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Aim Deep vein thrombosis (DVT) is a common complication of orthopedic surgery. Multiple lines of evidence indicate that genetic factors play an important role in the development of DVT following orthopedic surgery (DVTFOS). Recent evidence suggested that the solute carrier family 44 member 2 (SLC44A) gene may contribute to the risk of DVT. In this study, we aimed to investigate the associations of SLC44A2 and DVTFOS in Chinese Han individuals. Methods In the study, 2,655 subjects, including 689 DVTFOS patients and 1,966 controls, were recruited. Eighteen SNPs were genotyped in the study. Genetic association analyses were performed at both the single marker and haplotype levels. Bioinformatics analyses were conducted to predict the functional consequences of significant SNPs. Results SNP rs2288904 of SLC44A2 was identified as being significantly associated with DVTFOS (P=0.0003, OR [95%CI]=1.28[1.12-1.46]). Allelic analyses showed that the G allele of this SNP significantly elevated the risks of DVTFOS, which was replicated in the genotypic association analyses. Moreover, a two-SNP haplotype, including rs2288904, was found to be strongly correlated with the risk of DVTFOS (P=4.15×10－11). Widespread effects in the expression quantitative trait loci were identified for rs2288904 in multiple tissues. Conclusion In summary, our results provide further supportive evidence of the association of SLC44A2 with the risk of DVTFOS, which also provide clues for understanding the important roles of the SLC44A2 gene in the pathogenesis of DVTFOS and in the development of preventive strategies.

Osteoarthritis (OA) is one of the most popular degenerative joint diseases. The nucleolar GTP binding protein 3 (GNL3) gene encodes guanine nucleotide binding protein-like 3, which is related in cell proliferation, differentiation, and cell cycle regulation. Our study aimed to examine the contribution of GNL3 gene polymorphisms to the risk of hand OA and its related clinical features. A total of 3387 study participants including 1160 patients with hand OA and 2227 controls were recruited in this study. Eleven SNPs in GNL3 gene were selected for genotyping. Genetic association signals were examined using Plink. Relationships between significant SNPs and clinical features of hand OA were also explored. SNP rs11177 was found to be strongly associated with susceptibility of hand OA (P = 4.32 × 10–5). The minor allele of rs11177 was associated with increased susceptibility of hand OA. In addition, significant associations were also identified between genotypes of rs11177 and clinical features of hand OA patients including K-L grade (P P GNL3 in multiple types of human tissues were also identified in GTEx database. Our results have established the link between GNL3 gene and susceptibility of hand OA.

Osteoarthritis (OA), the most common type of arthritis, is an age-associated disease, characterized by the progressive degradation of articular cartilage, synovial inflammation, and degeneration of subchondral bone. Chondrocyte proliferation is regulated by the Indian hedgehog (IHH in humans, Ihh in animals) signaling molecule, which regulates hypertrophy and endochondral ossification in the development of the skeletal system. microRNAs (miRNAs, miRs) are a family of about 22-nucleotide endogenous non-coding RNAs, which negatively regulate gene expression. In this study, the expression level of IHH was upregulated in the damaged articular cartilage tissues among OA patients and OA cell cultures, while that of miR-199a-5p was the opposite. Further investigations demonstrated that miR-199a-5p could directly regulate IHH expression and reduce chondrocyte hypertrophy and matrix degradation via the IHH signal pathway in the primary human chondrocytes. The intra-articular injection of synthetic miR-199a-5p agomir attenuated OA symptoms in rats, including the alleviation of articular cartilage destruction, subchondral bone degradation, and synovial inflammation. The miR-199a-5p agomir could also inhibit the Ihh signaling pathway in vivo. This study might help in understanding the role of miR-199a-5p in the pathophysiology and molecular mechanisms of OA and indicate a potential novel therapeutic strategy for OA patients.

Baicalein is a traditional Chinese medicine with multiple pharmacological effects, including anti-inflammatory activity, anti-pathogen activity, antitumor activity and neuroprotective activity. How...

Additional file 1: Supplemental Tables S1. Genetic information of the 4 genotyped SNPs. Supplemental Figure S1. Linkage disequilibrium structure of the 4 genotyped SNPs. Values of D’ were indicated in each cell. LD block was indicated by black bold frame.

