A multi-view latent variable model reveals cellular heterogeneity in complex tissues for paired multimodal single-cell data.

MOTIVATION: Single-cell multimodal assays allow us to simultaneously measure two different molecular features of the same cell, enabling new insights into cellular heterogeneity, cell development and diseases. However, most existing methods suffer from inaccurate dimensionality reduction for the joint-modality data, hindering their discovery of novel or rare cell subpopulations. RESULTS: Here, we present VIMCCA, a computational framework based on variational-assisted multi-view canonical correlation analysis to integrate paired multimodal single-cell data. Our statistical model uses a common latent variable to interpret the common source of variances in two different data modalities. Our approach jointly learns an inference model and two modality-specific non-linear models by leveraging variational inference and deep learning. We perform VIMCCA and compare it with 10 existing state-of-the-art algorithms on four paired multi-modal datasets sequenced by different protocols. Results demonstrate that VIMCCA facilitates integrating various types of joint-modality data, thus leading to more reliable and accurate downstream analysis. VIMCCA improves our ability to identify novel or rare cell subtypes compared to existing widely used methods. Besides, it can also facilitate inferring cell lineage based on joint-modality profiles. AVAILABILITY AND IMPLEMENTATION: The VIMCCA algorithm has been implemented in our toolkit package scbean (≥0.5.0), and its code has been archived at https://github.com/jhu99/scbean under MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Possible Role of Sclerostin in the Pathogenesis of Tympanosclerosis.

OBJECTIVE: The aim of this study was to investigate sclerostin (SOST) expression in a rat model of experimental tympanosclerosis (TS) and its possible role in the formation of TS. MATERIALS AND METHODS: Thirty-four SD rats were randomly divided into 2 groups: experimental group (n = 17) and normal group (n = 17). The left tympanic cavities in the experimental group were inoculated with methicillin-resistant Staphylococcus aureus. The changes of tympanic membranes were examined and recorded under otoendoscope. Haematoxylin-eosin staining was adopted to detect the morphological changes in the tympanic membrane and middle ear mucosa. Immunohistochemistry and Western blot analysis were used to observe the expression of SOST, Wnt3a, ß-catenin, and P-ERK1/2. RESULTS: In the experimental group, sclerotic lesions were observed in 54.5% ears in the end of 6 weeks. Morphological changes such as mucosa incrassation, inflammatory cells infiltration, fibrous tissue proliferation, and interstitial tissue incrassation prominently appeared in the tympanic membrane and middle ear mucosa. SOST protein was mainly distributed in the cytoplasm of epithelial cells and gland cells, the expression of which increased significantly in the calcified experimental ears. In addition, expression levels of Wnt3a, ß-catenin, and P-ERK1/2 increased significantly in the calcified group too. CONCLUSION: The upregulated expression level of SOST may be involved in the formation of TS, first, through the pro-phosphorylation of ERK1/2 in the inflammatory stage, and then through the enhancement of Wnt3a in the osteogenic stage.

Mendelian randomization study of inflammatory bowel disease and bone mineral density.

BACKGROUND: Recently, the association between inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and BMD has attracted great interest in the research community. However, the results of the published epidemiological observational studies on the relationship between inflammatory bowel disease and BMD are still inconclusive. Here, we performed a two-sample Mendelian randomization analysis to investigate the causal link between inflammatory bowel disease and level of BMD using publically available GWAS summary statistics. METHODS: A series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. To make the conclusions more robust and reliable, we utilized several robust analytical methods (inverse-variance weighting, MR-PRESSO method, mode-based estimate method, weighted median, MR-Egger regression, and MR.RAPS method) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on BMD. Outlier variants identified by the MR-PRESSO outlier test were removed step-by-step to reduce heterogeneity and the effect of horizontal pleiotropy. RESULTS: Our two-sample Mendelian randomization analysis with two groups of exposure GWAS summary statistics and four groups of outcome GWAS summary statistics suggested a definitively causal effect of genetically predicted ulcerative colitis on TB-BMD and FA-BMD but not on FN-BMD or LS-BMD (after Bonferroni correction), and we merely determined a causal effect of Crohn's disease on FN-BMD but not on the others, which was somewhat inconsistent with many published observational researches. The causal effect of inflammatory bowel disease on TB-BMD was significant and robust but not on FA-BMD, FN-BMD, and LS-BMD, which might result from the cumulative effect of ulcerative colitis and Crohn's disease on BMDs. CONCLUSIONS: Our Mendelian randomization analysis supported the causal effect of ulcerative colitis on TB-BMD and FA-BMD. As to Crohn's disease, only the definitively causal effect of it on decreased FN-BMD was observed. Updated MR analysis is warranted to confirm our findings when a more advanced method to get less biased estimates and better precision or GWAS summary data with more ulcerative colitis and Crohn's disease patients was available.

