Proteomics Analysis of Knee Subchondral Bone Identifies Differentially Expressed Proteins Associated with Osteoarthritis.

Osteoarthritis (OA) is a prevalent debilitating whole-joint disorder. Currently, a growing number of proteomic studies have been performed to evaluate molecular biomarkers in several tissues from OA patients; however, little is known about the protein profiles in subchondral bone of OA. In this study, proteomic analysis was performed on subchondral bone from patients with OA to identify differentially expressed proteins (DEPs). Bioinformatics tools were used to further investigate these DEPs. Thereafter, DEPs were validated in the samples from patients with OA, as well as in bilateral ovariectomy-induced OA (OVX-OA) rats using immunohistochemistry. A comprehensive subchondral bone proteome profile of patients with OA was constructed. Additionally, biological information analysis showed that a majority of DEPs participated in the dysregulation of the complement and coagulation cascades. The validation experiments suggested that SerpinA5, the protein involved in the complement and coagulation cascades, was significantly increased in severely damaged subchondral bone of patients with OA compared to the control group. Furthermore, the increase of SerpinA5 in OVX-OA rats compared to control rats was also confirmed. Our results indicated that the dysregulation of coagulation and complement pathways plays a role in the progression of OA, and it provides a promising therapeutic target of OA.

Hypoxia-induced Wnt/ß-catenin signaling activation in subchondral bone osteoblasts leads to an osteoarthritis-like phenotype of chondrocytes in articular cartilage.

Background: Osteoarthritis (OA) is a whole-joint disease and characterized by alterations in the articular cartilage, subchondral bone, ligaments, and synovial membrane. The crosstalk between cartilage and subchondral bone plays a crucial role in the pathogenesis and progression of OA. Hypoxia has been reported to play an important role in cartilage degradation and subchondral bone remodeling in OA. In this study, we aimed to identify the involvement of hypoxia in modifying the osteoblast phenotypes and determine whether these alterations could influence the metabolism of chondrocytes. Methods: First, the levels of Hif-1α in subchondral bone of different compartments in patients with OA were assessed using immunohistochemistry (IHC). In in vitro, human primary osteoblasts were cultured under hypoxic and normoxic conditions, and the hypoxic or normoxic conditioned media (HCM and NCM) were used to culture human primary chondrocytes. Then, phenotypic changes in osteoblasts were assessed using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Furthermore, the expression of type II collagen (COL2A1), aggrecan (ACAN), SRY-related high-mobility group-box gene 9 (SOX9), matrix metalloproteinase 13 (MMP13), and matrix metalloproteinase 3 (MMP3) in chondrocytes was measured using RT-PCR. Finally, the serum levels of Wnt-related proteins were determined using ELISA. Results: Hif-1α was significantly increased in severely sclerotic subchondral bone compared to less damaged subchondral bone. ß-Catenin and SOST were identified as upregulated and downregulated in hypoxic osteoblasts, respectively. The hypoxia-induced results were confirmed by ELISA. Stimulating human primary chondrocytes with HCM significantly induced MMP13 and MMP3 and inhibited COL2A1, ACAN, and SOX9 mRNA expression. The serum levels of DKK-1 were significantly increased in human OA. Conclusion: Together, these findings revealed that hypoxia in subchondral bone is a key factor in the crosstalk between chondrocytes and osteoblasts and facilitates the shift of chondrocytes toward an OA-like phenotype probably by activating the Wnt/ß-catenin signaling pathway in osteoblasts.

Construction of Processable Ultrastiff Hydrogel for Periarticular Fracture Strutting and Healing.