Deep vein thrombosis (DVT) is the blood clot formed in a vein deep in body, mostly occurred in the lower leg or thigh. Early studies indicate that DVT is a complex disorder affected by both environmental and genetic factors. Previous biological evidence have indicated that KEAP1 gene may play an important role in the pathogenesis of DVT. In the present study, we aimed to investigate the genetic association between genetic polymorphisms of KEAP1 gene and the risk of DVT in Han Chinese population. A total of 2558 study subjects comprised of 660 DVT following orthopedics surgery cases and 1898 controls were recruited as discovery sample. In addition, we have also recruited another independent sample sets including 704 DVT following orthopedics surgery cases and 1056 controls for replication. Ten tag SNPs located on KEAP1 gene were selected for genotyping. Single marker based association analyses were conducted at both allelic and genotypic levels. SNPs that passed the Bonferroni correction in the discovery stage were genotyped in the replication dataset. Bioinformatics tools including PolymiRTS, GTEx, STRING and Gene Ontology database were utilized to investigate the functional consequences of the significant SNPs. SNP rs3177696 was identified to be significantly associated with risk of DVT in the study subjects. The G allele of SNP rs3177696 was significantly related to decreased risk of DVT. Functional consequences of SNP rs3177696 were obtained based on bioinformatics analyses. The G allele of SNP rs3177696 was related to the increased gene expression level of KEAP1. In summary, we have identified KEAP1 gene to be a potential susceptible locus for DVT in Han Chinese population. Further bioinformatics analyses have provided supportive evidence for the functional consequence of the significant SNP.

Postmenopausal osteoporosis is a major health problem with important genetic factors in postmenopausal women. We explored the relationship between SQRDL and osteoporosis in a cohort of 1006 patients and 2027 controls from Han Chinese postmenopausal women. Our evidence supported the significant role of SQRDL in the etiology of postmenopausal osteoporosis. Postmenopausal osteoporosis (PMOP) is a metabolic bone disease leading to progressive bone loss and the deterioration of the bone microarchitecture. The sulfide-quinone reductase-like protein is an important enzyme regulating the cellular hydrogen sulfide levels, and it can regulate bone metabolism balance in postmenopausal women. In this study, we aimed to investigate whether SQRDL is associated with susceptibility to PMOP in the Han Chinese population. A total of 3033 postmenopausal women, comprised of 1006 cases and 2027 controls, were recruited in the study. Twenty-two SNPs were selected for genotyping to evaluate the association of SQRDL gene with BMD and PMOP. Association analyses in both single marker and haplotype levels were performed for PMOP. Bone mineral density (BMD) was also utilized as a quantitative phenotype in further analyses. Bioinformatics tools were applied to predict the functional consequences of targeted polymorphisms in SQRDL. The SNP rs1044032 (P = 6.42 × 10−5, OR = 0.80) was identified as significantly associated with PMOP. Three SNPs (rs1044032, rs2028589, and rs12913151) were found to be significantly associated with BMD. Although limited functional significance can be obtained for these polymorphisms, significant hits for association with PMOP were found. Moreover, further association analyses with BMD identified three SNPs with significantly independent effects. Our evidence supported the significant role of SQRDL in the etiology of PMOP and suggest that it may be a genetic risk factor for BMD and osteoporosis in Han Chinese postmenopausal women.

Although genome-wide association studies (GWASs) have identified some risk single-nucleotide polymorphisms in East Asian never-smoking females, the unexplained missing heritability is still required to be investigated. Runs of homozygosity (ROHs) are thought to be a type of genetic variation acting on human complex traits and diseases. We detected ROHs in 8,881 East Asian never-smoking women. The summed ROHs were used to fit a logistic regression model which noteworthily revealed a significant association between ROHs and the decreased risk of lung cancer (P < 0.05). We identified 4 common ROHs regions located at 2p22.1, which were significantly associated with decreased risk of lung cancer (P = 2.00 × 10-4 - 1.35 × 10-4). Functional annotation was conducted to investigate the regulatory function of ROHs. The common ROHs were overlapped with potential regulatory elements, such as active epigenome elements and chromatin states in lung-derived cell lines. SOS1 and ARHGEF33 were significantly up-regulated as the putative target genes of the identified ROHs in lung cancer samples according to the analysis of differently expressed genes. Our results suggest that ROHs could act as recessive contributing factors and regulatory elements to influence the risk of lung cancer in never-smoking East Asian females.

