The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25–30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation – which is a potentially curative strategy unique to HCC management – as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.

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We developed a synthetic route for producing 3-amino-2hydroxy acetophenone (3AHAP) from m-nitroacetophenone (3NAP) using an in vitro approach. Various reaction systems were evaluated, and a direct reaction method with crude enzyme and supersaturated substrates for optimal catalytic efficiency was chosen. The reaction system included three enzymes and was enhanced by adjusting enzyme molar ratios and optimizing ribosomal binding sites. We performed substrate docking and alanine scanning to identify key sites in the enzymes nitrobenzene nitroreductase (nbzA) and hydroxylami-nobenzene mutase (habA). The optimal mutant was obtained through site-directed mutagenesis, and incorporated into the reaction system, resulting in increased product yield. After optimization, the yield of 3AHAP increased from 75 mg/L to 580 mg/L within 5 hours, the highest reported yield using biosynthesis. This work provides a promising strategy for the efficient and sustainable production of 3AHAP, which has critical applications in the chemical and pharmaceutical industries.

The chemokine network such as interaction between CXCR4 and CXCL12 plays a role in the induction of organ-specific metastases. The present study evaluated CXCR4/CXCL12 expression pattern in colorectal liver metastases (CRLM) and determined whether the expression patterns affect tumor progression. Methods: We examined pattern of CXCR4 and CXCL12 immunohistochemistry in 92 CRLM patients. CXCL12/ CD133 immunoreactivity was also evaluated. The median follow-up time of these patients was 38 months. Clinicopathological data of these patients were evaluated. Overall survival rates were evaluated by the Kaplan-Meier method. The expression profile of CXCR4 in the colorectal cancer cell line was determined by fluorescence microscopy. Results: The cytoplasmic CXCR4 expression was greater in 36 patients than that indicated by CXCR4 staining intensity of hepatocytes. CXCL12 was also expressed in hepatocytes surrounding the tumors at high and low levels in 68 (74%) and 24 (26%), respectively. High levels of nuclear CXCR4 expression were observed in 23 patients which significantly correlated with CXCL12 expression in hepatocytes. The nuclear CXCR4 expression in the cancer cell line increased after exposure to CXCL12. The univariate and multivariate analyses demonstrated that high levels of nuclear CXCR4 and the increased CXCL12 expression in hepatocytes were significantly better prognostic factors for overall and hepatic disease-free survival in patients with CRLM. Conclusion:The CXCR4 expression in CRLM together with the upregulation of CXCL12 in hepatocytes may help to predict the clinical outcomes of patients with CRLM after hepatic resection and to determine whether adjuvant chemotherapy may be required.

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