Development of bioactive bone and joint implants that offer superior mechanical properties to facilitate personalized surgical procedures remains challenging in the field of biomedical materials. As for the hydrogel, mechanical property and processability are major obstructions hampering its application as load-bearing scaffolds in orthopedics. Herein, we constructed implantable composite hydrogels with appealing processability and ultrahigh stiffness. Central to our design is the incorporation of a thixotropic composite network into an elastic polymer network via dynamic interactions to synthesize a percolation-structured double-network (DN) hydrogel with plasticity, followed by in situ strengthening and self-strengthening mechanisms for fostering the DN structure to the cojoined-network structure and subsequently mineralized-composite-network structure to harvest excellent stiffness. The ultrastiff hydrogel is shapeable and can reach a compressive modulus of 80-200 MPa together with a fracture energy of 6-10 MJ/m3, comparable to the mechanical performance of cancellous bone. Moreover, the hydrogel is cytocompatible, osteogenic, and showed almost no volume shrinkage within 28 days in simulated body fluid or culture medium. Such characteristics enabled the utility of a hydrogel in the reduction and stabilization of periarticular fracture treatment on a distal femoral AO/OTA B1 fracture rabbit model and successfully avoided the recollapse of the articular surface.

Serum periostin level is not sufficient to serve as a clinically applicable biomarker of osteoarthritis.

BACKGROUND: Emerging knowledge has highlighted the role of periostin (POSTN) in osteoarthritis (OA) process; however, whether POSTN is suitable as a biomarker of OA remains unclear. This study aimed to investigate the potential value of POSTN as a biomarker of OA. METHODS: Ten 6-month-old female Sprague-Dawley (SD) rats were used in this study. Five rats underwent ovariectomy (OVX) operation and the others were carried out sham operation. Thirty-two patients with OA and eighteen patients who had meniscus injuries or ligament injuries but with intact articular cartilages were recruited in this study from January to July 2019 at the Peking University International Hospital. We first detected the expression of POSTN in the cartilage of OVX induced OA rats and different compartments of the knee joint in patients with OA using immunohistochemistry. Besides, serum POSTN levels in patients with or without OA were examined using enzyme-linked immunosorbent assay (ELISA). The associations among serum POSTN levels, clinical symptoms, and radiological severity were assessed according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and, Kellgren-Lawrence (KL) grading, respectively. Finally, multivariable cumulative link models were established to evaluate the validity of serum POSTN level as a predictor of knee OA. RESULTS: The significantly higher POSTN expression was found in OVX-OA rats than Sham rats, while, the expression of POSTN was significantly higher in the torn cartilage of patients with OA. However, the serum POSTN level did not differ significantly between patients with and without OA. Additionally, we found no remarkable associations between serum POSTN level and WOMAC scores and KL grading. Subsequent analysis revealed that serum POSTN was not a significant predictor of OA. CONCLUSION: Thus, although POSTN may be involved OA process and local POSTN is valuable in disease diagnosis and distinguishing of the severity of disease, its serum level is not sufficient to serve as a candidate biomarker of OA given the current analysis technology.

High efficacy of tetra-PEG hydrogel sealants for sutureless dural closure.

Advances in meticulous dural closure technique remain a great challenge for watertight dural closure in the aged society, because the cerebrospinal fluid (CSF) leakage after spinal surgery is often accompanied with the disgusting wound infection, meningitis and pseudomeningocele. Here, a tetra-poly (ethylene glycol) (PEG)-based hydrogel sealant is developed with collective advantages of facile operation, high safety, quick set time, easy injectability, favorable mechanical strength and powerful tissue adhesion for effective sutureless dural closure during the surgery procedure. Impressively, this tetra-PEG sealant can instantaneously adhere to the irregular tissue surfaces even in a liquid environment, and effectively prevent or block off the intraoperative CSF leakage for sutureless dural closure and dura regeneration. Together, this sutureless tetra-PEG adhesive can be utilized as a very promising alternative for high-efficient watertight dural closure of the clinical patients who incidentally or deliberately undergo the durotomy during the spinal surgery.

Proteomic analysis of human articular cartilage unravels the dyscoagulation in osteoarthritis and the potential value of serpinA5 as a biomarker for osteoarthritis.

