Antibody-antibiotic conjugate targeted therapy for orthopedic implant-associated intracellular S. aureus infections.

INTRODUCTION: Treating orthopedic implant-associated infections, especially those caused by Staphylococcus aureus (S. aureus), remains a significant challenge. S. aureus has the ability to invade host cells, enabling it to evade both antibiotics and immune responses during infection, which may result in clinical treatment failures. Therefore, it is critical to identify the host cell type of implant-associated intracellular S. aureus infections and to develop a strategy for highly targeted delivery of antibiotics to the host cells. OBJECTIVES: Introduced an antibody-antibiotic conjugate (AAC) for the targeted elimination of intracellular S. aureus. METHODS: The AAC comprises of a human monoclonal antibody (M0662) directly recognizes the surface antigen of S. aureus, Staphylococcus protein A, which is conjugated with vancomycin through cathepsin-sensitive linkers that are cleavable in the proteolytic environment of the intracellular phagolysosome. AAC, vancomycin and vancomycin combined with AAC were used in vitro intracellular infection and mice implant infection models. We then tested the effect of AAC in vivo and in vivo by fluorescence imaging, in vivo imaging, bacterial quantitative analysis and bacterial biofilm imaging. RESULTS: In vitro, it was observed that AAC captured extracellular S. aureus and co-entered the cells, and subsequently released vancomycin to induce rapid elimination of intracellular S. aureus. In the implant infection model, AAC significantly improved the bactericidal effect of vancomycin. Scanning electron microscopy showed that the application of AAC effectively blocked the formation of bacterial biofilm. Further histochemical and micro-CT analysis showed AAC significantly reduced the level of bone marrow density (BMD) and bone volume fraction (BV/TV) reduction caused by bacterial infection in the distal femur of mice compared to vancomycin treatment alone. CONCLUSIONS: The application of AAC in an implant infection model showed that it significantly improved the bactericidal effects of vancomycin and effectively blocked the formation of bacterial biofilms, without apparent toxicity to the host.

Evaluation and Application of Silk Fibroin Based Biomaterials to Promote Cartilage Regeneration in Osteoarthritis Therapy.

Osteoarthritis (OA) is a common joint disease characterized by cartilage damage and degeneration. Traditional treatments such as NSAIDs and joint replacement surgery only relieve pain and do not achieve complete cartilage regeneration. Silk fibroin (SF) biomaterials are novel materials that have been widely studied and applied to cartilage regeneration. By mimicking the fibrous structure and biological activity of collagen, SF biomaterials can promote the proliferation and differentiation of chondrocytes and contribute to the formation of new cartilage tissue. In addition, SF biomaterials have good biocompatibility and biodegradability and can be gradually absorbed and metabolized by the human body. Studies in recent years have shown that SF biomaterials have great potential in treating OA and show good clinical efficacy. Therefore, SF biomaterials are expected to be an effective treatment option for promoting cartilage regeneration and repair in patients with OA. This article provides an overview of the biological characteristics of SF, its role in bone and cartilage injuries, and its prospects in clinical applications to provide new perspectives and references for the field of bone and cartilage repair.

CCAR2 promotes a malignant phenotype of osteosarcoma through Wnt/ß-catenin-dependent transcriptional activation of SPARC.

CCAR2 plays a pivotal role in the regulation of the DNA damage response and cancer progression. Although aberrant expression of CCAR2 has been reported in several types of cancer, its biological function and molecular mechanism in osteosarcoma (OS) have not yet been fully elucidated. Here, we show that silence of CCAR2 prevented the malignant phenotype of OS cell in vitro and decreased tumor growth in nude mice. By analyzing the transcriptomic profile of CCAR2 knockdown U2OS cells, we identified secreted protein acidic and rich in cysteine (SPARC) is tightly regulated by CCAR2. Mechanically, we found that SPARC is transcriptionally regulated by Wnt/ß-catenin signaling, and CCAR2 acts as a co-activator of Wnt/ß-catenin signaling to regulate the expression of SPARC in OS cells. Additionally, SPARC knockdown largely eliminated the malignant phenotype induced by CCAR2 overexpression and forced expression of SPARC promoted the malignant phenotype of CCAR2-depleted cells. In conclusion, our results suggest that CCAR2 exerted oncogenic roles in OS cells mainly via up-regulating SPARC expression and targeting the CCAR2-SPARC axis might have promising application prospect for the treatment of osteosarcoma.