Association of COL9A3 trp3 polymorphism with intervertebral disk degeneration: a meta-analysis.

BACKGROUND: Intervertebral disk degeneration (IDD) is a common musculoskeletal disease associated with genetic factors. COL9A3 gene encodes the α3 (IX) chain of type IX collagen that is part of the interior structure of the disc. Mutations in COL9A3 gene sequence, leading to an Arg103Trp substitution in its 3 chain (the Trp3 allele at rs61734651 site), respectively, have been found to be connected with IDD occurrence in several studies. However, those studies have showed conflict results. Thus, a meta-analysis has been performed to assess the associations between the COL9A3 trp3 polymorphism and IDD. METHODS: Data were gathered from the following four electronic databases: PubMed, Web of Science (WOS), Embase and Cochrane library up to January 01, 2018. The pooled odds ratio (polled ORs) and 95% confidence interval (CI) were calculated to evaluate the strength of relationship between the COL9A3 trp3 polymorphism and IDD. RESULTS: Eleven eligible studies with 1631 cases of IDD and 1366 controls were included in this meta-analysis. The results indicated that the COL9A3 trp3 polymorphism was not associated with IDD (trp3 positive versus trp3 negative: OR = 1.31, 95%CI = 0.78-2.21, P = 0.309). Furthermore, the Egger's test and the Begg funnel plot did not show any evidence of publication bias. CONCLUSIONS: Our results suggest that the COL9A3 trp3 polymorphism might not be associated with IDD. Nor did we find any relationship in subgroup analyses stratified by gender and ethnicity. Future researches with larger samples are required to verify this outcome.

Association between Fas/FasL gene polymorphism and musculoskeletal degenerative diseases: a meta-analysis.

BACKGROUND: It was reported that Fas (rs1800682, rs2234767) and FasL (rs5030772, rs763110) gene polymorphism might be related to the risk of musculoskeletal degenerative diseases (MSDD), such as osteoarthritis (OA), intervertebral disc degeneration (IVDD) and rheumatoid arthritis (RA). However, data from different studies was inconsistent. Here we aim to elaborately summarize and explore the association between the Fas (rs1800682, rs2234767) and FasL (rs5030772, rs763110) and MSDD. METHODS: Literatures were selected from PubMed, Web of Science, Embase, Scopus and Medline in English and VIP, SinoMed, Wanfang and the China National Knowledge Infrastructure (CNKI) in Chinese up to August 21, 2017. All the researches included are case-control studies about human. We calculated the pooled odds ratios (ORs) with 95% confidence intervals (95% CI) to evaluate the strengths of the associations of Fas (rs1800682, rs2234767) and FasL (rs5030772, rs763110) polymorphisms with MSDD risk. RESULTS: Eleven eligible studies for rs1800682 with 1930 cases and 1720 controls, 6 eligible studies for rs2234767 with 1794 cases and 1909 controls, 3 eligible studies for rs5030772 with 367 cases and 313 controls and 8 eligible studies for rs763110 with 2010 cases and 2105 controls were included in this analysis. The results showed that the G allele of Fas (rs1800682) is associated with an increased risk of IVDD in homozygote and recessive models. The G allele of Fas (rs2234767) is linked to a decreased risk of RA but an enhanced risk of OA in allele and recessive models. In addition, the T allele of FasL (rs763110) is correlated with a reduced risk of IVDD in all of models. However, no relationship was found between FasL (rs5030772) and these three types of MSDD in any models. CONCLUSIONS: Fas (rs1800682) and FasL (rs763110) polymorphism were associated with the risk of IVDD and Fas (rs2234767) was correlated to the susceptibility of OA and RA. Fas (rs1800682) and Fas (rs2234767) are more likely to be associated with MSDD for Chinese people. FasL (rs763110) is related to the progression of MSDD for both Caucasoid and Chinese race groups. But FasL (rs5030772) might not be associated with any types of MSDD or any race groups statistically.

POLE2 promotes osteosarcoma progression by enhancing the stability of CD44.