PURPOSE: Nowadays, there is no clinically applicable biomarker for osteoarthritis (OA). Therefore, the aim of the study is to discover a potential biomarker for OA. EXPERIMENTAL DESIGN: We performed a proteomics of eight cartilage samples (four damaged cartilage and four macroscopically intact cartilage) from four OA patients without any comorbidities to search for valuable OA biomarkers. Four rats underwent bilateral ovariectomy to induce the OA (OVX-OA) model, while another four underwent a sham procedure wherein the ovaries were exteriorized but not removed (SHAM). Selected candidate proteins were further verified in the patients and the OVX-OA animal model. RESULTS: A comprehensive cartilage proteome profile of patients with OA was constructed. Additionally, the complement and coagulation cascades were found to be significantly altered, and serpinA5 was chosen as a protein of interest based on biological information analysis. The reduction of serpinA5 in locally damaged cartilage and serum of patients with OA compared to the control group was determined. Furthermore, we found that serpinA5 was decreased in OVX-OA rats compared to that in SHAM rats. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that there is dyscoagulation in the OA process and that serpinA5 can serve as a potentially valuable OA biomarker.

Potential Value of Matrix Metalloproteinase-13 as a Biomarker for Osteoarthritis.

Background: Emerging knowledge has highlighted the role of matrix metalloproteinase (MMP)-13 in osteoarthritis (OA); however, the suitability of MMP-13 as a biomarker for OA remains unclear. Therefore, this study aimed to assess the potential value of MMP-13 as a biomarker for OA. Methods: The study enrolled 51 patients, of which 33 had advanced varus OA and 18 did not have OA. Immunohistochemistry and western blotting analyses were performed to measure MMP-13 activity in the cartilage and subchondral bone of patients with OA. Enzyme-linked immunosorbent assay was used to measure serum MMP-13 levels in patients with or without OA. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to assess the association between serum MMP-13 levels and clinical symptoms. Furthermore, the association between serum MMP-13 levels and radiological severity of OA was evaluated using the Kellgren-Lawrence (KL) grading system. Finally, we built the proportional odds logistic regression models to evaluate serum MMP-13 levels as a potential predictor for OA. Results: MMP-13 levels were significantly higher in the severe-worn cartilage of the medial tibial plateau than in the relatively intact portion of the lateral cartilage (p < 0.05). This was contrary to the findings for MMP-13 differential expression in the subchondral bone in knee OA (p < 0.05). Patients with OA had significantly higher serum MMP-13 levels compared with patients without OA. Additionally, remarkable associations among serum MMP-13 levels, WOMAC scores, and KL grading scores were found in the end-stage OA. Furthermore, the subsequent analysis suggested that serum MMP-13 level was a significant predictor for OA. Conclusion: MMP-13 is valuable for diagnosing, measuring disease severity, and predicting OA in the advanced period of the disease, suggesting that it has potential possibility as a biomarker for OA. However, the underlying mechanisms and clinical application of MMP-13 as a biomarker for OA require to be further investigated.

Association Between Clinical Symptoms and Radiographic Features in Late-Stage Knee Osteoarthritis Using a New Radiographic Parameter.

OBJECTIVE: In this study, we proposed a new radiographic parameter, the plateau attrition index (PAI), and the PAI grades (PAIs) to explore the relationship between subchondral attrition of the tibial plateau and symptoms of knee osteoarthritis (OA) in patients with late-stage knee osteoarthritis. METHOD: One hundred nineteen patients with late-stage knee osteoarthritis were enrolled. The Kellgren and Lawrence (K/L) grades and hip-knee-ankle (HKA) angle were used to characterize the radiographic features of knee OA. The bone attrition of the tibial plateau was determined by the PAI and PAIs. The symptoms of knee OA were assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), which is composed of the WOMAC pain (WOMP), WOMAC stiffness (WOMS), and WOMAC function (WOMF) subscores. WOMAC pain scores were divided into non-weight-bearing pain (NWBP) and weight-bearing pain (WBP) subcategories. The Pearson correlation coefficient was used to determine the relationship between the PAI, HKA angle, and WOMAC scores. The Spearman rank correlation coefficient was used to evaluate the correlation between the WOMAC score and the PAIs and K/L grades. RESULTS: The distribution of the WOMAC scores according to the PAIs was significant (P < .01). A positive correlation was identified between the PAI and the WOMAC, WOMP, WOMF and WBP scores (r = 0.29, 0.34, 0.26 and 0.34, P < .01, respectively). In addition, the PAIs was also significantly correlated with the WOMAC, WOMP, WOMF, and WBP scores (r = 0.37, 0.38, 0.35 and 0.44, P < .01, respectively). CONCLUSIONS: The attrition of tibial subchondral bone determined by the new parameter, the plateau attrition index, was correlated with symptoms, especially weight-bearing pain in late-stage knee OA.