The association of TRIM29 overexpression with cancer progression and poor clinical prognosis has been reported in the context of several types of cancers. In the present study, we investigated the prognostic relevance of TRIM29 and its involvement in the progression of human osteosarcoma. To the best of our knowledge, this is the first study to demonstrate a major role of TRIM29 in osteosarcoma. Our results showed that the expression of TRIM29 in osteosarcoma tissues was much higher than that in normal bone tissues. Furthermore, TRIM29 expression was significantly correlated with tumor size, recurrence, metastasis and overall survival time. High expression of TRIM29 and presence of metastasis were independent predictors of poor prognosis in these patients. Both protein and mRNA expression of TRIM29 in osteosarcoma cell lines were significantly higher than those in osteoblast cell line, hFOB1.19. Moreover, the results indicated that TRIM29 promoted migration and invasive growth of osteosarcoma cells by inducing epithelial-mesenchymal transition. Therefore, ectopic expression of TRIM29 potentially contributes to metastasis and poor prognosis in patients with osteosarcoma. In summary, TRIM29 is a potential prognostic biomarker and a therapeutic target for patients with osteosarcoma.

The aim of the present study was to investigate the molecular circuitry of osteoarthritis (OA) and identify more potential target genes for OA treatment. Microarray data of GSE32317 was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in samples of synovial membrane from patients with early stage of knee OA (OA_Early) and late stage of knee OA (OA_End) that were compared with healthy specimens. Bioinformatics analysis was applied to analyze the significant functions and pathways that were enriched by the common DEGs identified in OA_Early and OA_End samples. Furthermore, a protein‑protein interaction (PPI) network was constructed and significant modules were extracted. Transcription factors (TFs) that could regulate genes in the significant modules were identified. A total of 1,207 and 1,575 DEGs were identified in OA_Early and OA_End samples compared with healthy samples, respectively. A total of 740 genes were upregulated and 308 genes were downregulated across the OA_Early and OA_End samples. These common DEGs were enriched in different gene ontology terms and pathways, such as immune response. Angiotensinogen (AGT) and C‑X‑C motif chemokine ligand 12 (CXCL12) were identified to be hub proteins in the PPI network or in the selected module 1. In addition, the DEG lysine demethylase 2B (KDM2B) was identified as a TF that can regulate genes in the significant modules 2 and 3. In conclusion, the present study has identified AGT, CXCL12 and KDM2B as potentially essential genes associated with the pathogenesis of knee OA.

Background Long noncoding RNA (lncRNA) OIP5 antisense RNA 1 (OIP5-AS1) is an oncogenic lncRNA; however, its role in osteoarthritis (OA) pathology still remains unknown. Materials and Methods qRT-PCR was performed to measure the expressions of OIP5-AS1, miR-29b-3p and progranulin (PGRN) mRNA in OA cartilage tissues and normal cartilage tissues. Chondrocyte cell lines, CHON-001 and ATDC5, were treated with different doses of interleukin-1β (IL-1β) to induce the inflammatory response. Overexpression plasmids, microRNA mimics, microRNA inhibitors and small interfering RNAs were constructed and transfected into CHON-001 and ATDC5 cells. CCK-8 assay was used for determining the cell viability and Transwell assay was used for monitoring cell migration. Western blot was applied to measure the expressions of apoptosis-related proteins. Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the contents of inflammatory factors. StarBase and TargetScan were used to predict the binding sites between OIP5-AS1 and miR-29b-3p, miR-29b-3p and 3′-UTR of PGRN respectively, which were verified by dual luciferase reporter assay. Results OIP5-AS1 and PGRN mRNA were downregulated while miR-29b-3p was upregulated in OA tissues and models. The up-regulated OIP5-AS1 facilitated the proliferation and migration of CHON-001 and ATDC5 cells, while ameliorated the apoptosis and inflammatory response. However, miR-29b-3p had opposite effects. PGRN was identified as a target gene of miR-29b-3p, which could be indirectly suppressed by OIP5-AS1 knockdown. Conclusion Downregulation of OIP5-AS1 induced by IL-1β could inhibit the proliferation and migration abilities of CHON-001 and ATDC5 cells and facilitate the apoptosis and inflammation response via regulating miR-29b-3p/PGRN axis.

