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BACKGROUND. Despite an increasing appreciation of the roles that myeloid cells play in tumor progression and therapy, challenges remain in interpreting the tumor-associated myeloid response balance and its translational value. We aimed to construct a simple and reliable myeloid signature for hepatocellular carcinoma (HCC). METHODS. Using in situ immunohistochemistry, we assessed the distribution of major myeloid subtypes in both peri-and intratumoral regions of HCC. A 2-feature-based, myeloid-specific prognostic signature, named the myeloid response score (MRS), was constructed using an L1-penalized Cox regression model based on data from a training subset (n = 244), a test subset (n = 244), and an independent internal (n = 341) and 2 external (n = 94; n = 254) cohorts. RESULTS. The MRS and the MRS-based nomograms displayed remarkable discriminatory power, accuracy, and clinical usefulness for predicting recurrence and patient survival, superior to current staging algorithms. Moreover, an increase in MRS was associated with a shift in the myeloid response balance from antitumor to protumor activities, accompanied by enhanced CD8 + T cell exhaustion patterns. Additionally, we provide evidence that the MRS was associated with the efficacy of sorafenib treatment for recurrent HCC. CONCLUSION. We identified and validated a simple myeloid signature for HCC that showed remarkable prognostic potential and may serve as a basis for the stratification of HCC immune subtypes.

Background Biosynthesis of noble metallic nanoparticles (NPs) has attracted significant interest due to their environmental friendly and biocompatible properties. Methods In this study, we investigated syntheses of Au, Ag and Au–Ag bimetallic NPs using protein extracts of Deinococcus radiodurans , which demonstrated powerful metal-reducing ability. The obtained NPs were characterized and analyzed by various spectroscopy techniques. Results The D. radiodurans protein extract-mediated silver nanoparticles (Drp-AgNPs) were preferably monodispersed and stably distributed compared to D. radiodurans protein extract-mediated gold nanoparticles (Drp-AuNPs). Drp-AgNPs and Drp-AuNPs exhibited spherical morphology with average sizes of 37.13±5.97 nm and 51.72±7.38 nm and zeta potential values of −18.31±1.39 mV and −15.17±1.24 mV at pH 7, respectively. The release efficiencies of Drp-AuNPs and Drp-AgNPs measured at 24 h were 3.99% and 18.20%, respectively. During the synthesis process, Au(III) was reduced to Au(I) and further to Au(0) and Ag(I) was reduced to Ag(0) by interactions with the hydroxyl, amine, carboxyl, phospho or sulfhydryl groups of proteins and subsequently stabilized by these groups. Some characteristics of Drp-AuNPs were different from those of Drp-AgNPs, which could be attributed to the interaction of the NPs with different binding groups of proteins. The Drp-AgNPs could be further formed into Au–Ag bimetallic NPs via galvanic replacement reaction. Drp-AuNPs and Au–Ag bimetallic NPs showed low cytotoxicity against MCF-10A cells due to the lower level of intracellular reactive oxygen species (ROS) generation than that of Drp-AgNPs. Conclusions These results are crucial to understand the biosynthetic mechanism and properties of noble metallic NPs using the protein extracts of bacteria. The biocompatible Au or Au–Ag bimetallic NPs are applicable in biosensing, bioimaging and biomedicine.

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Understanding the synthetic mechanisms and cell–nanoparticle interactions of biosynthesized and functionalized gold nanoparticles (AuNPs) using natural products is of great importance for developing their applications in nanomedicine. In this study, we detailed the biotransformation mechanism of Au­(III) into AuNPs using a hydroxylated tetraterpenoid deinoxanthin (DX) from the extremophile Deinococcus radiodurans. During the process, Au­(III) was rapidly reduced to Au­(I) and subsequently reduced to Au(0) by deprotonation of the hydroxyl head groups of the tetraterpenoid. The oxidized form, deprotonated 2-ketodeinoxanthin (DX3), served as a surface-capping agent to stabilize the AuNPs. The functionalized DX–AuNPs demonstrated stronger inhibitory activity against cancer cells compared with sodium citrate–AuNPs and were nontoxic to normal cells. DX–AuNPs accumulated in the cytoplasm, organelles, and nuclei, and induced reactive oxygen species generation, DNA damage, and apoptosis within MCF-7 cancer cells. In the cells treated with DX–AuNPs, 374 genes, including RRAGC gene, were upregulated; 135 genes, including the genes encoding FOXM1 and NR4A1, were downregulated. These genes are mostly involved in metabolism, cell growth, DNA damage, oxidative stress, autophagy, and apoptosis. The anticancer activity of the DX–AuNPs was attributed to the alteration of gene expression and induction of apoptosis. Our results provide significant insight into the synthesis mechanism of AuNPs functionalized with natural tetraterpenoids, which possess enhanced anticancer potential.