ concentrations revealed increased sodium occupancy around Glu381, supporting experimental data associating Na+ concentration to molecule transport. In conclusion, this study provides valuable insights into the 3D structure of OCTN1, its substrate-binding preferences, and the role of sodium in the recognition. These findings contribute to the understanding of OCTN1 involvement in various physiological and pathological processes and may have implications for drug development and disease management.