Identification of key eRNAs for intervertebral disc degeneration by integrated multinomial bioinformatics analysis.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a common degenerative condition leading to abnormal stress distribution under load, causing intervertebral stenosis, facet joint degeneration, and foraminal stenosis. Very little is known about the molecular mechanism of eRNAs in IVDD. METHODS: Gene expression profiles of 38 annulus disc samples composed of 27 less degenerated discs (LDs) and 11 more degenerated discs (MDs) were retrieved from the GEO database. Then, differentially expressed enhancer RNAs (DEeRNAs), differentially expressed target genes (DETGs), and differentially expressed transcription factors (DETFs), hallmark of cancer signalling pathways according to GSVA; the types and quantity of immune cells according to CIBERSORT; and immune gene sets according to ssGSEA were analysed to construct an IVDD-related eRNA network. Then, multidimensional validation was performed to explore the interactions among DEeRNAs, DETFs and DEGs in space. RESULTS: A total of 53 components, 14 DETGs, 15 DEeRNAs, 3 DETFs, 5 immune cells, 9 hallmarks, and 7 immune gene sets, were selected to construct the regulatory network. After validation by online multidimensional databases, 21 interactive DEeRNA-DEG-DETF axes related to IVDD exacerbation were identified, among which the C1S-CTNNB1-CHD4 axis was the most significant. CONCLUSION: Based upon the results of our study, we theorize that the C1S-CTNNB1-CHD4 axis plays a vital role in IVDD exacerbation. Specifically, C1S recruits CTNNB1 and upregulates the expression of CHD4 in IVDD, and subsequently, CHD4 suppresses glycolysis and activates oxidative phosphorylation, thus generating insoluble collagen fibre deposits and leading to the progression of IVDD. Overall, these DEeRNAs could comprise promising therapeutic targets for IVDD due to their high tissue specificity.

Comparison of cement-augmented pedicle screw and conventional pedicle screw for the treatment of lumbar degenerative patients with osteoporosis.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: To compare the safety and clinical efficacy between using cement-augmented pedicle screws (CAPS) and conventional pedicle screws (CPS) for the treatment of lumbar degenerative patients with osteoporosis. Management of lumbar degenerative patients with osteoporosis undergoing spine surgery is challenging. The clinical efficacy and potential complications of the mid-term performance of the CAPS technique in the treatment of lumbar degenerative patients with osteoporosis remain to be evaluated. PATIENTS AND METHODS: The data of 131 lumbar degenerative patients with osteoporosis who were treated with screw fixation from May 2016 to December 2019 were retrospectively analyzed in this study. The patients were divided into the following two groups according to the type of screw used: (I) the CAPS group (n = 85); and (II) the CPS group (n = 46). Relevant data were compared between two groups, including the demographics data, clinical results and complications. RESULTS: The difference in the VAS, ODI and JOA scores at three and 6 months after the operation between the two groups was statistically significant (P < 0.05). At 12 months after surgery and the final follow-up, a significant difference in the fusion rate was found between the two groups (P < 0.05). Four cemented screws loosening were observed in the CAPS group (loosening rate 4/384, 1.04%) and 15 screws loosening were observed in the CPS group (loosening rate 15/214, 7.01%). In the CAPS group, a total of 384 augmented screws were used, and cement leakage was observed in 25 screws (25/384, 6.51%), but no obvious clinical symptoms or serious complications were observed. Adjacent vertebral fractures occurred in six patients in the CAPS group and one in the CPS group. CONCLUSIONS: CAPS technique is an effective strategy for the treatment of lumbar degenerative patients with osteoporosis, with a higher fusion rate and lower screw loosening rate than CPS.

Identification of Bone Metastatic and Prognostic Alternative Splicing Signatures in Prostate Adenocarcinoma.