Osteosarcoma (OS) is the most prevalent primary malignancy of bone in children and adolescents. It is extremely urgent to develop a new therapy for OS. In this study, the GSE14359 chip from the GEO database was used to screen differentially expressed genes in OS. DNA polymerase epsilon 2 (POLE2) was confirmed to overexpress in OS tissues and cell lines by immunohistochemical staining, qPCR and Western blot. Knockdown of POLE2 inhibited the proliferation and migration of OS cells in vitro, as well as the growth of tumors in vivo, while the apoptosis rate was increased. Bioinformatics analysis revealed that CD44 and Rac signaling pathway were the downstream molecule and pathway of POLE2, which were inhibited by knockdown of POLE2. POLE2 reduced the ubiquitination degradation of CD44 by acting on MDM2. Moreover, knockdown of CD44 inhibited the tumor-promoting effects of POLE2 overexpression on OS cells. In conclusion, POLE2 augmented the expression of CD44 via inhibiting MDM2-mediated ubiquitination, and then activated Rac signaling pathway to influence the progression of OS, indicating that POLE2/CD44 might be potential targets for OS treatment.

Synthetic peptides activating discoidin domain receptor 2 and collagen-binding integrins cooperate to stimulate osteoblast differentiation of skeletal progenitor cells.

Skeletal progenitor: collagen interactions are critical for bone development and regeneration. Both collagen-binding integrins and discoidin domain receptors (DDR1 and DDR2) function as collagen receptors in bone. Each receptor is activated by a distinct collagen sequence; GFOGER for integrins and GVMGFO for DDRs. Specific triple helical peptides containing each of these binding domains were evaluated for ability to stimulate DDR2 and integrin signaling and osteoblast differentiation. GVMGFO peptide stimulated DDR2 Y740 phosphorylation and osteoblast differentiation as measured by induction of osteoblast marker mRNAs and mineralization without affecting integrin activity. In contrast, GFOGER peptide stimulated focal adhesion kinase (FAK) Y397 phosphorylation, an early measure of integrin activation, and to a lesser extent osteoblast differentiation without affecting DDR2-P. Significantly, the combination of both peptides cooperatively enhanced both DDR2 and FAK signaling and osteoblast differentiation, a response that was blocked in Ddr2-deficient cells. These studies suggest that the development of scaffolds containing DDR and integrin-activating peptides may provide a new route for promoting bone regeneration. STATEMENT OF SIGNIFICANCE: A method for stimulating osteoblast differentiation of skeletal progenitor cells is described that uses culture surfaces coated with a collagen-derived triple-helical peptide to selectively activate discoidin domain receptors. When this peptide is combined with an integrin-activating peptide, synergistic stimulation of differentiation is seen. This approach of combining collagen-derived peptides to stimulate the two main collagen receptors in bone (DDR2 and collagen-binding integrins) provides a route for developing a new class of tissue engineering scaffolds for bone regeneration.

Poly(N-Isopropylacrylamide) Based Electrically Conductive Hydrogels and Their Applications.

Poly(N-isopropylacrylamide) (PNIPAM) based electrically conductive hydrogels (PNIPAM-ECHs) have been extensively studied in recent decades due to their thermal-responsive (leading to the volume change of hydrogels) and electrically conductive performance. The incorporation of conductive components into the PNIPAM hydrogel network makes it become conductive hydrogel, and as a result, the PNIPAM hydrogel could become sensitive to an electrical signal, greatly expanding its application. In addition, conductive components usually bring new stimuli-responsive properties of PNIPAM-based hydrogels, such as near-infrared light and stress/strain responsive properties. PNIPAM-ECHs display a wide range of applications in human motion detection, actuators, controlled drug release, wound dressings, etc. To summarize recent research advances and achievements related to PNIPAM-ECHs, this manuscript first reviews the design and structure of representative PNIPAM-ECHs according to their conductive components. Then, the applications of PNIPAM-ECHs have been classified and discussed. Finally, the remaining problems related to PNIPAM-ECHs have been summarized and a future research direction is proposed which is to fabricate PNIPAM-ECHs with integrated multifunctionality.

Mendelian randomization study of telomere length and bone mineral density.