Expression Patterns and Prognostic Values of ORMDL1 in Different Cancers.

The mammalian orosomucoid-like gene family (ORMDL), containing ORMDL1, ORMDL2, and ORMDL3, is the important regulator of sphingolipid metabolism, which is relevant to cell growth, proliferation, migration, and invasion. Since the role of ORMDL1 in cancers remained unclear, the main purpose of our study was to explore the expression patterns and prognostic values of ORMDL1 in different tumors, especially in cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B cell lymphoma (DLBCL), acute myeloid leukemia (LAML), and thymoma (THYM). Bioinformatics tools including GEPIA, CCLE, LinkedOmics, cBioPortal, and TIMER databases were used. As a result, the expression levels of ORMDL1 in tumor tissues and normal tissues varied in different cancers, especially significantly upregulated in CHOL, DLBCL, LAML, and THYM. Moreover, ORMDL1 mRNA was also highly expressed in cell lines of DLBCL and LAML. Further studies showed that ORMDL1 overexpression was associated with poor prognosis in DLBCL, but not significant in CHOL, LAML, and THYM. Consistently, there were genetic alterations of ORMDL1 in DLBCL, and patients with genetic alterations indicated worse survival. Coexpressed genes and related biological events with ORMDL1 in DLBCL were found via LinkedOmics, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The relationship between ORMDL1 and cancer immune cells was investigated, and ORMDL1 expression was positively correlated with infiltrating levels of B cells. In conclusion, ORMDL1 is suggested to be a tumorigenic factor and considered as the potential therapeutic target and prognostic biomarker in DLBCL.

Recent Advances of Magnetic Nanomaterials in Bone Tissue Repair.

The magnetic field has been proven to enhance bone tissue repair by affecting cell metabolic behavior. Magnetic nanoparticles are used as biomaterials due to their unique magnetic properties and good biocompatibility. Through endocytosis, entering the cell makes it easier to affect the physiological function of the cell. Once the magnetic particles are exposed to an external magnetic field, they will be rapidly magnetized. The magnetic particles and the magnetic field work together to enhance the effectiveness of their bone tissue repair treatment. This article reviews the common synthesis methods, the mechanism, and application of magnetic nanomaterials in the field of bone tissue repair.

Expression profiles and prognostic significance of AFTPH in different tumors.

Aftiphilin (AFTPH) plays an important role in regulating intracellular trafficking, exocytosis, and the pro-inflammatory response. However, the potential prognostic role of AFTPH in cancers remains unclear. Here, we examined the expression profiles and prognostic significance of AFTPH in breast invasive carcinoma (BRCA), diffuse large B-cell lymphoma (DLBC), lung squamous cell carcinoma (LUSC), and pancreatic adenocarcinoma (PADD) using the GEPIA and UALCAN databases. AFTPH expression was observed to be higher in cancer tissues than in normal tissues, but expression did not differ significantly between tumor stages for the four cancer types. AFTPH expression in cancer cell lines was investigated using the CCLE database; AFTPH was found to be highly expressed in four cancer cell lines. The relationship between AFTPH expression and patient prognosis was analyzed using GEPIA, LinkedOmics, and Kaplan-Meier plotter databases. Low expression of AFTPH was associated with improved prognosis for BRCA, DLBC, LUSC, and PAAD. Genetic alterations of AFTPH in cancers were explored using the cBioPortal website, revealing that gene copy number gains and amplification are common in BRCA, DLBC, LUSC, and PAAD. Related genes and markers associated with AFTPH were discovered using the LinkedOmics database. Furthermore, transfection of cells with AFTPH siRNA demonstrated that AFTPH exerts positive effects on cell proliferation in BRCA, LUSC, and PAAD cells. In conclusion, AFTPH may be a potential therapeutic target and prognostic biomarker for BRCA, DLBC, LUSC, and/or PAAD.

