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Intervertebral disc (IVD) degeneration (IVDD) is the most common spinal disorder, which can lead to the symptoms of neck pain or low back pain. In healthy mature IVD tissues, extracellular matrix (ECM) complex possesses favorable biochemical and biomechanical properties, withstanding compression and torsion forces. IVD cells and ECM associate with each other to form a coordinated functional system. IVD cells are the main producers of ECM components, while ECM could modulate the viability and phenotype of IVD cells via direct interactions or indirect regulations. However, with the process of IVDD and ageing, ECM of IVD undergoes content loss and structure degeneration. Moreover, the accumulation of catabolic products may further deteriorate the IVD microenvironment. A better understanding of the physiology and the pathology of ECM within the IVD provides new insight into potential IVD regeneration strategies. Natural ECM components, functional motifs, or mimetic peptides are widely used in IVD repair by not only restoring structural support but also regulating cell fate and tissue microenvironment. Herein, we reviewed recent advances in the involvement of ECM in IVD health and disease, with an emphasis on ECM composition and organization, cell-matrix interactions, pathological ECM degradation, and promising matrix-based biomaterials for IVD regeneration.

Intervertebral disc (IVD) degeneration (IDD), the leading cause of low back pain (LBP), remains intractable due to a lack of effective therapeutic strategies. Several lines of studies have documented that nucleus pulposus cell (NPC) death induced by excessive oxidative stress is a crucial contributor to IDD. However, the concrete role and regulation mechanisms have not been fully clarified. Selenium (Se), a vital prosthetic group of antioxidant enzymes, is indispensable for maintaining redox homeostasis and promoting cell survival. However, no light was shed on the role of Se on IDD progression, especially regulation on mitochondrial dynamics and homeostasis. To fill this research gap, the current study focuses on the effects of Se, including sodium selenite (SS) and selenomethionine (Se-Met), on IDD progression and the underlying mechanisms. In vitro, we found that both SS and Se-Met alleviated tert-butyl hydroperoxide- (TBHP-) induced oxidative stress, protected mitochondrial function, and inhibited apoptosis of NPCs. Further experiments indicated that Se suppressed TBHP-induced mitochondrial fission and rescued the imbalance of mitochondrial dynamics. Promoting mitochondrial fission by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) partially counteracted the cytoprotective effects of Se. Moreover, blocking nuclear factor erythroid 2-related factor 2 (Nrf2) with ML385 proved that the effect of Se on regulating mitochondrial dynamics was attributed to the activation of the Nrf2 pathway. In the puncture-induced rat IDD model, a supplement of Se-Met ameliorated degenerative manifestations. Taken together, our results demonstrated that Se suppressed TBHP-induced oxidative stress and mitochondrial fission by activating the Nrf2 pathway, thereby inhibiting the apoptosis of NPCs and ameliorating IDD. Regulation of mitochondrial dynamics by Se may have a potential application value in attenuating the pathological process of IDD.

c‐Jun activation domain‐binding protein‐1 (Jab1) is aberrantly overexpressed in multiple cancers and plays an oncogenic role in cancer progression. We examined the association between Jab1 expression and prognosis in patients with cancer by conducting a meta‐analysis. A comprehensive search strategy was performed using the PubMed, Web of Science, Ovid and EMBASE in July 2020. Eligible studies were enrolled according to definite criteria. Twenty‐seven studies involving 2609 patients were enrolled in this meta‐analysis. A significant association between high Jab1 expression and poor overall survival (pooled hazard ratio [HR] 2.344, 95% confidence interval [CI]: 2.037‐2.696) was observed. Subgroup analyses of the type of cancer, sample size, follow‐up period, Jab1 detection method and preoperative treatment did not alter the significance. On pooling data from Cox multivariate analyses, high Jab1 expression was found to be an independent prognostic indicator for overall survival. In addition, high Jab1 expression was found to be associated with advanced clinicopathological features such as clinical stage, lymphatic metastasis, histological grade and distant metastasis in cancers. Our meta‐analysis is the first to demonstrate that high Jab1 expression may be a promising indicator of poor prognosis and has an independent prognostic value for overall survival in patients with cancer.