Circular RNAs (circRNAs) have been implicated in the pathological regulation of human diseases by acting as microRNA (miRNA) sponges to affect gene expression. CircRNA Fragile Mental Retardation 2 (circ_AFF2) was dysregulated in rheumatoid arthritis (RA), but little is known about its specific function and hidden molecular mechanism in RA. Circ_AFF2, miR-375 and TAK1-binding 2 (TAB2) expression levels were determined through the quantitative real-time polymerase chain reaction (qRT-PCR). Flow cytometry was performed to analyze cell cycle and apoptosis. Cell proliferation detection was conducted by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The protein levels were measured using western blot. Inflammatory response was evaluated by enzyme-linked immunosorbent assay (ELISA). RNA pull-down assay was used to select the miRNA target of circ_AFF2. The interaction between miR-375 and circ_AFF2 or TAB2 was analyzed using the dual-luciferase reporter assay. Contrasted to normal samples and fibroblast-like synoviocytes (FLS), circ_AFF2 expression was upregulated in RA blood samples and FLS-RA cells. Cell cycle, proliferation and inflammatory response were blocked while apoptosis was promoted in FLS-RA after the downregulation of circ_AFF2. In addition, circ_AFF2 could interact with miR-375 and the function of circ_AFF2 was achieved by sponging miR-375 in FLS-RA cells. Moreover, TAB2 was a target of miR-375 and miR-375 repressed RA progression by decreasing TAB2 expression in FLS-RA cells. More importantly, circ_AFF2 promoted the expression of TAB2 by targeting miR-375. These findings clarified that circ_AFF2 induced cell progression, inflammatory response in FLS-RA cells via the miR-375/TAB2 axis. Circ_AFF2 could be used as a biomarker in the diagnosis and treatment of RA.

T-cell immunoglobulin and mucin-domain-3-containing molecule 3 (TIM-3) plays a pivotal role in immune regulation and has been found in various tumors. However, the prevalence and distribution of Tim-3 in osteosarcoma (OS) is still unclear. The aim of this study was to investigate the prevalence and distribution of Tim-3 in OS. Tim-3 on peripheral T cells from 82 OS patients and 60 healthy controls were examined by flow cytometry. Plasma levels of IL-2, IFN-γ, and TNF-α were measured by ELSIA. Tim-3 on both CD4(+) T and CD8(+) T cells were significantly upregulated in OS patients compared with healthy controls, Tim-3(+) CD4(+) T, and Tim-3(+) CD8(+) T cells were both negatively associated with serum levels of IL-2 and IFN-γ and TNF-α. In addition, Tim-3 showed similar levels in patients with different tumor sites. Nevertheless, patients with advanced tumor stage, metastasis, and pathological tumor fracture displayed significantly higher Tim-3 on both CD4(+) T cells and CD8(+) T cells than those with early tumor stage, without metastasis and pathological tumor fracture. Moreover, high Tim-3 on peripheral CD4(+) T cells or CD8(+) T were significantly related to poor overall survival (P = 0.014, P = 0.035, respectively). In conclusion, Tim-3 may be a potential diagnostic and prognostic biomarker for OS progression.

BACKGROUND Osteosarcoma (OS) is a highly complicated bone cancer involving imbalance of signaling transduction networks in cells. Development of new anti-osteosarcoma drugs is very challenging, mainly due to lack of known key targets. MATERIAL AND METHODS In this study, we attempted to reveal more promising targets for drug design by "Target-Pathway" network analysis, providing the new therapeutic strategy of osteosarcoma. The potential targets used for the treatment of OS were selected from 4 different sources: DrugBank, TCRD database, dbDEMC database, and recent scientific literature papers. Cytoscape was used for the establishment of the "Target-Pathway" network. RESULTS The obtained results suggest that tankyrase 2 (TNKS2) might be a very good potential protein target for the treatment of osteosarcoma. An in vitro MTT assay proved that it is an available option against OS by targeting the TNKS2 protein. Subsequently, cell cycle and apoptosis assay by flow cytometry showed the TNKS2 inhibitor can obviously induce cell cycle arrest, apoptosis, and mitotic cell death. CONCLUSIONS Tankyrase 2 (TNKS2), a member of the multifunctional poly(ADP-ribose) polymerases (PARPs), could be a very useful protein target for the treatment of osteosarcoma.

The pathology of non-traumatic osteonecrosis of the femoral head (ONFH) is complex. Several studies have linked some polymorphisms of vascular endothelial growth factors A (VEGFA) with ONFH, but the results are not consistent and are even conflicting. In the study, 22 single nucleotide polymorphisms (SNPs) in VEGFA were genotyped in 1,762 subjects (489 cases and 1,273 controls). Genetic association analyses were performed in single markers and haplotype levels. Stratification analysis was conducted for ONFH patients. Gene by environment interactions were tested between VEGFA and the smoking status of the subjects. Gene expression and eQTL data of significant SNPs were extracted from GTEx to examine their potential biological function. The SNP, rs2010963, was identified to be significantly associated with ONFH (χ2 = 11.66, P = 0.0006, OR = 1.29). Haplotypes including rs2010963 were also identified to be correlated with ONFH in the haplotype-based analyses. After stratifying by the causes of ONFH, a significant signal from rs2010963 could only be identified in alcohol-induced patients (Pallelic = 0.0009) but not in steroid-induced patients (Pallelic = 0.055). No significant results were obtained from the gene by environmental interaction analyses. Significant expression differences of VEGFA were identified in multiple human tissues for different genotypes of rs2010963. Our findings indicate that SNP rs2010963 is significantly associated with ONFH.