Biphasic Double-Network Hydrogel With Compartmentalized Loading of Bioactive Glass for Osteochondral Defect Repair.

Periarticular injury usually causes the defects of superficial cartilage and the underlying subchondral bone. Although some efficacious outcomes have been achieved by the existing therapeutic methods both in clinics and research, like symptomatic treatment, microfracture surgery, and tissue engineering technology, they still present specific disadvantages and complications. To improve this situation, we designed a biphasic (bi-) scaffold aiming to repair the structure of cartilage and subchondral bone synchronously. The scaffold consisted of a superior double-network (DN) hydrogel layer and a lower bioactive glass (BG) reinforced hydrogel layer, and the DN hydrogel included glycol chitosan (GC) and dibenzaldhyde functionalized poly(ethylene oxide) network, and sodium alginate (Alg) and calcium chloride (CaCl2) network. To investigate its effectiveness, we applied this biphasic scaffold to repair osteochondral full-thickness defects in rabbit models. We set up six observation groups in total, including Untreated group, Microfracture group, BG only group, DN gel group, bi-DN gel group, and bi-DN/TGF-ß gel group. With a follow-up period of 24 weeks, we evaluated the treatment effects by gross observation, micro-CT scan and histological staining. Besides, we further fulfilled the quantitative analysis of the data from ICRS score, O'Driscoll score and micro-CT parameters. The results revealed that neat GC/Alg DN hydrogel scaffold was only conductive to promoting cartilage regeneration and neat BG scaffold merely showed the excellent ability to reconstruct subchondral bone. While the biphasic scaffold performed better in repairing osteochondral defect synchronously, exhibiting more well-integrated cartilage-like tissue with positive staining of toluidine blue and col II immunohistochemistry, and more dense trabecular bone connecting closely with the surrounding host bone. Therefore, this method possessed the clinical application potential in treating articular injury, osteochondral degeneration, osteochondral necrosis, and sclerosis.

Progressive 3D Printing Technology and Its Application in Medical Materials.

Three-dimensional (3D) printing enables patient-specific anatomical level productions with high adjustability and resolution in microstructures. With cost-effective manufacturing for high productivity, 3D printing has become a leading healthcare and pharmaceutical manufacturing technology, which is suitable for variety of applications including tissue engineering models, anatomical models, pharmacological design and validation model, medical apparatus and instruments. Today, 3D printing is offering clinical available medical products and platforms suitable for emerging research fields, including tissue and organ printing. In this review, our goal is to discuss progressive 3D printing technology and its application in medical materials. The additive overview also provides manufacturing techniques and printable materials.

Role of miRNA-542-5p in the tumorigenesis of osteosarcoma.

Osteosarcoma, one of the most common malignant bone tumors, is characterized by a high rate of metastasis, and the survival rate of patients with metastatic osteosarcoma is poor. Previous studies have reported that miRNAs often regulate the occurrence and development of various tumors. In this work, we identified miRNA-542-5p as a critical miRNA in osteosarcoma by overlapping three Gene Expression Omnibus datasets, and then evaluated miRNA-542-5p expression profiles using Gene Expression Omnibus and Sarcoma-microRNA Expression Database. We used MISIM to investigate miRNAs correlated with miR-542 and identified potential target genes of miRNA-542-5p using miRWalk. Functional and pathway enrichment analyses were performed using The Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction was performed using Search Tool for the Retrieval of Interacting Genes and Cytoscape. We report that the relative level of miRNA-542-5p was significantly higher in osteosarcoma than in healthy bone. Expressions of hsa-miR-330 and hsa-miR-1202 were found to be strongly correlated with that of miR-542-5p. Furthermore, we identified a total of 514 down-regulated genes as possible targets of miR-542-5p. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the putative target genes of miR-542-5p were most enriched in the cell-cycle process. The differentially expressed genes CDCA5, PARP12 and HSPD1 were found to be hub genes in protein-protein interaction networks. Finally, transfection of the osteosarcoma cell line U2OS with miR-542-5p mimics or inhibitor revealed that miR-542-5p can promote cell proliferation. In conclusion, our results suggest that miR-542-5p may promote osteosarcoma proliferation; thus, this miRNA may have potential as a biomarker for diagnosis and prognosis.