To assess the efficacy and safety of interleukin (IL)-17A inhibitors in patients with ankylosing spondylitis (AS). PubMed, EMBASE, and Web of Science were searched up to 5 February 2020 for randomized controlled trials (RCTs) that assessed the efficacy and safety of IL-17A inhibitors in patients with AS. We used a meta-analytic approach to perform a random effects analysis or fixed effects analysis according to heterogeneity. Subgroup analyses between studies included medication, time to primary endpoint, and data source. Odds ratios (ORs) or mean differences (MDs) were used to assess the efficacy and safety of IL-17A inhibitors in AS. A total of ten RCTs with 2613 patients were eligible for inclusion in the analysis (six for secukinumab, two for ixekizumab, one for netakimab, and one for bimekizumab). Compared to placebo, IL-17A inhibitors improved ASAS20 response rate (OR = 2.58;p p p = 0.03) and nasopharyngitis (OR = 1.72;p p = 0.60). IL-17A inhibitors demonstrated better efficacy in patients with AS in several evaluation indicators. However, the safety of IL-17A inhibitors remains to be further studied in studies with larger sample size and longer follow-up times.

Wrist reconstruction after en bloc resection of bone tumors of the distal radius has been a great challenge. Although many techniques have been used for the reconstruction of long bone defects following en bloc resection of the distal radius, the optimal reconstruction method remains controversial. This is the first review to systematically describe various reconstruction techniques. We not only discuss the indications, functional outcomes, and complications of these reconstruction techniques but also review the technical refinement strategies for improving the stability of the wrist joint. En bloc resection should be performed for Campanacci grade III giant cell tumors (GCT) as well as malignant tumors of the distal radius. However, wrist reconstruction after en bloc resection of the distal radius represents a great challenge. Although several surgical techniques, either achieving a stable wrist by arthrodesis or reconstructing a flexible wrist by arthroplasty, have been reported, the optimal reconstruction procedure remains controversial. The purpose of this review was to investigate which reconstruction methods might be the best option by analyzing the indications, techniques, limitations, and problems of different reconstruction methods. With the advancement of imaging, surgical techniques and materials, some reconstruction techniques have been further refined. Each of the techniques discussed in this review has its advantages and disadvantages. Wrist arthrodesis seems to be preferred over wrist arthroplasty in terms of grip strength and long-term complications, while wrist arthroplasty seems to be superior to wrist arthrodesis in terms of wrist motion. All things considered, wrist arthroplasty with a vascularized fibular head autograft might be a good option because of better wrist function, acceptable grip strength, and a relatively lower complication rate. Moreover, wrist arthrodesis is still an option if the fibular head autograft reconstruction fails. Orthopaedic oncologists should familiarize themselves with the characteristics of each technique to select the most appropriate reconstruction method depending on each patient's situation.

The epithelial-to-mesenchymal transition (EMT) is a reversible process that may interact with tumor immunity through multiple approaches. Increasing evidence has demonstrated the interconnections among EMT-related processes, tumor microenvironment, immune activity, as well as the potential influence on immunotherapy response. Long non-coding RNAs (lncRNAs) are emerging as critical modulators of gene expression. They can play fundamental roles in tumor immunity and act as promising biomarkers of immunotherapy response. However, the potential roles of lncRNA in the crosstalk of EMT and tumor immunity are still unclear in sarcoma. We obtained multi-omics profiling of 1440 pan-sarcoma patients from 19 datasets. Through an unsupervised consensus clustering approach, we categorized EMT molecular subtypes. We subsequently identified 26 EMT molecular subtype and tumor immune-related lncRNAs (EILncRNA) across pan-sarcoma types and developed an EILncRNA signature-based weighted scoring model (EILncSig). The EILncSig presented a favorable performance in predicting the prognosis of sarcoma, and the high-EILncSig was associated with exclusive TME characteristics with desert-like infiltration of immune cells. Multiple altered pathways, somatically mutated genes and recurrent CNV regions associated with EILncSig were identified. Notably, the EILncSig was associated with the efficacy of immune checkpoint inhibition (ICI) therapy. We additionally screened compounds such as Irinotecan that may have the potential to convert the EILncSig phenotype. By integrative analysis on multi-omics profiling, our findings provide a comprehensive resource for understanding the functional role of lncRNA-mediated immune regulation in sarcomas, which may advance the understanding of tumor immune response and the development of lncRNA-based immunotherapeutic strategies for sarcoma.

