Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1

Macrophages (Mφ) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of Mφ to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/Mφ in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1+ and HLA-DRhigh on tumor-infiltrating monocytes. Autocrine tumor necrosis factor α and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1+ monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/Mφ may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu

Multi-Type Object Tracking Based on Residual Neural Network Model

In this paper, a tracking algorithm based on the residual neural network model and machine learning is proposed. Compared with the widely used VGG network, the residual neural network has deeper characteristic layers and special additional layer structure, which break the symmetry of the network and reduce the degradation of the neural network. The additional layer and convolution layer are used for feature fusion to represent the target. The multi-features of the object can be captured by using the developed algorithm, so that the accuracy of tracking can be improved in some complex scenarios. In addition, we defined a new measure to calculate the similarity of different image regions and find the optimal matched region. The search area is delimited according to the continuity of the target motion, which improves the real-time performance of tracking. The experimental results illustrate that the proposed algorithm achieved a higher accuracy while taking into account the real time performance, especially in dealing with some complex scenarios such as deformation, rotation changes and background clutters, in comparison with the Multi-Domain Network (MDNet) algorithm based on a convolutional neural network

Effect of Processing Parameters on the Dynamic Characteristic of Material Extrusion Additive Manufacturing Plates

Material extrusion (ME), an additive manufacturing technique, can fabricate parts almost without geometrical limitations. With the growing application of ME parts, especially in actual working conditions, the dynamic characteristics are needed to be studied to accurately determine their reliability. This study provides an experimental validation of the theoretical model for predicting the dynamic characteristics of ME plates fabricated with three different key processing parameters, i.e., extrusion width, layer height and build direction. The model is set up based on the bidirectional beam function combination method, and a series of experimental tests are performed. It is found that different processing parameters result in the material properties of the samples to vary, thus leading to different dynamic characteristics. Through the comparison between predictions and measurements, it is shown that the influencing trend of the processing parameters is predicted precisely. The theoretical model gives reliable predictions in dynamic characteristics of ME plates. The natural frequency discrepancy is below 13.4%, and the predicted mode shapes are the same as the measured ones. This present work provides theoretical basis and technical support for further research in improving the dynamic performance of ME products, and helps extend the applications of this technique

Effects of ZrO2 ceramics doped with varying content on the mechanical properties and energy release characteristics of W-Zr alloys

A W-Zr alloy doped with ceramic powder W _54.5 Zr _35-x Ni _6.7 Fe _3.3 Mo _0.5 (ZrO _2 ) _x was prepared by powder metallurgy. The effects of the ceramic content on the dynamic and static compressive mechanical behavior and energy release properties of the alloy were studied. The results showed that the addition of ceramics enhanced the energy release characteristics of the W-Zr alloy, and made the alloy break more thoroughly and the fragment cloud distribute evenly. The reaction delay time was shorter and the energy release reaction was more complete. However, the maximum temperature of the alloy reaction decreased. In addition, the addition of ceramics improves the mechanical properties of the material, and its compressive strength is much higher than that of traditional W-Zr alloys.(ZrO _2 )1 exhibited good mechanical behavior and energy release characteristics. The aftereffect damage performance was further verified using a ballistic gun experiment. Ballistic gun test results showed that (ZrO _2 ) 1 can penetrate A92124 aluminum targets with a thickness of 2 mm at a speed of 809.3 m s ^−1 and ignite post-target absorbent cotton, with both penetration and post-target damage capabilities

Kupffer cells determine intrahepatic traffic of PEGylated liposomal doxorubicin

Abstract Intrahepatic accumulation dominates organ distribution for most nanomedicines. However, obscure intrahepatic fate largely hampers regulation on their in vivo performance. Herein, PEGylated liposomal doxorubicin is exploited to clarify the intrahepatic fate of both liposomes and the payload in male mice. Kupffer cells initiate and dominate intrahepatic capture of liposomal doxorubicin, following to deliver released doxorubicin to hepatocytes with zonated distribution along the lobule porto-central axis. Increasing Kupffer cells capture promotes doxorubicin accumulation in hepatocytes, revealing the Kupffer cells capture-payload release-hepatocytes accumulation scheme. In contrast, free doxorubicin is overlooked by Kupffer cells, instead quickly distributing into hepatocytes by directly crossing fenestrated liver sinusoid endothelium. Compared to free doxorubicin, liposomal doxorubicin exhibits sustained metabolism/excretion due to the extra capture-release process. This work unveils the pivotal role of Kupffer cells in intrahepatic traffic of PEGylated liposomal therapeutics, and quantitively describes the intrahepatic transport/distribution/elimination process, providing crucial information for guiding further development of nanomedicines

Mycobacterium tuberculosis-Specific IL-21+IFN-γ+CD4+ T Cells Are Regulated by IL-12.

In the current study of Mycobacterium tuberculosis (MTB)-specific T and B cells, we found that MTB-specific peptides from early secreted antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) induced the expression of IL-21 predominantly in CD4(+) T cells. A fraction of IL-21-expressing CD4(+) T cells simultaneously expressed Th1 cytokines but did not secrete Th2 or Th17 cytokines, suggesting that MTB-specific IL-21-expressing CD4(+) T cells were different from Th1, Th2 and Th17 subpopulations. The majority of MTB-specific IL-21-expressing CD4(+) T cells co-expressed IFN-γ and IL-21+IFN-γ(+)CD4(+) T cells exhibited obviously polyfunctionality. In addition, MTB-specific IL-21-expressing CD4(+) T cells displayed a CD45RO+CD62Ll(ow)CCR7(low)CD40L(high)ICOS(high) phenotype. Bcl-6-expression was significantly higher in IL-21-expressing CD4(+) T cells than IL-21-CD4(+) T cells. Moreover, IL-12 could up-regulate MTB-specific IL-21 expression, especially the frequency of IL-21(+)IFN-γ+CD4(+) T cells. Taken together, our results demonstrated that MTB-specific IL-21(+)IFN-γ(+)CD4(+) T cells from local sites of tuberculosis (TB) infection could be enhanced by IL-12, which have the features of both Tfh and Th1 cells and may have an important role in local immune responses against TB infection