As the most common nonepithelial malignancy, prostate adenocarcinoma (PRAD) is the fifth chief cause of cancer mortality in men. Distant metastasis often occurs in advanced PRAD and most patients are dying from it. However, the mechanism of PRAD progression and metastasis is still unclear. It's widely reported that more than 94% of genes are selectively splicing in humans and many isoforms are particularly related with cancer progression and metastasis. Spliceosome mutations occur in a mutually exclusive manner in breast cancer, and different components of spliceosomes are targets of somatic mutations in different types of breast cancer. Existing evidence strongly supports the key role of alternative splicing in breast cancer biology, and innovative tools are being developed to use splicing events for diagnostic and therapeutic purposes. In order to identify if the PRAD metastasis is associated with alternative splicing events (ASEs), the RNA sequencing data and ASEs data of 500 PRAD patients were retrieved from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. By Lasso regression, five genes were screened to construct the prediction model, with a good reliability by ROC curve. Additionally, results in both univariate and multivariate Cox regression analysis confirmed the well prognosis efficacy of the prediction model (both P < 0.001). Moreover, a potential splicing regulatory network was established and after multiple-database validation, we supposed that the signaling axis of HSPB1 up-regulating the PIP5K1C - 46,721 - AT (P < 0.001) might mediate the tumorigenesis, progression and metastasis of PRAD via the key members of Alzheimer's disease pathway (SRC, EGFR, MAPT, APP and PRKCA) (P < 0.001).

Research hotspots and trends of chordoma: A bibliometric analysis.

Background: Chordoma is a type of mesenchymal malignancy with a high recurrence rate and poor prognosis. Due to its rarity, the tumorigenic mechanism and optimal therapeutic strategy are not well known. Methods: All relevant articles of chordoma research from 1 January 2000 to 26 April 2022 were obtained from Web of Science Core Collection database. Blibliometrix was used to acquire basic publication data. Visualization and data table of collaboration network, dynamic analysis, trend topics, thematic map, and factorial analysis were acquired using Blibliometrix package. VOSviewer was used to generate a visualization map of co-citation analysis and co-occurrence. Results: A total of 2,285 articles related to chordoma were identified. The most influential and productive country/region was the United States, and Capital Medical University has published the most articles. Among all high-impact authors, Adrienne M. Flanagan had the highest average citation rate. Neurosurgery was the important periodical for chordoma research with the highest total/average citation rate. We focused on four hotspots in recent chordoma research. The research on surgical treatment and radiotherapy was relatively mature. The molecular signaling pathway, targeted therapy and immunotherapy for chordoma are not yet mature, which will be the future trends of chordoma research. Conclusion: This study indicates that chordoma studies are increasing. Surgery and radiotherapy are well reported and always play fundamental roles in chordoma treatment. The molecular signaling pathway, targeted therapy, and immunotherapy of chordoma are the latest research hotspots.

Repression of enhancer RNA PHLDA1 promotes tumorigenesis and progression of Ewing sarcoma via decreasing infiltrating T-lymphocytes: A bioinformatic analysis.

Background: The molecular mechanisms of EWS-FLI-mediating target genes and downstream pathways may provide a new way in the targeted therapy of Ewing sarcoma. Meanwhile, enhancers transcript non-coding RNAs, known as enhancer RNAs (eRNAs), which may serve as potential diagnosis markers and therapeutic targets in Ewing sarcoma. Materials and methods: Differentially expressed genes (DEGs) were identified between 85 Ewing sarcoma samples downloaded from the Treehouse database and 3 normal bone samples downloaded from the Sequence Read Archive database. Included in DEGs, differentially expressed eRNAs (DEeRNAs) and target genes corresponding to DEeRNAs (DETGs), as well as the differentially expressed TFs, were annotated. Then, cell type identification by estimating relative subsets of known RNA transcripts (CIBERSORT) was used to infer portions of infiltrating immune cells in Ewing sarcoma and normal bone samples. To evaluate the prognostic value of DEeRNAs and immune function, cross validation, independent prognosis analysis, and Kaplan-Meier survival analysis were implemented using sarcoma samples from the Cancer Genome Atlas database. Next, hallmarks of cancer by gene set variation analysis (GSVA) and immune gene sets by single-sample gene set enrichment analysis (ssGSEA) were identified to be significantly associated with Ewing sarcoma. After screening by co-expression analysis, most significant DEeRNAs, DETGs and DETFs, immune cells, immune gene sets, and hallmarks of cancer were merged to construct a co-expression regulatory network to eventually identify the key DEeRNAs in tumorigenesis of Ewing sarcoma. Moreover, Connectivity Map Analysis was utilized to identify small molecules targeting Ewing sarcoma. External validation based on multidimensional online databases and scRNA-seq analysis were used to verify our key findings. Results: A six-different-dimension regulatory network was constructed based on 17 DEeRNAs, 29 DETFs, 9 DETGs, 5 immune cells, 24 immune gene sets, and 8 hallmarks of cancer. Four key DEeRNAs (CCR1, CD3D, PHLDA1, and RASD1) showed significant co-expression relationships in the network. Connectivity Map Analysis screened two candidate compounds, MS-275 and pyrvinium, that might target Ewing sarcoma. PHLDA1 (key DEeRNA) was extensively expressed in cancer stem cells of Ewing sarcoma, which might play a critical role in the tumorigenesis of Ewing sarcoma. Conclusion: PHLDA1 is a key regulator in the tumorigenesis and progression of Ewing sarcoma. PHLDA1 is directly repressed by EWS/FLI1 protein and low expression of FOSL2, resulting in the deregulation of FOX proteins and CC chemokine receptors. The decrease of infiltrating T-lymphocytes and TNFA signaling may promote tumorigenesis and progression of Ewing sarcoma.