PURPOSE: Some epidemiological studies and animal studies have reported a relationship between leukocyte telomere length (LTL) and bone mineral density (BMD). However, the causality underlying the purported relationship has not been determined. Here we performed a two-sample MR analysis to test the causal link between telomere length and BMD. RESULTS: Our research suggested no causal link of LTL and BMD using IVW method. The weighted median, MR-Egger regression and MR.RAPS method yielded a similar pattern of effects. MR-Egger intercept test demonstrated our results were not influenced by pleiotropy. Heterogeneities among the genetic variants on heel estimated BMD and TB-BMD vanished after excluding rs6028466. "Leave-one-out" sensitivity analysis confirmed the stability of our results. CONCLUSION: Our MR analysis did not support causal effect of telomere length on BMD. METHODS: We utilized 5 independent SNPs robustly associated with LTL as instrument variables. The outcome results were obtained from GWAS summary data of BMD. The two-sample MR analysis was conducted using IVW, weighted median, MR-Egger regression and MR.RAPS method. MR-Egger intercept test, Cochran's Q test and I2 statistics and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities and stability of these genetic variants on BMD.

A Meta-analysis Assessing the Association Between COL11A1 and GDF5 Genetic Variants and Intervertebral Disc Degeneration Susceptibility.

STUDY DESIGN: Meta-analysis to collect relevant studies to assess the association between COL11A1 and GDF5 genetic variants and susceptibility to IDD. OBJECTIVE: The aim of this study was to assess whether or not COL11A1 and GDF5 genetic variants were associated with susceptibility to IDD. SUMMARY OF BACKGROUND DATA: IDD or LDH is a major public health problem. There have been several studies evaluating the relationship between COL11A1 and GDF5 genetic variants with risk of intervertebral disc degeneration (IDD). However, the studies were limited in discrete outcome and sample size, and some of the results were contradictory. METHODS: We systematically searched the relevant publications in electronic databases. Eligible studies were included based on the defined criteria. The pooled odds ratios (ORs) with its 95% confidence intervals (CIs) were received using STATA 15. Subgroup analysis, sensitivity analysis, publication bias, and the "Trim and fill" method were performed in the meta-analysis. RESULTS: A total of 3287 IDD cases and 5115 controls were incorporated into the meta-analysis. Our results demonstrated that COL11A1 rs1676486 was significantly associated with increased IDD susceptibility under all genetic models (allele model T vs. C: OR = 1.40, 95% CI 1.23-1.59, P = 0.000; homozygote model TT vs. CC: OR = 1.89, 95%CI 1.40-2.56, P = 0.000; dominant model TT+TC vs. CC: OR = 1.52, 95% CI 1.29-1.80, P = 0.000; recessive model TT vs. TC + CC: OR = 1.58, 95% CI 1.18-2.12, P = 0.002). However, GDF5 rs143383 was not (allele model T vs. C: OR = 1.15, 95% CI 0.91-1.44, P = 0.244; homozygote model TT vs. CC: OR = 1.22, 95% CI 0.75-2.00, P = 0.429; dominant model TT vs. CC+CT: OR = 1.22, 95% CI 0.95-1.57, P = 0.112; recessive model TC + TT vs. CC: OR = 1.12, 95% CI 0.73-1.73, P = 0.594). Subgroup analysis indicated ethnicity was not the source of heterogeneity. Sensitivity analysis, publication bias, and the "Trim and fill" method demonstrated the meta-analysis was of reliability. CONCLUSION: Our results suggested that COL11A1 rs1676486 was significantly associated with IDD and the T allele was a risky factor. However, GDF5 rs143383 was not. LEVEL OF EVIDENCE: 1.

Correction to: LncRNA AFAP1-AS1 promotes tumorigenesis and epithelial-mesenchymal transition of osteosarcoma through RhoC/ROCK1/p38MAPK/Twist1 signaling pathway.

In the original publication of this manuscript [1], Fig. 5a needs to be revised, and adjustments have also been made to the captions for Figs. 2, 4, 5 and S1 to improve clarity for the reader.

99mTc-MIBI Scintigraphy for the Preoperative Assessment of Histological Response to Neoadjuvant Chemotherapy in Patients With Osteosarcoma: A Systematic Review and a Bivariate Meta-Analysis.