Estimation and projection about the standardized prevalence of osteoporosis in mainland China.

We performed a systematic analysis of the standardized prevalence of osteoporosis in mainland China from 1990 to 2050. INTRODUCTION: Osteoporosis is the most common bone disease. We aimed to investigate the standardized prevalence of osteoporosis in mainland China at the national and regional levels, with projections until 2050. METHODS: A comprehensive literature search was performed in PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, and CBM-SinoMed. We constructed resample sets to calculate the standardized prevalence in each study. Multilevel mixed-effects logistic regression was used to estimate the age-specific and sex-specific prevalence. The United Nations Population Division (UNPD) data and regional population data from the fifth and sixth censuses in mainland China were used to estimate and project the national and regional prevalence of osteoporosis. RESULTS: The standardized prevalence of osteoporosis ranged from 5.04% (2.12~11.34%) to 7.46% (3.13~16.32%) in males aged ≥ 50 years and from 26.28% (15.38~40.40%) to 39.19% (25.74~53.95%) in females aged ≥ 50 years from 1990 to 2050. Moreover, we did not find a significant difference in the standardized prevalence among three geographic regions (Central China, West China, and East China). CONCLUSION: We found that osteoporosis is a serious public health challenge in mainland China. The findings in our study add insight into the epidemiology of osteoporosis and would be beneficial for the prevention and treatment of osteoporosis in mainland China.

Preliminary mechanisms of regulating PD­L1 expression in non­small cell lung cancer during the EMT process.

Non­small cell lung cancer (NSCLC) is one of the most severe malignant tumor types worldwide. Recent studies have reported an important role of PD­L1 in mediating immune evasion in the tumor microenvironment. In addition, increasing research has indicated that the expression of PD­L1 is related to the epithelial­mesenchymal transition (EMT) process, but the related mechanisms remain to be explored. In the present study, we explored the molecular mechanisms underlying the regulation of PD­L1 expression during the EMT process in NSCLC cells treated with transforming growth factor­ß1 (TGF­ß1) and fibroblast growth factor 2 (FGF2). The phenotypic alteration associated with EMT was evaluated by western blotting and confirmed by a wound­healing assay. The results revealed that EMT markedly promoted the expression of PD­L1 in the A549 cell line, while having no obvious influence on the H1650 and H1975 cells. Furthermore, the AKT pathway inhibitor LY294002, the ERK pathway inhibitor PD98059 and the TAK1 pathway inhibitor 5Z­7 inhibited the expression of PD­L1 in A549 and H1650 cells, but not in H1975 cells, during the EMT process. Moreover, our study indicated that the AKT, ERK and TAK1 pathways regulated the expression of PD­L1 by mediating transportation of the transcription factor Stat3 and the p65 subunit of NF­κB from the cytoplasm to the nucleus, with such findings determined by western blotting and flow cytometric analyses. Furthermore, the expression of PD­L1 was significantly increased following treatment with gefitinib in a tumor xenograft model. In summary, our results support the role of ERK, AKT and TAK1 in mediating the expression of PD­L1 during the EMT process, and indicate a promising strategy of PD­L1­targeted therapy for the clinical treatment of NSCLC.

Porous Particle-Reinforced Bioactive Gelatin Scaffold for Large Segmental Bone Defect Repairing.