Background Joint-preserving intercalary tumor resection can result in better proprioception and a more normal joint function after reconstruction. However, most reported reconstruction techniques are usually associated with frequent complications. Therefore, the approach of reconstruction following joint-preserving tumor resection warrants further study. Methods Between September 2016 and October 2018, 12 patients with metaphyseal malignant bone tumors around the knee joint were treated by joint-preserving intercalary resections with the aid of three-dimensional (3D)-printed osteotomy guide plates and reconstructions using 3D-printed intercalary prostheses. We assessed the accuracy of the resection by comparing the cross sections at the resection plane with 3D-printed matching surface of the prostheses. The functional outcomes, complications and oncological status were also evaluated. Results All patients were observed for 7 to 32 months with an average follow-up of 22.5 months. The achieved resection was accurate, with accurate matching between the residual bone and prosthesis. The mean MSTS score was 28 (range, 26-30). Superficial infection occurred in two patients. Local recurrence was observed in one patient, while pulmonary metastasis was identified in one patient. Conclusions The personalized osteotomy guide plate and prosthesis based on 3D printing technique facilitate joint-preserving tumor resection and functional reconstruction. However, longer follow-up and larger sample size are required to clarify its long-term outcomes. Level of evidence Level IV, therapeutic study.

Compression-induced apoptosis of nucleus pulposus (NP) cells plays a pivotal role in the pathogenesis of intervertebral disc degeneration (IVDD). Recent studies have shown that the dysregulation of mitochondrial fission and fusion is implicated in the pathogenesis of a variety of diseases. However, its role in and regulatory effects on compression-induced apoptosis of NP cells have not yet been fully elucidated. Heat shock protein 70 (HSP70) is a major cytoprotective heat shock protein, but its physiological role in IVDD, especially its effect on mitochondrial fission and fusion, is still unknown. Herein, we found that compression could induce mitochondrial fission, which ultimately trigger apoptosis of NP cells via the mitochondrial apoptotic pathway. In addition, we identified the cytoprotective effects of HSP70 on NP cells, and we found that promoting the expression of HSP70 could protect NP cells from abnormal mechanical loading in vitro and in vivo. Finally, we showed that HSP70 inhibited compression-induced mitochondrial fission by promoting SIRT3 expression, thereby attenuating mitochondrial dysfunction and the production of reactive oxygen species and ultimately inhibiting the mitochondrial apoptotic pathway in NP cells. In conclusion, our results demonstrated that HSP70 could attenuate compression-induced apoptosis of NP cells by suppressing mitochondrial fission via upregulating SIRT3 expression. Promoting the expression of HSP70 might be a novel strategy for the treatment of IVDD.

Intervertebral disc (IVD) degeneration is considered to be the primary reason for low back pain. Despite remarkable improvements in both pharmacological and surgical management of IVD degeneration (IVDD), therapeutic effects are still unsatisfactory. It is because of the fact that these therapies are mainly focused on alleviating the symptoms rather than treating the underlying cause or restoring the structure and biomechanical function of the IVD. Accumulating evidence has revealed that the endogenous stem/progenitor cells exist in the IVD, and these cells might be a promising cell source in the regeneration of degenerated IVD. However, the biological characteristics and potential application of IVD-derived stem/progenitor cells (IVDSCs) have yet to be investigated in detail. In this review, the authors aim to perform a review to systematically discuss (1) the isolation, surface markers, classification, and biological characteristics of IVDSCs; (2) the aging- and degeneration-related changes of IVDSCs and the influences of IVD microenvironment on IVDSCs; and (3) the potential for IVDSCs to promote regeneration of degenerated IVD. The authors believe that this review exclusively address the current understanding of IVDSCs and provide a novel approach for the IVD regeneration.

Due to the rarity and heterogeneity, it is challenging to explore and develop new therapeutic targets for patients with sarcoma. Recently, immune cell infiltration in the tumor microenvironment (TME) was widely studied, which provided a novel potential approach for cancer treatment. The competing endogenous RNA (ceRNA) regulatory network has been reported as a critical molecular mechanism of tumor development. However, the role of the ceRNA regulatory network in the TME of sarcoma remains unclear. In this study, gene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) sarcoma datasets, and an immune infiltration-related ceRNA network was constructed, which comprised 14 lncRNAs, 13 miRNAs, and 23 mRNAs. Afterward, we constructed an immune infiltration-related risk score model based on the expression of IRF1, MFNG, hsa-miR-940, and hsa-miR-378a-5p, presenting a promising performance in predicting the prognosis of patients with sarcoma.

Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX -/- mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX -/- mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.

Background: Tumor-infiltrating natural killer (NK) cells (TINKs) are crucial immune cells in tumor defense, and might be related to tumor prognosis. However, the results were discrepant among different studies. The present meta-analysis was performed to comprehensively assess the prognostic value of NK cell markers in solid tumor tissues.Methods: PubMed, Web of Science, and EMBASE were searched to identify original researches reporting the prognostic significance of TINKs in solid tumors. NK cell markers CD56, CD57, NKp30, and NKp46 were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated by STATA software 14.0 to assess the prognostic significance.Results : Of the 56 included studies, there were 18 studies on CD56, 31 studies on CD57, 1 study on NKp30, and 7 studies on NKp46. High levels of CD56, CD57, NKp30, and NKp46 were significantly correlated with better OS of patients with solid malignancies (HR = 0.473, 95%CI: 0.315–0.710, p < 0.001; HR = 0.484, 95%CI: 0.380–0.616, p < 0.001; HR = 0.34, 95%CI: 0.14–0.80, p = 0.014; HR = 0.622, 95%CI: 0.470–0.821, p < 0.001, respectively). Our results also revealed that CD56, CD57, and NKp46 could act as independent prognostic predictors for favorable OS (HR = 0.372, 95%CI: 0.261–0.531, p < 0.001; HR = 0.525, 95%CI: 0.346–0.797, p = 0.003; HR = 0.559, 95%CI: 0.385–0.812, p = 0.002, respectively).Conclusions : Our results indicated that high levels of NK cell markers in solid tumor tissues could predict favorable prognosis for solid tumor patients.

The endogenous repair failure of degenerated intervertebral disk (IVD) is highly related to the exhaustion of nucleus pulposus stem cells (NPSCs). Excessive oxidative stress could induce apoptosis and senescence of NPSCs, thus, declining the quantity and quality of NPSCs. Heat shock protein 70 (HSP70) is a family of cytoprotective and antioxidative proteins. However, there is no report on the protective effects of HSP70 on oxidative stress-induced NPSC impairments and underlying mechanisms. In the present study, we treated NPSCs with tert-butyl hydroperoxide (t-BHP) in vitro to simulate an oxidative stress condition. HSP70 inducer TRC051384 was used to evaluate the cytoprotective effects of HSP70. The results suggested that HSP70 impeded t-BHP-mediated cell viability loss and protected the ultrastructure of NPSCs. Moreover, t-BHP could induce mitochondrial apoptosis and p53/p21-mediated senescence of NPSCs, both of which were significantly inhibited in HSP70 activation groups. Excessive oxidative stress and mitochondrial dysfunction reinforced each other and contributed to the cellular damage processes. HSP70 decreased reactive oxygen species (ROS) production, rescued mitochondrial membrane potential (MMP) collapse, and blocked ATP depletion. Finally, our data showed that HSP70 downregulated the JNK/c-Jun pathway. Taken together, activation of HSP70 could protect against t-BHP-induced NPSC apoptosis and senescence, thus, improving the quantity and quality of NPSCs. Therefore, HSP70 may be a promising therapeutic target for IVD degeneration.

