In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.

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In the context of the International GNSS Service (IGS), several IGS Ionosphere Associated Analysis Centers (IAAC) have developed different techniques to provide Global Ionospheric Maps (GIMs) of Vertical Total Elec-

Hepatocellular carcinoma (HCC) is a common malignant tumor in the digestive tract with limited therapeutic choices. Although sorafenib, an orally administered multikinase inhibitor, has produced survival benefits for patients with advanced HCC, favorable clinical outcomes are limited due to individual differences and resistance. The application of immunotherapy, a promising approach for HCC is urgently needed. Macrophage infiltration, mediated by the CCL2/CCR2 axis, is a potential immunotherapeutic target. Here, we report that a natural product from Abies georgei, named 747 and related in structure to kaempferol, exhibits sensitivity and selectivity as a CCR2 antagonist. The specificity of 747 on CCR2 was demonstrated via calcium flux, the binding domain of CCR2 was identified in an extracellular loop by chimera binding assay, and in vivo antagonistic activity of 747 was confirmed through a thioglycollate-induced peritonitis model. In animals, 747 elevated the number of CD8 + T cells in tumors via blocking tumor-infiltrating macrophage-mediated immunosuppression and inhibited orthotopic and subcutaneous tumor growth in a CD8 + T cell-dependent manner. Further, 747 enhanced the therapeutic efficacy of low-dose sorafenib without obvious toxicity, through elevating the numbers of intra-tumoral CD8 + T cells and increasing death of tumor cells. Thus, we have discovered a natural CCR2 antagonist and have provided a new perspective on development of this antagonist for treatment of HCC. In mouse models of HCC, 747 enhanced the tumor immunosuppressive microenvironment and potentiated the therapeutic effect of sorafenib, indicating that the combination of an immunomodulator with a chemotherapeutic drug could be a new approach for treating HCC.

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Tropospheric delay is one of the main sources of measurement error in global navigation satellite systems. It is usually compensated by using an empirical correction model. In this paper, temporal and spatial variations of the global zenith tropospheric delay (ZTD) are further analyzed by ZTD time series from global International GNSS Service stations and annual ZTDs derived from global National Centers for Environmental Prediction reanalysis data, respectively. A new ZTD correction model, named IGGtrop, is developed based on the characteristics of ZTD. Experimental results show that this new 3D-grid-based model that accommodates longitudinal as well as latitudinal variations of ZTD performs better than latitude-only based models (such as UNB3, EGNOS, and UNB3m). The global average bias and RMS for IGGtrop are about −0.8 cm and 4.0 cm, respectively. Bias values for UNB3, EGNOS, and UNB3m are 2.0, 2.0, and 0.7 cm, respectively, and respective RMS values 5.4, 5.4, and 5.0 cm. IGGtrop shows much more consistent prediction errors for different areas than EGNOS and UNB3m. In China, the performance of IGGtrop (bias values from −2.0 to 0.4 cm and RMS from 2.1 to 6.4 cm) is clearly superior to those of EGNOS and UNB3m. It is also demonstrated that IGGtrop biases vary little with height, and its RMS values tend to decrease with increasing height. In addition, IGGtrop generally estimates ZTD with greater accuracy than EGNOS and UNB3m in the Southern Hemisphere.

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