Purpose: There have been many attempts to preoperatively evaluate the chemotherapy response of osteosarcoma patients using 99mTc-MIBI scintigraphy. However, the evaluations were lacking in consistency. We performed this systematic review and meta-analysis to systematically evaluate the ability of 99mTc-MIBI scintigraphy in preoperatively assessing the response of osteosarcoma patients to neoadjuvant chemotherapy. Methods: For this systematic review and meta-analysis, PubMed, Web of Science, OVID, the Cochrane Library, and CNKI were searched. Eligible studies were included based on the defined criteria. The index test was 99mTc-MIBI scintigraphy, the reference standard was tumor necrosis rate. Quality Assessment of Diagnostic Accuracy Studies-2 was adopted for quality assessment of included studies. The statistical pooling analysis, meta-regression analysis, subgroup analysis, sensitivity analysis, and publication bias of our research were performed using STATA 15. Results: Eight articles with 189 osteosarcoma patients were included in this systematic review and meta-analysis. Our results demonstrated that the threshold effect of our meta-analysis was significant. The uptake change ratio of 99mTc-MIBI scintigraphy had a pooled sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio, and the area under curve of 0.98 (0.58-1.00), 0.68 (0.47-0.84), 3.1 (1.7-5.5), 0.03 (0.00-0.90), 103 (4-3,003), and 0.91 (0.88-0.93) in preoperative assessment of response of osteosarcoma patients to neoadjuvant chemotherapy. Meta-regression analysis and subgroup analysis indicated the factors of method and cut off value may introduce the heterogeneity. The pooled sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio, and the area under curve of washout rate of 99mTc-MIBI were 0.87 (0.69-0.95), 0.91 (0.75-0.97), 9.3 (3.2-27.0), 0.15 (0.06-0.37), 64 (14-301), and 0.89 (0.86-0.92), respectively. Sensitivity analysis and publication bias demonstrated our meta-analysis was reliable. Conclusion: Both the ΔUR and WR derived from 99mTc-MIBI scintigraphy were valuable in preoperatively assessing the response of osteosarcoma patients to neoadjuvant chemotherapy, and ΔUR may possess a more outstanding diagnostic accuracy than WR.

Association between TP53 rs1042522 gene polymorphism and the risk of malignant bone tumors: a meta-analysis.

TP53 is a tumor suppressor gene which is essential for regulating cell division and preventing tumor formation. Several studies have assessed the associations of TP53 single-nucleotide polymorphisms (SNP) with susceptibility of malignant bone tumors, including osteosarcoma and Ewing sarcoma, but the results are inconsistent. In the present meta-analysis, we aimed to elucidate the associations of TP53 rs1042522 genetic polymorphism with the risk of osteosarcoma or Ewing sarcoma. We systematically searched Medline, PubMed, Web of Science, Embase, and the Cochrane Library databases. Eligible studies assessing the polymorphisms in the TP53 rs1042522 gene and risk of malignant bone tumors were incorporated. The pooled odds ratio (OR) with its 95% confidence intervals (95% CIs) were used to assess these possible associations. Five studies with a total of 567 cases and 935 controls were finally included the meta-analysis. Meta-analysis of TP53 rs1042522 polymorphism was significantly associated with an increased risk of malignant bone tumors (G versus C: OR = 1.27, 95% CI 1.08-1.50, P=0.005; GG versus GC/CC: OR = 1.55, 95% CI 1.21-2.00, P=0.001). Moreover, in a stratified analysis, a statistically significant correlation between this SNP and osteosarcoma risk was also observed. Our results suggest that there are significant associations of TP53 rs1042522 polymorphism with malignant bone tumors risk. More studies based on larger sample sizes and homogeneous samples are warranted to confirm these findings.

LncRNA AFAP1-AS1 promotes tumorigenesis and epithelial-mesenchymal transition of osteosarcoma through RhoC/ROCK1/p38MAPK/Twist1 signaling pathway.

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.

Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients' health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.

Prognostic and clinicopathological significance of DEPTOR expression in cancer patients: a meta-analysis.

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 DEP-TOR 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.

Prognostic Value of Programmed Cell Death 1 Ligand-1 (PD-L1) or PD-1 Expression in Patients with Osteosarcoma: A Meta-Analysis.