Background An increasing number of studies have demonstrated that long non-coding RNAs (lncRNAs) play pivotal roles in cancer onset and development. LncRNA AFAP1-AS1 has been validated to be abnormally upregulated and play oncogenic roles in various malignant tumors. The biological role and mechanism of AFAP1-AS1 in OS (osteosarcoma) remains unclear. Methods Quantitative reverse transcription PCR (qRT-PCR) is applied to examine AFAP1-AS1 expression in OS tissues and OS cell lines. The function of AFAP1-AS1 in OS cells is investigated via in-vitro and in-vivo assays. Western bolt and rescue experiments are applied to detect the expression changes of key molecules including epithelial-mesenchymal transition markers and identify the underlying molecular mechanism. RNA immunoprecipitation is performed to reveal the interaction between AFAP1-AS1 and RhoC. Results AFAP1-AS1 expression is upregulated in human OS tissues and cell lines. AFAP1-AS1 knockdown induces OS cell apoptosis and cell cycle G0/G1 arrest, suppresses OS cells growth, migration, invasion, vasculogenic mimicry formation and epithelial-mesenchymal transition (EMT), and affects actin filament integrity. AFAP1-AS1 knockdown suppresses OS tumor formation and growth in nude mice. AFAP1-AS1 knockdown elicits a signaling inhibition including decreased levels of RhoC, ROCK1, p38MAPK and Twist1. Moreover, AFAP1-AS1 interacts with RhoC. Overexpression of RhoC can partly reverse AFAP1-AS1 downregulation-induced cell EMT inhibition. Conclusions AFAP1-AS1 is overexpressed in osteosarcoma and plays an oncogenic role in osteosarcoma through RhoC/ROCK1/p38MAPK/Twist1 signaling pathway, in which RhoC acts as the interaction target of AFAP1-AS1. Our findings indicated a novel molecular mechanism underlying the tumorigenesis and progression of osteosarcoma. AFAP1-AS1 could serve as a promising therapeutic target in OS treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1363-0) contains supplementary material, which is available to authorized users.

Binwu Hu,1 Deyao Shi,1 Xiao Lv,1 Fashuai Wu,1 Songfeng Chen,2 Zengwu Shao1 1Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Background: DEP domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR), a recently discovered endogenous inhibitor of mTOR, has been found to be abnormally expressed in various tumors. Recent studies have demonstrated that DEPTOR could serve as a potential prognostic biomarker in several kinds of cancer. However, the prognostic value of DEPTOR is still controversial so far. Patients and methods: PubMed, Embase and Web of Science were systematically searched to obtain all relevant articles about the prognostic value of DEPTOR in cancer patients. ORs or HRs with corresponding 95% CIs were pooled to estimate the association between DEPTOR expression and the clinicopathological characteristics or survival of cancer patients. Results: A total of nine eligible studies with 974 cancer patients were included in our meta-analysis. Our results demonstrated that the expression of DEPTOR was not associated with the overall survival (OS) (pooled HR=0.795, 95% CI=0.252–2.509) and event-free survival (EFS) (pooled HR=1.244, 95% CI=0.543–2.848) in cancer patients. Furthermore, subgroup analysis divided by sample size, type of cancer, Newcastle–Ottawa Scale (NOS) score and evaluation of DEPTOR expression showed identical prognostic value. In addition, our analysis also revealed that there was no significant association between expression level of DEPTOR and clinicopathological characteristics, such as tumor stage, lymph node metastasis, differentiation grade and gender. Conclusion: Our meta-analysis suggested that despite the fact that DEPTOR could be overexpressed or downregulated in cancer patients, it might not be a potential marker to predict the prognosis of cancer patients. Keywords: DEPTOR, cancer, overall survival, event-free survival, meta-analysis

Aims This study aims to investigate the protective effects and potential mechanisms of cyclosporine A (CsA), which efficiently inhibits mitochondrial permeability transition pore (MPTP) opening, on compression-induced apoptosis of human nucleus pulposus mesenchymal stem cells (NP-MSCs). Materials and methods Human NP-MSCs were subjected to various periods of 1.0 MPa compression. Cell viability was evaluated using cell counting kit-8 (CCK-8) assay. The cellular ultrastructure and ATP level were analyzed via transmission electron microscopy (TEM) and ATP detection kit respectively. The apoptosis ratio was determined using Annexin V/PI dual staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. The levels of apoptosis-associated molecules (cleaved caspase-3, Bax and Bcl-2) were analyzed by western blot and qRT-PCR. Additionally, MPTP opening, mitochondrial membrane potential (MMP) and the levels of oxidative stress-related indicators (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA) were monitored. Key findings Annexin V/PI dual staining and detection of apoptosis-associated molecules demonstrated that compression significantly up-regulated apoptosis level of NP-MSCs in a time-dependent manner. CsA greatly down-regulated compression-mediated NP-MSC apoptosis and the cell death ratio. Compression also notably exacerbated mitochondrial dysfunction, ATP depletion and oxidative stress in NP-MSCs, all of which were rescued by CsA. Significance Our results demonstrated that CsA efficiently inhibited compression-induced NP-MSCs apoptosis by alleviating mitochondrial dysfunction and oxidative stress. These findings provide new insights into intervertebral disc (IVD) degeneration (IVDD), and suggest CsA treatment as a potential strategy for delaying or even preventing IVDD.

