ObjectiveLiver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively.DesignThis study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria.ResultsCompared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), α-fetoprotein (AFP) >100 ng/mL and tumour burden>8 cm were the only two independent prognostic factors (p<0.001). Accordingly, the Hangzhou criteria were stratified as type A (tumour burden ≤8 cm, or tumour burden >8 cm but AFP≤100 ng/mL) and type B (tumour burden >8 cm but AFP between 100 and 400 ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p<0.001).ConclusionsThe Milan criteria can be expanded safely and effectively. The prognostic stratification system based on the Hangzhou criteria serves as a hierarchy of transplant candidates for hepatocellular carcinoma.
The availability of precisely modulated chemical modifi cations dramatically affects the physicochemical properties of pristine drugs and should facilitate the amphiphilic self-assembly of prodrugs into supramolecular nanoprodrugs (SNPs). However, rationally designing such prodrugs to achieve favorable clinical outcomes still remains a challenge. Here, a library of prodrugs through site-specifi c attachment of a variety of lipophilic moieties to the antitumor agent SN-38 (7-ethyl-10-hydroxycamptothecin) is constructed. Taking advantage of the role of hydroxyl groups as solvophilic moieties, these prodrugs exhibit self-assembly in aqueous environments, allowing for the identifi cation of fi ve prodrugs capable of self-assembling into SNPs at high drug concentrations. Importantly, in vivo studies demonstrate that the antitumor activity of the SNPs correlates well with their stability and long-term circulation. In addition, the modular feature of this SNP design strategy offers the opportunity to readily incorporate additional valuable functionalities (e.g., tumor-specifi c targeting ligands) to the particle surface, which is further exploited to improve antitumor effi cacy in mouse xenograft models. Thus, this structure-based reconstruction of SN-38 molecules signifi cantly improves the potency of SNPs for clinical use. These results also provide novel mechanistic insights into the rational design of prodrugs.
BackgroundOxymatrine, an isolated extract from traditional Chinese herb Sophora Flavescens Ait, has been traditionally used for therapy of anti-hepatitis B virus, anti-inflammation and anti-anaphylaxis. The present study was to investigate the anti-cancer effect of oxymatrine on human pancreatic cancer PANC-1 cells, and its possible molecular mechanism.MethodsThe effect of oxymatrine on the viability and apoptosis was examined by methyl thiazolyl tetrazolium and flow cytometry analysis. The expression of Bax, Bcl-2, Bcl-x (L/S), Bid, Bad, HIAP-1, HIAP-2, XIAP, NAIP, Livin and Survivin genes was accessed by RT-PCR. The levels of cytochrome c and caspase 3 protein were assessed by Western blotting.ResultsOxymatrine inhibited cell viability and induced apoptosis of PANC-1 cells in a time- and dose-dependent manner. This was accompanied by down-regulated expression of Livin and Survivin genes while the Bax/Bcl-2 ratio was upregulated. Furthermore, oxymatrine treatment led to the release of cytochrome c and activation of caspase-3 proteins.ConclusionOxymatrine can induce apoptotic cell death of human pancreatic cancer, which might be attributed to the regulation of Bcl-2 and IAP families, release of mitochondrial cytochrome c and activation of caspase-3.
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