Human RecQ helicase family, consisting of RECQL, RECQL4, RECQL5, BLM and WRN, has critical roles in genetic stability and tumorigenesis. Although RECQL5 has been reported to correlate with the susceptibility to malignances including osteosarcoma, the specific effect on tumor genesis and progression is not yet clarified. Here we focused on the relationship between RECQL5 expression and osteosarcoma disease progression, and further investigated the function of RECQL5 on MG-63 cell proliferation and apoptosis. By immunohistochemical analysis, qRT-PCR and western blot, we found that RECQL5 expression was downregulated in osteosarcoma tissues and cells. Patients with advanced tumor stage and low grade expressed lower RECQL5. To construct a stable RECQL5 overexpression osteosarcoma cell line (MG-63-RECQL5), RECQL5 gene was inserted into the human AAVS1 safe harbor by CRISPR/Cas9 system. The overexpression of RECQL5 was verified by qRT-PCR and western blot. Cell proliferation, cell cycle and apoptosis assay revealed that RECQL5 overexpression inhibited proliferation, induced G1-phase arrest and promoted apoptosis in MG-63 cells. Collectively, our results suggested RECQL5 as a tumor suppressor in osteosarcoma and may be a potential therapeutic target for osteosarcoma treatment.

Background Low haematocrit (Hct) is associated with a higher rate of post-operative complications, increased mortality, and additional medical costs following cardiac surgery. Predictors of post-operative Hct in lumbar fusion are unclear and may be beneficial in avoiding adverse surgical outcomes. Methods A total of 704 lumbar disc herniation patients (385 males, 319 females) who underwent primary lumbar fusion surgery were reviewed in this retrospective study. Results In the 687 patients who met the selection criteria, the pre-operative Hct was 41.23 ± 4.57%, the post-operative Hct was 32.61 ± 4.52%, the peri-operative Hct decline was 8.62 ± 4.07%, the estimated intra-operative blood loss was 586.76 ± 346.62 mL, and the post-operative drainage was 489.33 ± 274.32 mL. Pre-operative Hct, estimated blood volume, estimated intra-operative blood loss, post-operative drainage, allogeneic blood transfusion, and age showed significant correlations with post-operative Hct, and all factors were involved in the final multiple regression model. Patients who received intensive care had lower post-operative Hct values, and the length of post-operative hospital stay was negatively correlated with post-operative Hct. Conclusions Dangerously low post-operative Hct is related to the length of ICU stay and post-operative hospital stay. Age, pre-operative Hct, intra-operative blood loss, post-operative drainage, and units of allogeneic blood transfusion are significant predictors of post-operative Hct and Hct decline. Hct variations during the operation make the calculation of total blood loss difficult.

This aim of this study was to explore novel biomarkers related to osteosarcoma. The mRNA expression profile GSE41293 dataset was downloaded from the Gene Expression Omnibus (GEO) database, which included seven osteosarcoma and six control samples. After preprocessing, the FASTQ format reads of 13 samples were mapped to the reference sequences to screen for unique mapping reads. Differentially expressed genes (DEGs) were selected, which were then used for pathway and protein-protein interaction (PPI) network analyses. Moreover, the microarray data GSE63631 were downloaded from GEO database to verify our results. The percentages of unique mapping reads for osteosarcomas and control samples were both >85%. A total of 6157 DEGs were identified between the two groups. DEGs that were upregulated were significantly enriched in 19 pathways, and those that were downregulated were enriched in 14 pathways. In the PPI network, DEGs such as SRC, ERBB2, and CAV3 in cluster 1 were enriched in the pathway responsible for focal adhesions. The DEGs in cluster 2, such as CDK4 and CDK6, were enriched in the cell cycle pathway. In GSE63631, DEGs were significantly enriched in focal adhesion pathway, which was in accordance with the result in GSE41293. Thus, the focal adhesion and cell cycle pathways may play important roles in osteosarcoma progression, and SRC, ERBB2, CAV3, CDK4, and CDK6 may be used as critical biomarkers of osteosarcoma.