Hepatitis B virus (HBV)-associated chronic liver diseases are treated with nucleoside analogs that target the virus polymerase. While these analogs are potent, drugs are needed to target other virus-encoded gene products to better block the virus replication cycle and chronic liver disease. This work further characterized GLS4 and compared it to the related BAY 41-4109, both of which trigger aberrant HBV core particle assembly, where the virus replication cycle occurs. This was done in HepAD38 cells, which replicate HBV to high levels. In vitro, GLS4 was significantly less toxic for primary human hepatocytes (P < 0.01 up to 100 M), inhibited virus accumulation in the supernantant of HepAD38 cells (P < 0.02 up to 100 nM), inhibited HBV replicative forms in the liver with a significantly lower 50% effective concentration (EC 50 ) (P < 0.02), and more strongly inhibited core gene expression (P < 0.001 at 100 to 200 nM) compared to BAY 41-4109. In vivo characterization was performed in nude mice inoculated with HepAD38 cells, which grew out as tumors, resulting in viremia. Treatment of mice with GLS4 and BAY 41-4109 showed strong and sustained suppression of virus DNA to about the same extents both during and after treatment. Both drugs reduced the levels of intracellular core antigen in the tumors. Alanine aminotransferase levels were normal. Tumor and total body weights were not affected by treatment. Thus, GLS4 was as potent as the prototype, BAY 41-4109, and was superior to lamivudine, in that there was little virus relapse after the end of treatment and no indication of toxicity.

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Gamma-glutamyltransferase (γ-GGT) is a membrane-bound enzyme that is involved in biotransformation, nucleic acid metabolism, and tumourigenesis. Elevated serum γ-GGT levels are related to an increased cancer risk and worse prognosis in many cancers. In the present study, we evaluated the prognostic value of preoperative serum γ-GGT in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). A total of 130 HCC patients after LT were included in the study. The optimal cut-off value of γ-GGT was 128U/L by receiver operating characteristic analysis, with a sensitivity and specificity of 60.0% and 72.9%, respectively. Elevated preoperative serum γ-GGT was significantly associated with high alpha-fetoprotein (AFP), large tumor size, and macro- and micro-vascular invasion. The 1-, 3-, 5-year disease-free survival (DFS) and overall survival (OS) rates of HCC patients in the γ-GGT > 128U/L group were poorer than those in the γ-GGT ≤ 128U/L group. Stratification analysis revealed that γ-GGT exhibited a greater predictive value for DFS and OS in HCC patients beyond the Milan criteria and no macro-vascular invasion. In conclusion, elevated preoperative serum γ-GGT was significantly associated with advanced tumor stage and aggressive tumor behaviors, and serum γ-GGT can be considered as a prognostic factor for HCC patients after LT, especially for patients beyond the Milan criteria or without macro-vascular invasion.

The development of advanced charged polymers with multifunctionality for heterogeneous catalysis is glamorous but still challenging. Herein, on the basis of function-oriented design philosophy, a series of metalloporphyrin-based porous ionic polymers (PiPs) were first synthesized through a facile and green method via Debus–Radziszewski reaction following click-chemistry principles. Benefiting from the enhancement of rigidity and contortion of the framework, these charged polymers presented improved specific surface area with hierarchical porous structures. The in situ polymerization method also endows them with extremely high density of biactive sites, anion tunability, and good CO2/N2 adsorptive selectivity. As a result, they exhibited excellent catalytic performance, robust recyclability, and good substrate expansibility in the solvent-free synthesis of cyclic carbonates from epoxides and CO2 even at ambient conditions. Exhilaratingly, CoTPP-PiP­(Br) could smoothly catalyze this reaction by using simulated flue gas (15% CO2 in 85% N2, v/v) as a raw material under mild conditions. Thus, these functional PiPs diversified the types of porous polymers and provided a promising opportunity for the industrial synthesis of valuable cyclic carbonates from real-world CO2.