No abstract

The two major causes for implant failure are postoperative infection and poor osteogenesis. Initial period of osteointegration is regulated by immunocytes and osteogenic‐related cells resulting in inflammatory response and tissue healing. The healing phase can be influenced by various environmental factors and biological cascade effect. To synthetically orchestrate bone‐promoting factors on biomaterial surface, built is a dual delivery system coated on a titanium surface (abbreviated as AH‐Sr‐AgNPs). The results show that this programmed delivery system can release Ag+ and Sr2+ in a temporal‐spatial manner to clear pathogens and activate preosteoblast differentiation partially through manipulating the polarization of macrophages. Both in vitro and in vivo assays show that AH‐Sr‐AgNPs‐modified surface renders a microenvironment adverse for bacterial survival and favorable for macrophage polarization (M2), which further promotes the differentiation of preosteoblasts. Infected New Zealand rabbit femoral metaphysis defect model is used to confirm the osteogenic property of AH‐Sr‐AgNPs implants through micro‐CT, histological, and histomorphometric analyses. These findings demonstrate that the programmed surface with dual delivery of Sr2+ and Ag+ has the potential of achieving an enhanced osteogenic outcome through favorable immunoregulation.

Purpose: To identify the miRNA regulators of C-X-C motif chemokine receptor 4 (CXCR4) and the underlying mechanism as well as the therapeutic and prognostic values in human glioblastoma (GBM).Experimental Design: miRNA profile analyses and bioinformatics predictions were used to identify the mediators of CXCR4, which were confirmed by luciferase reporter assay, Western blot assay and immunohistochemistry. The effects of miR-663 on CXCR4-mediated GBM malignancy were investigated by gainof-function experiments. Orthotopic xenografts derived from constitutive or induced miR-663-expressing GBM cells were used to determine the antitumor effects of miR-663 and CXCR4-specific antagonist AMD3100. Bivariate correlation analyses were used to examine the correlation of miR-663 and CXCR4 levels in glioma. The prognostic values of miR-663 and CXCR4 were examined in 281 cases of astrocytic glioma from our hospital and 476 cases of GBM from The Cancer Genome Atlas database using the multivariate Cox regression analysis and Kaplan-Meier analysis.Results: miR-663 negatively regulated CXCR4 expression by targeting its coding sequence in GBM and compromised the proliferative and invasive capacities of GBM cells induced by CXCR4 overexpression. Constitutive or induced miR-663 overexpression combined with CXCR4 antagonist AMD3100 suppressed orthotopic GBM growth and prolonged tumor-bearing mice survival. Clinically, miR-663 and CXCR4 were inversely correlated in GBM and composed a valuable biomarker set in predicting the outcomes of GBM patients.Conclusions: miR-663 negatively regulated CXCR4 to inhibit its oncogenic effect. Combination of miR-663 and CXCR4 can serve as a valuable prognostic biomarker set as well as molecular targets for therapeutic intervention of GBM.

Acinetobacter baumannii, a Gram-negative opportunistic pathogen, is a leading cause of hospital-and communityacquired infections. Acinetobacter baumannii can rapidly acquire diverse resistance mechanisms and undergo genetic modifications that confer resistance and persistence to all currently used clinical antibiotics. In this study, we found exogenous L-lysine sensitizes Acinetobacter baumannii, other Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae) and a Gram-positive bacterium (Mycobacterium smegmatis) to aminoglycosides. Importantly, the combination of L-lysine with aminoglycosides killed clinically isolated multidrug-resistant Acinetobacter baumannii and persister cells. The exogenous L-lysine can increase proton motive force via transmembrane chemical gradient, resulting in aminoglycoside acumination that further accounts for reactive oxygen species production. The combination of L-lysine and antibiotics highlights a promising strategy against bacterial infection.