Background CXCL5 is a member of the CXC-type chemokine family, which has been found to play important roles in tumorigenesis and cancer progression. Recent studies have demonstrated that CXCL5 could serve as a potential prognostic biomarker for cancer patients. However, the prognostic value of CXCL5 is still controversial. Methods We systematically searched PubMed, Embase and Web of Science to obtain all relevant articles investigating the prognostic significance of CXCL5 expression in cancer patients. Hazards ratios (HR) with corresponding 95% confidence intervals (CI) were pooled to estimate the association between CXCL5 expression levels with survival of cancer patients. Results A total of 15 eligible studies including 19 cohorts and 5070 patients were enrolled in the current meta-analysis. Our results demonstrated that elevated expression level of CXCL5 was significantly associated with poor overall survival (OS) (pooled HR 1.70; 95% CI 1.36–2.12), progression-free survival (pooled HR 1.65; 95% CI 1.09–2.49) and recurrence-free survival (pooled HR 1.49; 95% CI 1.15–1.93) in cancer patients. However, high or low expression of CXCL5 made no difference in predicting the disease-free survival (pooled HR 0.63; 95% CI 0.11–3.49) of cancer patients. Furthermore, we found that high CXCL5 expression was associated with reduced OS in intrahepatic cholangiocarcinoma (HR 1.91; 95% CI 1.31–2.78) and hepatocellular carcinoma (HR 1.87; 95% CI 1.55–2.27). However, there was no significant association between expression level of CXCL5 with the OS in lung cancer (HR 1.25; 95% CI 0.79–1.99) and colorectal cancer (HR 1.16; 95% CI 0.32–4.22, p = 0.826) in current meta-analysis. Conclusions In conclusion, our meta-analysis suggested that elevated CXCL5 expression might be an adverse prognostic marker for cancer patients, which could help the clinical decision making process.

The aim of this study was to investigate whether RIPK1 mediated mitochondrial dysfunction and oxidative stress contributed to compression-induced nucleus pulposus (NP) cells necroptosis and apoptosis, together with the interplay relationship between necroptosis and apoptosis in vitro. Rat NP cells underwent various periods of 1.0 MPa compression. To determine whether compression affected mitochondrial function, we evaluated the mitochondrial membrane potential, mitochondrial permeability transition pore (mPTP), mitochondrial ultrastructure and ATP content. Oxidative stress-related indicators reactive oxygen species, superoxide dismutase and malondialdehyde were also assessed. To verify the relevance between oxidative stress and necroptosis together with apoptosis, RIPK1 inhibitor necrostatin-1(Nec-1), mPTP inhibitor cyclosporine A (CsA), antioxidants and small interfering RNA technology were utilized. The results established that compression elicited a time-dependent mitochondrial dysfunction and elevated oxidative stress. Nec-1 and CsA restored mitochondrial function and reduced oxidative stress, which corresponded to decreased necroptosis and apoptosis. CsA down-regulated mitochondrial cyclophilin D expression, but had little effects on RIPK1 expression and pRIPK1 activation. Additionally, we found that Nec-1 largely blocked apoptosis; whereas, the apoptosis inhibitor Z-VAD-FMK increased RIPK1 expression and pRIPK1 activation, and coordinated regulation of necroptosis and apoptosis enabled NP cells survival more efficiently. In contrast to Nec-1, SiRIPK1 exacerbated mitochondrial dysfunction and oxidative stress. In summary, RIPK1-mediated mitochondrial dysfunction and oxidative stress play a crucial role in NP cells necroptosis and apoptosis during compression injury. The synergistic regulation of necroptosis and apoptosis may exert more beneficial effects on NP cells survival, and ultimately delaying or even retarding intervertebral disc degeneration.