Large segmental bone defect repairing remains a big challenge in clinics, and synthetic bone grafts suitable for this purpose are still highly demanded. In this article, hydrophilic composite scaffolds (bioactive hollow particle (BHP)-gel scaffold) composed of bioactive hollow nanoparticles and cross-linked gelatin have been developed. The bioactive nanoparticles have a porous structure as well as high specific surface area; thus, they interact strongly with gelatin to overcome the swelling problem that a hydrophilic polymer scaffold will usually face. With this combination, these BHP-gel scaffolds showed porous structure and mechanical properties similar to those of the cancellous bone. They also showed excellent bioactivity and cell growth promotion performance in vitro. The best of them, namely, 10BHP-gel scaffold, was evaluated in vivo on a rat femur model, where it was found that the 5 mm segmental bone defect almost healed with new bone tissue formed in 12 weeks and the scaffold itself degraded at the same time. Thus, 10BHP-gel scaffold may become a potential bone graft for large segmental bone defect healing in the future.

Apatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-rechallenged therapy for EGFR-mutant non-small cell lung cancer (NSCLC) patients who acquired resistance showed moderate efficacy. Considering the high interrelation between EGFR and vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) pathways, we firstly evaluated EGFR-TKI combined with apatinib (a highly selective VEGFR2 inhibitor) in EGFR-TKI-resistant model and patients. METHODS: Effects of apatinib, gefitinib and gefitinib plus apatinib were assessed on four NSCLC cell lines (A549 with wild-type EGFR, H1975 harbouring L858R and T790M, H1650 and HCC827 harbouring E746_A750 deletion) and xenograft model of acquired resistance that was established by injecting H1975 cells. Furthermore, we retrospectively evaluated EGFR-TKI rechallenge with apatinib in 16 patients. RESULTS: Gefitinib plus apatinib strengthened the effect of gefitinib and apatinib alone on the four NSCLC cell lines, and H1975 was the most susceptible one. Co-administration delayed the tumour growth than mono-therapy in the xenograft model and had better effect on inhibiting the activation of EGFR and VEGFR2 and expression of CD31 (an angiogenesis marker) and vascular endothelial growth factor A (an important pro-angiogenesis factor in the tumour microenvironment). Changes in protein expression of protein kinase B/mammalian target of rapamycin and extracellular signal-regulated kinase pathways demonstrated the potent inhibitory effect on the pro-survival signalling pathways by combined therapy. EGFR-TKI rechallenge with apatinib achieved a median progression-free survival of 4.60 months (95% confidence interval, 2.23-12.52 months) in the patients. CONCLUSIONS: Apatinib significantly potentiated the antitumour effect of gefitinib in NSCLC with T790M-related EGFR-TKI resistance both in vivo and vitro. EGFR-TKI rechallenge with apatinib might represent a new option for NSCLC with T790M or unknown resistance mechanism.

Novel bioactive glass based injectable bone cement with improved osteoinductivity and its in vivo evaluation.

Recently, more and more attention has been paid to the development of a new generation of injectable bone cements that are bioactive, biodegradable and are able to have appropriate mechanical properties for treatment of vertebral compression fractures (VCFs). In this study, a novel PSC/CS composite cement with high content of PSC (a phytic acid-derived bioactive glass) was prepared and evaluated in both vitro and vivo. The PSC/CS cement showed excellent injectability, good resistance to disintegration, radiopacity and suitable mechanical properties. The in vitro test showed that the cement was bioactive, biocompatible and could maintain its shape sustainably, which made it possible to provide a long-term mechanical support for bone regeneration. Radiography, microcomputed tomography and histology of critical sized rabbit femoral condyle defects implanted with the cements proved the resorption and osteoinductivity of the cement. Compared with the PMMA and CSPC, there were more osteocyte and trabeculae at the Bone-Cement interface in the group PSC/CS cement. The volume of the residual bone cement suggested that PSC/CS had certain ability of degradation and the resorption rate was much lower than that of the CSPC cement. Together, the results indicated that the cement was a promising bone cement to treat the VCFs.