No abstract

Macrophages (MΦs)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of MΦs/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated MΦ inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-β1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of MΦ/microglia phagocytosis, induction of MΦ/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-β1, and MIC-1, cytokines known to recruit and polarize the MΦs/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the MΦ/microglia to an M2 phenotype, inhibited MΦ/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-β1 by the MΦs/microglia, and enhanced the capacity of MΦs/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive MΦs/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.

The robust detection of small targets is one of the key techniques in infrared search and tracking applications. A novel small target detection method in a single infrared image is proposed in this paper. Initially, the traditional infrared image model is generalized to a new infrared patch-image model using local patch construction. Then, because of the non-local self-correlation property of the infrared background image, based on the new model small target detection is formulated as an optimization problem of recovering low-rank and sparse matrices, which is effectively solved using stable principle component pursuit. Finally, a simple adaptive segmentation method is used to segment the target image and the segmentation result can be refined by post-processing. Extensive synthetic and real data experiments show that under different clutter backgrounds the proposed method not only works more stably for different target sizes and signal-to-clutter ratio values, but also has better detection performance compared with conventional baseline methods.

Feature pyramids are widely exploited by both the state-ofthe-art one-stage object detectors (e.g., DSSD, RetinaNet, RefineDet) and the two-stage object detectors (e.g., Mask R-CNN, DetNet) to alleviate the problem arising from scale variation across object instances. Although these object detectors with feature pyramids achieve encouraging results, they have some limitations due to that they only simply construct the feature pyramid according to the inherent multiscale, pyramidal architecture of the backbones which are originally designed for object classification task. Newly, in this work, we present Multi-Level Feature Pyramid Network (MLFPN) to construct more effective feature pyramids for detecting objects of different scales. First, we fuse multi-level features (i.e. multiple layers) extracted by backbone as the base feature. Second, we feed the base feature into a block of alternating joint Thinned U-shape Modules and Feature Fusion Modules and exploit the decoder layers of each Ushape module as the features for detecting objects. Finally, we gather up the decoder layers with equivalent scales (sizes) to construct a feature pyramid for object detection, in which every feature map consists of the layers (features) from multiple levels. To evaluate the effectiveness of the proposed MLFPN, we design and train a powerful end-to-end onestage object detector we call M2Det by integrating it into the architecture of SSD, and achieve better detection performance than state-of-the-art one-stage detectors. Specifically, on MS-COCO benchmark, M2Det achieves AP of 41.0 at speed of 11.8 FPS with single-scale inference strategy and AP of 44.2 with multi-scale inference strategy, which are the new state-of-the-art results among one-stage detectors. The code will be made available on https://github.com/ qijiezhao/M2Det.

Glioblastoma multiforme (GBM) is a lethal cancer that responds poorly to radiotherapy and chemotherapy. Glioma cancer-initiating cells have been shown to recapitulate the characteristic features of GBM and mediate chemotherapy and radiation resistance. However, it is unknown whether the cancer-initiating cells contribute to the profound immune suppression in GBM patients. Recent studies have found that the activated form of signal transducer and activator of transcription 3 (STAT3) is a key mediator in GBM immunosuppression. We isolated and generated CD133+ cancer-initiating single colonies from GBM patients and investigated their immunesuppressive properties. We found that the cancer-initiating cells inhibited T-cell proliferation and activation, induced regulatory Tcells, and triggered T-cell apoptosis. The STAT3 pathway is constitutively active in these clones and the immunosuppressive properties were markedly diminished when the STAT3 pathway was blocked in the cancer-initiating cells. These findings indicate that cancer-initiating cells contribute to the immune evasion of GBM and that blockade of the STAT3 pathway has therapeutic potential. Mol Cancer Ther; 9(1); 67-78. ©2010 AACR.

von Willebrand factor (VWF) released from endothelium is ultralarge (UL) and hyperreactive. If released directly into plasma, it can spontaneously aggregate platelets, resulting in systemic thrombosis. This disastrous consequence is prevented by the ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin motif) cleavage of ULVWF into smaller, less active forms. We previously showed that ULVWF, on release, forms extremely long stringlike structures. ADAMTS13 cleaves these strings under flow significantly faster than it does under static conditions. As ULVWF tethering to endothelium is important for its rapid proteolysis, we investigated 2 molecules for their potential to anchor the ULVWF strings: Pselectin and integrin ␣ v ␤ 3 . We demonstrated that P-selectin anchors ULVWF to endothelium by several means. First, Chinese hamster ovary (CHO) cells expressing P-selectin specifically adhered to immobilized ULVWF and ULVWF-coated beads to immobilized P-selectin. Second, an anti-VWF antibody coimmunoprecipitates P-selectin from the histamine-activated endothelial cells. Third, P-selectin antibody or soluble P-selectin, but not a ␣ v ␤ 3 antibody, RGDS peptide, or heparin, blocked the formation of ULVWF strings. Fourth, P-selectin expression was in clusters predominantly along the ULVWF strings. Finally, the strength of the minimal ULVWF-P-selectin bond was measured to be 7.2 pN. We, therefore, conclude that P-selectin may anchor ULVWF strings to endothelial cells and facilitate their cleavage by ADAMTS13. (Blood.

HHP effectively retained anthocyanins, phenolic compounds and color of strawberry pulps, and partly inactivated enzymes.

Purpose CMV has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited. Experimental Design Glioblastoma multiforme (GBM) tumors were analyzed by flow cytometry to determine CMV antigen expression within various glioma-associated immune populations. The gCSC CMV IL-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF, TGF-β, viral IE1 and pp65 were determined by flow cytometry. The influence of CMV IL-10 treated monocytes on gCSC biology was ascertained by functional assays. Results CMV demonstrated a tropism for macrophages (MΦs)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the CNS MΦs/microglia) to assume an M2 immunosuppressive phenotype (as manifested by down modulation of the major histocompatibility complex and costimulatory molecules) while up regulating immune inhibitory B7-H1. CMV IL-10 also induces expression of viral IE1, a modulator of viral replication and transcription in the monocytes. Finally, the CMV IL-10-treated monocytes produced angiogeneic VEGF, immunosuppressive TGF-β, and enhanced migration of gCSCs. Conclusions CMV triggers a feed-forward mechanism of gliomagenesis by inducing tumor-supportive monocytes.