Inflammatory cytokines such as interleukin-17 (IL-17) promote inflammatory autoimmune diseases. Although several microRNAs (miRNAs) have been shown to regulate autoimmune pathogenesis by affecting lymphocyte development and function, the role of miRNAs in resident cells present in inflammatory lesions remains unclear. Here we show that miR-23b is downregulated in inflammatory lesions of humans with lupus or rheumatoid arthritis, as well as in the mouse models of lupus, rheumatoid arthritis or multiple sclerosis. IL-17 downregulates miR-23b expression in human fibroblast-like synoviocytes, mouse primary kidney cells and astrocytes and is essential for the downregulation of miR-23b during autoimmune pathogenesis. In turn, miR-23b suppresses IL-17-, tumor necrosis factor α (TNF-α)- or IL-1β-induced NF-κB activation and inflammatory cytokine expression by targeting TGF-β-activated kinase 1/MAP3K7 binding protein 2 (TAB2), TAB3 and inhibitor of nuclear factor κ-B kinase subunit α (IKK-α) and, consequently, represses autoimmune inflammation. Thus, IL-17 contributes to autoimmune pathogenesis by suppressing miR-23b expression in radio-resident cells and promoting proinflammatory cytokine expression.

We report a new environmentally-friendly synthetic strategy for large-scale preparation of 16 nm-ultrathin NiCo based layered double hydroxides (LDH). The Ni50Co50-LDH electrode exhibited excellent specific capacitance of 1537 F g−1 at 0.5 A g−1 and 1181 F g−1 even at current density as high as 10 A g−1, which 50% cobalt doped enhances the electrical conductivity and porous and ultrathin structure is helpful with electrolyte diffusion to improve the material utilization. An asymmetric ultracapacitor was assembled with the N-doped graphitic ordered mesoporous carbon as negative electrode and the NiCo LDH as positive electrode. The device achieves a high energy density of 33.7 Wh kg−1 (at power density of 551 W kg−1) with a 1.5 V operating voltage.

No abstract

To better understand the mechanism underlying the hepatocellular carcinoma (HCC) metastasis and to search potential markers for HCC prognosis, differential proteomic analysis on two well-established HCC cell strains with high and low metastatic potentials, MHCC97-H and MHCC97-L, was conducted using two-dimensional gel electrophoresis followed by matrix-assisted laser desorption/time-of-flight mass spectrometry. Cytokeratin 19 (CK19) was identified and found to be overexpressed in MHCC97-H as compared with MHCC97-L. This result was further confirmed by twodimensional Western blot analysis and immunofluorescence assay. Furthermore, one-dimensional Western blot analysis showed consistently increased CK19 expression in progressively more metastatic cells. Immunohistochemical study on 102 human HCC specimens revealed that more patients in the CK19-positive group had overt intrahepatic metastases (satellite nodules, p < 0.05; vascular tumor emboli, p < 0.001; tumor node metastatis staging, p < 0.001). For a better insight into the mechanisms of HCC metastasis, a high metastatic human HCC cell line, MHCC97, its clonal cells, MHCC97-H and MHCC97-L, with high and low metastatic potentials, and progressively more metastatic cells from lung metastatic lesions were established via repeated in vivo selection (3-5). These cells provide appropriate model systems with similar genetic background for the comparative study on the molecular events involved in HCC metastasis.Among the currently available techniques, proteomics permits the analysis of thousands of modified or unmodified proteins simultaneously and becomes increasingly popular for identifying biomarkers for early detection, classification, and prognosis of tumors, as well as pinpointing targets for improved treatment outcomes (6). We had used this approach to identify differentially expressed proteins between human HCC and normal liver cell line and investigated malignant growthassociated proteins in human hepatoma cells transfected with antisense-epidermal growth factor receptor (7,8). In this study, this technique was combined with immunology methods to study MHCC97-H and MHCC97-L for screening metastasis-associated proteins.Cytokeratins represent important structural components of the epithelial cytoskeleton, and their expression is remarkably tissue specific, suggesting that the type of cytokeratins present in the cells is related to their biological function (9). Recent

IL-17 is a pro-inflammatory cytokine implicated a variety of autoimmune diseases. We have recently reported that FGF2 cooperates with IL-17 to protect intestinal epithelium during dextran sodium sulfate (DSS)-induced colitis. Here, we report a pathogenic role of the FGF2-IL-17 cooperation in the pathogenesis of autoimmune arthritis. Combined treatment with FGF2 and IL-17 synergistically induced ERK activation as well as the production of cytokines and chemokines in human synovial intimal resident fibroblast-like synoviocytes (FLS). Furthermore, ectopic expression of FGF2 in mouse joints potentiated IL-17-induced inflammatory cytokine and chemokine production in the tissue. In the collagen-induced arthritis (CIA) model, while ectopic expression of FGF2 in vivo exacerbated tissue inflammation and disease symptom in the wild-type controls, the effect was largely blunted in Il17a −/− mice. Taken together, our study suggests that FGF2 cooperates with IL-17 to promote the pathogenesis of autoimmune arthritis by cooperating with IL-17 to induce inflammatory response.

Purpose: The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study.Experimental Design: We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade.Results: Administration of the ligand-blocking anti-mouse surrogate antibody OX40.23 or BMS-986178 as monotherapy or in combination with checkpoint blockade led to increased peripheral CD4 þ and CD8 þ T-cell activation in tumor-bearing mice and patients with solid tumors, respectively. OX40 receptor occupancy between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a receptor occupancy > 40% led to a profound loss in OX40 receptor expression, with clear implications for availability for repeat dosing.Conclusions: Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic.

No abstract

This paper explores the effectiveness of mass customization strategies in a manufacturing firm. The manufacturing firm produces standard products in a flexible factory where mass customization is technologically feasible. We integrate product strategy and channel design to explore whether the firm should adopt mass customization and how the distribution channel should be configured for custom products. We find that the mixed mass customization strategy dominates the pure standard product strategy in the centralized system. For the decentralized system, we identify the parameters that would impact superiority of each product strategy. We further discuss two channel structures for mass customization: single-channel strategy and dual-channel strategy, and find that the dual-channel strategy is always superior to the single-channel strategy when mixed mass customization is adopted.Index Terms-Channel structure, flexible capacity, mixed mass customization, pure standard product strategy.