The role of tetraspanins pan-cancer.

Tetraspanins (TSPANs) are a class of four-transmembrane segmented proteins. The precise functions of TSPANs and their roles in pan-cancer are unclear. In this work, we analyzed TSPAN1, TSPAN10, TSPAN11, TSPAN12, TSPAN13, TSPAN14, TSPAN15, TSPAN16, TSPAN17, TSPAN18, TSPAN18-AS1, TSPAN19, TSPAN2, TSPAN3, TSPAN31, TSPAN32, TSPAN33, TSPAN4, TSPAN5, TSPAN6, TSPAN7, TSPAN8, TSPAN9, TSPAN9-IT1 (24 TSPAN family genes) in relation to tumor characteristics from 11,057 TCGA samples across 33 cancer types. On 24 TSPAN family genes, multidimensional studies were conducted, including gene differential expression, immunological subtype analysis, clinical analysis, stemness indices analysis, drug sensitivity analysis, alteration analysis, and multi-omics validation (including ATAC-seq validation, single-cell sequencing validation, and other external validation). Genes were differentially expressed in 33 cancers, and several of them showed high consistency in terms of tumor characteristics. In particular, the potential roles of TSPAN15 and TSPAN1 in cancer deserve further attention.

Construction of the prognostic enhancer RNA regulatory network in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is a common malignant tumor in osteoarticular system, the 5-year overall survival of which is poor. Enhancer RNAs (eRNAs) have been implicated in the tumorigenesis of various cancer types, whereas their roles in OS tumorigenesis remains largely unclear. METHODS: Differentially expressed eRNAs (DEEs), transcription factors (DETFs), target genes (DETGs) were identified using limma (Linear Models for Microarray Analysis) package. Prognosis-related DEEs were accessed by univariate Cox regression analysis. A multivariate model was constructed to evaluate the prognosis of OS samples. Prognosis-related DEEs, DETFs, DETGs, immune cells, and hallmark gene sets were co-analyzed to construct an regulatory network. Specific inhibitors were also filtered by connectivity Map analysis. External validation and scRNA-seq analysis were performed to verify our key findings. RESULTS: 3,981 DETGs, 468 DEEs, 51 DETFs, and 27 differentially expressed hallmark gene sets were identified. A total of Multivariate risk predicting model based on 18 prognosis-related DEEs showed a high accuracy (area under curve (AUC) = 0.896). GW-8510 was the candidate inhibitor targeting prognosis-related DEEs (mean = 0.670, p < 0.001). Based on the OS tumorigenesis-related regulation network, we identified that CCAAT enhancer binding protein alpha (CEBPA, DETF) may regulate CD8A molecule (CD8A, DEE), thereby promoting the transcription of CD3E molecule (CD3E, DETG), which may affect allograft rejection based on CD8+ T cells. CONCLUSION: We constructed an eRNA-based prognostic model for predicting the OS patients' prognosis and explored the potential regulation network for OS tumorigenesis by an integrated bioinformatics analysis, providing promising therapeutic targets for OS patients.