The needs of society, organizations, enterprises, universities, colleges and schools have always been a combination of theory and practice. All the educational institutions recommend a cooperative teaching in order to explore, enhance and establish school-enterprise Cooperation which is practical-oriented. Most of the institutions go hand in hand with enterprises to cultivate high-level talents. The main purpose of the current study is to examine and explore the practice of school-enterprise cooperation in the field of education. An outline of different parameters such as concept, characteristics and evolution of school-enterprise cooperation are deeply discussed. Besides, this paper is going to shed light on the following aspects: (a) problems existing in school-enterprise cooperationwith special focus on vocational schools; (b) approaches and methods followed in vocational school-enterprise cooperation; (c)necessity and significance of school-enterprise cooperation in vocational education; (d)gaps in teacher resources with special focus on vocational education.For this, the study adopts quantitative approach to understand the gaps and present the solutions. Questionnaire survey is the instrument used to collect required information from the respondents. The study collects primary as well as secondary data.

Binwu Hu,1,* Xiao Lv,1,* Feng Gao,1 Songfeng Chen,2 Shangyu Wang,1 Xiangcheng Qing,1 Jianxiang Liu,1 Baichuan Wang,1 Zengwu Shao1 1Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China *These authors contributed equally to this work Abstract: Accumulating evidence reveals that DEP-domain containing mTOR-interacting protein (DEPTOR) plays pivotal roles in the pathogenesis and progression of many tumors. However, the expression level of DEPTOR and its function in the tumorigenesis of osteosarcoma (OS) remain unknown. In this study, we conducted quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry to detect DEPTOR expression level in human OS tissues and cell lines. To assess DEPTOR function, DEPTOR siRNA was designed and transfected into OS cells, which were then used in a series of in vitro assays. Our results indicated that DEPTOR was highly expressed in some OS tissues and cell lines. DEPTOR knockdown by siRNA dramatically inhibited cell proliferation, migration, invasion, and the formation of vasculogenic mimicry in OS cells. In addition, DEPTOR knockdown induced cell cycle arrest in the G0/G1 phase and apoptosis in the OS cell lines, MG63 and MNNG/HOS. Furthermore, we found that DEPTOR knockdown notably activated mTOR and inhibited the PI3K/Akt pathway. Taken together, these results suggest that DEPTOR overexpression is necessary for the proliferation, migration, invasion, formation of vasculogenic mimicry, and survival of OS cells and may be a potential target for the treatment of OS. Keywords: osteosarcoma, DEPTOR, PI3K/Akt/mTOR pathway, proliferation, apoptosis

Rationale: Mesenchymal cell-derived osteosarcoma is a rare malignant bone tumor affecting children and adolescents. PTEN down-regulation or function-loss mutation is associated with the aggressive of osteosarcoma. Explicating the regulatory mechanism of PTEN might highlight new targets for improving the survival rate of osteosarcoma patients. Methods: The clinical relevance of FGD1 was examined by the TCGA data set, Western blotting and immunohistochemistry of osteosarcoma microarray slides. Functional assays, such as the MTS assay, colony formation assay and xenografts, were used to determine the biological role of FGD1 in osteosarcoma. The protein-protein interaction between FGD1 and PTEN was detected via co-immunoprecipitation. The relationship between FGD1 and PD-L1 was examined by Western blot analysis, RT-qPCR and immunohistochemistry. Results: In this study, analysis of the TCGA data set of sarcomas revealed that FGD1 was over-expressed with the highest P values. Then, we demonstrated that FGD1 was also abnormally up-regulated in osteosarcoma with unfavorable prognosis. Aberrant expressed FGD1 promoted the osteosarcoma tumor cell proliferation and invasion. Moreover, we found that FGD1 was participated in activating PI3K/AKT signaling pathway by interacting with PTEN. Finally, we showed that FGD1 was capable of regulating the tumor immune response via the PTEN/PD-L1 axis in osteosarcoma. Conclusions: Our data suggested that abnormally over-expressed FGD1 functions as an oncogenic protein to promote osteosarcoma progression through inhibiting PTEN activity and activating PI3K/AKT signaling. Notably, FGD1 increased PD-L1 expression in a PTEN dependent manner and modulated the sensitivity of immune checkpoint-based immunotherapy in osteosarcoma. Thus, FGD1 might be a potential target for improving the survival rate of osteosarcomas.