Association of rs4552569 and rs17095830 single-nucleotide polymorphisms with susceptibility to ankylosing spondylitis in east Asian population: a meta-analysis.

Several studies have been conducted in east Asian population to evaluate the association between rs4552569 and rs17095830 single-nucleotide polymorphisms (SNPs) with susceptibility to ankylosing spondylitis (AS), but the outcomes are inconsistent. A summary evaluation of the evidence supporting the associations has not been performed. Therefore,we performed this meta-analysis to access whether the two SNPs are related to ankylosing spondylitis. We systematically searched PubMed, EMBASE, Web of Science and Cochrane Library for papers published up until 3 February 2017, to obtain relevant studies using our research strategy. The allele/genotype frequencies were extracted from each study. We calculated the summary odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations between the two SNPs and AS risk. Four papers including five studies were obtained for this meta-analysis. The included studies suggested that there was no significant association between rs4552569 SNP and AS (C vs T, OR = 1.08, 95% CI: 0.96-1.22, P = 0.20).With regard to rs17095830 SNP, significant association was observed (G vs A, OR = 1.19, 95% CI: 1.06-1.33, P = 0.002). Based on a comprehensive analysis of the currently available evidence, rs4552569 SNP is not significantly associated with the predisposition of AS, while rs17095830 SNP is likely a susceptibility variant for AS in east Asian population. Further studies with different population groups are needed to confirm these potential associations.

Association between IGF1 gene single nucleotide polymorphism (rs5742612) and adolescent idiopathic scoliosis: a meta-analysis.

PURPOSE: Insulin-like growth factor 1 (IGF1) gene single nucleotide polymorphism (rs5742612) has been associated with adolescent idiopathic scoliosis (AIS) in several studies with limited sample size and inconsistent outcomes. So we perform this meta-analysis to assess the precise association between IGF1 gene single nucleotide polymorphism (rs5742612) and AIS. METHODS: We systematically searched Pubmed, Embase, Web of Science and Cochrane Library up to January 19, 2016 to obtain relevant studies using our research strategy. Four articles all belonging to case-control studies were included in our meta-analysis. RESULTS: A total of four studies containing 763 cases and 559 controls satisfied the inclusion criteria after judgment by two reviewers. No significant associations were detected between IGF1 gene single nucleotide polymorphism (rs5742612) and AIS (T vs. C, OR = 1.10, 95 % CI 0.91-1.34, p = 0.32; TT vs. CC: OR = 1.28, 95 % CI 0.82-2.02, p = 0.28; TC vs. CC: OR = 1.29, 95 % CI 0.82-2.06, p = 0.27; TT/TC vs. CC: OR = 1.28, 95 % CI 0.83-1.98, p = 0.27; TT vs. TC/CC: OR = 1.06, 95 % CI 0.82-1.36, p = 0.66). CONCLUSIONS: IGF1 gene single nucleotide polymorphism (rs5742612) is not significant associated with susceptibility to AIS in either Asian or Caucasian populations. However, IGF1 gene rs5742612 may be associated with severity of AIS. Further studies with larger sample size and different population groups involving the relationship are required to confirm the potential association.

[RESEARCH PROGRESS OF ROLE OF ESTROGEN AND ESTROGEN RECEPTOR ON ONSET AND PROGRESSION OF ADOLESCENT IDIOPATHIC SCOLIOSIS].

OBJECTIVE: To review the recent progress in research on the role of estrogen and estrogen receptor on the onset and progression of adolescent idiopathic scoliosis (AIS). METHODS: The recently published clinical and experimental literature at home and abroad on abnormality of estrogen and its receptor in AIS was reviewed and summarized. RESULTS: There are many abnormal changes of estrogen and estrogen receptor in most AIS patients, including higher serum estrogen concentration, unusual cellular response to estrogen, late age at menarche, and gene polymorphisms of estrogen receptor, which are closely associated with AIS predisposition, curve severity, and scoliosis progression. CONCLUSION: Estrogen and its receptor participate in the onset and progression of AIS by certain mechanisms, but exact mechanism remains indefinite, which needs further research to better define the role of estrogen and its receptor in AIS.