Purpose: Programmed cell death 1 ligand-1 (PD-L1) and PD-1 as prognostic biomarkers have spurred considerable interest in several types of malignant tumors. In the present meta-analysis, we aimed to elucidate the clinicopathological and prognostic values of PD-L1/PD-1 in osteosarcoma. Methods: We systematically searched PubMed, Web of Science, EMBASE, Scopus, CBM and the Cochrane Library databases up to March 3, 2018. Eligible studies assessing the relationship between PD-L1 or PD-1 expression and clinicopathological and prognostic outcomes in osteosarcoma were incorporated. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were used to estimate the outcomes. Results: Eight studies involving 413 patients were incorporated into our meta-analysis. Pooled results showed that PD-L1/PD-1 overexpression was significantly associated with metastasis (RR = 1.54, 95% CI: 1.12-2.11, p = 0.008) in osteosarcoma. Furthermore, osteosarcoma patients exhibited a remarkably higher total mortality risk (RR = 1.86, 95% CI: 1.09-3.17, p = 0.021) with PD-L1/PD-1 overexpression. However, no significant reduced overall survival rate (RR = 0.70, 95% CI: 0.46-1.07, p = 0.103) was detected in the study. Conclusion: Our meta-analysis indicates that PD-L1/PD-1 may serve as an important biomarker for adverse clinicopathologic features and poor prognosis in patients with osteosarcoma.

Correction: Prognostic value of long non-coding RNA CCAT1 expression in patients with cancer: A meta-analysis.

[This corrects the article DOI: 10.1371/journal.pone.0179346.].

Prognostic value of long non-coding RNA CCAT1 expression in patients with cancer: A meta-analysis.

BACKGROUND: LncRNA CCAT1 is significantly overexpressed in various types of cancers, suggesting that it might be associated with prognosis and clinicopathological features in patients with cancer. METHODS: A comprehensive search was performed in Pubmed, Web of Science, OVID and CNKI databases. We also retrieved articles from other sources, such as retrieving from the reference lists of relevant articles. Eligible studies were included based on defined exclusion and inclusion criteria to perform a meta-analysis. STATA 14.0 was used to estimate pooled hazard ratios (HRs) with 95% confidence interval (95% CI), the heterogeneity among studies and publication bias to judge the prognostic value. RESULTS: A total of 1587 patients from 11 eligible studies were included in the meta-analysis. The results showed that high expression level of CCAT1 was significantly associated with shorter overall survival in cancer patients (HR 2.335, 95% CI:1.551-3.517); in the subgroup analysis, region (China or UK), sample size (more or less than 100), type of cancer (digestive or non-digestive disease) and paper quality (score more or less than 7) did not alter the association between CCAT1 expression and cancer prognosis but preoperative treatment did. And CCAT1 expression was an independent prognostic marker for overall survival in patients with cancer (pooled HR 2.195, 95%CI:1.316-3.664) using Cox multivariate analyses. The clinicopathological parameters analysis further showed that increased expression level of CCAT1 was correlated with tumor size, lymph node metastasis, TNM stage, distant metastasis, microvascular invasion and capsular formation in relevant cancers. CONCLUSIONS: The meta-analysis results from present study suggested that increased expression level of CCAT1 was associated with poor prognosis and can serve as an independent biomarker. And the expression level of CCAT1 was associated with clinicopathological features in relevant cancers.

Association of COL1A1 rs1800012 polymorphism with musculoskeletal degenerative diseases: a meta-analysis.

It has been reported that the single nucleotide polymorphism (SNP) rs1800012 in COL1A1 gene might be linked to the susceptibility of musculoskeletal degenerative diseases, such as osteoarthritis (OA) and intervertebral disc degeneration (IVDD). However, the data from different studies is contradictory. Here we aimed to comprehensively summarize and clarify the relationship between the SNP and musculoskeletal degenerative diseases. Seven eligible studies including 1339 cases and 5406 controls were screened out from PubMed, Web Of Science and Cochrane library databases. Significant association was identified in sub group analysis of IVDD in homozygote model (GG versus TT: OR = 0.33, 95% CI 0.14-0.78, P = 0.012), heterozygote model (GT versus TT: OR = 0.29, 95% CI 0.11-0.72, P = 0.008) and dominant model (GG/GT versus TT: OR = 0.31, 95% CI 0.13-0.74, P = 0.008). Additionally, significant relationship was also found in sub group analysis of severe degree of IVDD in homozygote model (GG versus TT: OR = 0.37, 95% CI 0.15-0.91, P = 0.031), heterozygote model (GT versus TT: OR = 0.33, 95% CI 0.13-0.87,P = 0.024) and dominant model (GG/GT versus TT: OR = 0.36, 95% CI 0.14-0.88, P = 0.025). Although no significance was observed, there is a trend that the more G allele at COL1A1 rs1800012 site, the less possibility of IVDD and severe IVDD would happen. Our results indicate that COL1A1 rs1800012 polymorphism associates with the susceptibility of IVDD. However, this polymorphism may not be associated with OA risk.