The primer sequences for PCR and the sequences of siRNAs used in this study. (DOCX 15 kb)

Clinicopathological characteristics of the patients enrolled in this study. (DOCX 16 kb)

Due to the ethical concern and inability to detect inner stress distributions of intervertebral disc (IVD), traditional methods for investigation of intervertebral disc degeneration (IVDD) have significant limitations. Many researchers have demonstrated that finite element analysis (FEA) is an effective tool for the research of IVDD. However, the specific application of FEA for investigation of IVDD has not been systematically elucidated before. In the present review, we summarize the current finite element models (FEM) used for the investigation of IVDD, including the poroelastic nonlinear FEM, diffusive-reactive theory model and cell-activity coupled mechano-electrochemical theory model. We further elaborate the use of FEA for the research of IVDD pathogenesis especially for nutrition and biomechanics associated etiology, and the biological, biomechanical and clinical influences of IVDD. In addition, the application of FEA for evaluation and exploration of various treatments for IVDD is also elucidated. We conclude that FEA is an excellent technique for research of IVDD, which could be used to explore the etiology, biology and biomechanics of IVDD. In the future, FEA may help us to achieve the goal of individualized precision therapy.

The aim of this study was to systematically investigate the role of necroptosis in compression-induced rat nucleus pulposus (NP) cells death, as well as explore the underlying mechanisms involved. Rat NP cells underwent various periods of exposure to 1.0 MPa pressure. Cell viability and cell death were quantified by using cell counting kit-8 (CCK-8), and Calcein-AM/propidium iodine (PI) staining respectively. Necroptosis-associated target molecules receptor-interacing protein kinase 1 (RIPK1), phosphorylated RIPK1 (pRIPK1), receptor-interacing protein kinase 3 (RIPK3), phosphorylated RIPK3 (pRIPK3) and mixed lineage kinase domain-like (MLKL) were analyzed by Western-blot and RT-PCR. NP cells were also examined for morphological and ultrastructural changes, which can indicate necroptosis. To indirectly establish the presence of necroptosis, the RIPK1 specific inhibitor necrostatin-1 (Nec-1), RIPK3 inhibitor GSK’872, MLKL inhibitor necrosulfonamide (NSA) and small interfering RNA (siRNA) were utilized. The results established necroptosis was taking place in NP cells. The level of necroptosis increased in a time-dependent manner, and this effect was reduced by Nec-1 in vitro. Additionally, NP cells death were significantly attenuated following treatment with Nec-1, GSK’872 or NSA. SiRNA-induced knockdown of RIPK3 or MLKL increased cell survival rate, while knockdown of RIPK1 resulted in a decreased cell survival rate. In summary, RIPK1/RIPK3/MLKL-mediated necroptosis may play an important role in NP cells death induced by continuous mechanical stress. Treatment strategies which aim to regulate necroptosis may prove beneficial, by both reducing NP cells death and slowing IVD degeneration.

The goal of treating articular cartilage (AC) injury is to regenerate cartilage tissue and to integrate the neo-cartilage with surrounding host cartilage. However, most current studies tend to focus on engineering cartilage; interface integration has been somewhat neglected. An endogenous regenerative strategy that simultaneously increases the recruitment of bone marrow mesenchymal stem cells (BMSCs) and chondrocytes may improve interface integration and cartilage regeneration. In this study, a novel functionalized self-assembling peptide hydrogel (KLD-12/KLD-12-LPP, KLPP) containing link protein N-peptide (LPP) was designed to optimize cartilage repair. KLPP hydrogel was characterized using transmission electron microscopy (TEM) and rheometry. KLPP hydrogel shared a similar microstructure to KLD-12 hydrogel which possesses a nanostructure with a fiber diameter of 25-35 nm. In vitro experiments showed that KLPP hydrogel had little cytotoxicity, and significantly induced chondrocyte migration and increased BMSC migration compared to KLD-12 hydrogel. In vivo results showed that defects treated with KLPP hydrogel had higher overall International Cartilage Repair Society (ICRS) scores, Safranin-O staining scores and cumulative histology scores than untreated defects or defects treated with KLD-12 hydrogel, although defects treated with KLD-12 and KLPP hydrogels received similar type II collagen immunostaining scores. All these findings indicated that the simple injectable functionalized self-assembling peptide hydrogel KLPP facilitated simultaneous recruitment of endogenous chondrocytes and BMSCs to promote interface integration and improve cartilage regeneration, holding great potential as a one-step surgery strategy for endogenous cartilage repair.