The role of toll-like receptors (TLRs) in pan-cancer.

BACKGROUND: Toll-like receptors (TLRs) are important components of the innate and adaptive immune systems, and abnormal TLR expression has been linked to a variety of cancers. However, there was a lack of clarity on the association of TLR stimulation with the carcinogenesis of cancer. The study's goal was to analyse the clinical importance of TLRs expression at the mRNA level in pan-cancer datasets, as well as the link between TLR expression and carcinogenesis, progression, and clinical prognosis. METHODS: The expression profile of TLRs derived from UCSC pan-cancer data was analysed in multiple dimensions, including clinical analysis, immunological subtype analysis, tumour microenvironment (TME) analysis, tumour stem cell correlation analysis, and drug sensitivity analysis. Additionally, we analyse protein-protein interactions, functional enrichment, and chromatin accessibility, as well as TLR expression in single-cell sequencing data. RESULTS: Our multi-omics analysis results imply that TLRs may operate as a biological marker for carcinogenesis and progression, a potential target for anti-tumour therapy, and a prognostic biomarker, laying the theoretical groundwork for future translational medicine research. CONCLUSION: TLRs are involved in the formation of malignancies and can be explored in further detail as potential prognostic indicators. Key MessagesToll-like receptors (TLRs) are key factors in the process of the innate and adaptive immune response, and their aberrant expression of TLRs have been widely reported in various cancer. However, the association between TLRs stimulation and tumorigenesis of cancer has not been well clarified.In this study, in the pan-cancer data, integrated TLR family gene expression analysis, clinical correlation analysis, immune subtype correlation analysis, tumour microenvironment correlation analysis, tumour stem cell correlation analysis, and drug sensitivity correlation analysis were performed.TLRs play an important role in the development of tumours and can be studied in depth as potential prognostic markers.

Construction of Bone Metastasis-Specific Regulation Network Based on Prognostic Stemness-Related Signatures in Prostate Cancer.

Background: We planned to uncover the cancer stemness-related genes (SRGs) in prostate cancer (PCa) and its underlying mechanism in PCa metastasis. Methods: We acquired the RNA-seq data of 406 patients with PCa from the TCGA database. Based on the mRNA stemness index (mRNAsi) calculated by one-class logistic regression (OCLR) algorithm, SRGs in PCa were extracted by WGCNA. Univariate and multivariate regression analyses were applied to uncover OS-associated SRGs. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Pearson's correlation analysis were performed to discover the possible mechanism of PCa metastasis. The significantly correlated transcription factors of OS-associated SRGs were also identified by Pearson's correlation analysis. ChIP-seq was applied to validate the binding relationship of TFs and OS-associated SRGs and spatial transcriptome and single-cell sequencing were performed to uncover the location of key biomarkers expression. Lastly, we explored the specific inhibitors for SRGs using CMap algorithm. Results: We identified 538 differentially expressed genes (DEGs) between non-metastatic and metastatic PCa. Furthermore, OS-associated SRGs were identified. The Pearson correlation analysis revealed that FOXM1 was significantly correlated with NEIL3 (correlation efficient =0.89, p < 0.001) and identified hallmark_E2F_targets as the potential pathway mechanism of NEIL3 promoting PCa metastasis (correlation efficient =0.58, p < 0.001). Single-cell sequencing results indicated that FOXM1 regulating NEIL3 may get involved in the antiandrogen resistance of PCa. Rottlerin was discovered to be a potential target drug for PCa. Conclusion: We constructed a regulatory network based on SRGs associated with PCa metastasis and explored possible mechanism.

The Identification of Prognostic and Metastatic Alternative Splicing in Skin Cutaneous Melanoma.

Skin cutaneous melanoma (SKCM) is a type of highly invasive cancer originated from melanocytes. It is reported that aberrant alternative splicing (AS) plays an important role in the neoplasia and metastasis of many types of cancer. Therefore, we investigated whether ASEs of pre-RNA have such an influence on the prognosis of SKCM and the related mechanism of ASEs in SKCM. The RNA-seq data and ASEs data for SKCM patients were obtained from the TCGA and TCGASpliceSeq database. The univariate Cox regression revealed 1265 overall survival-related splicing events (OS-SEs). Screened by Lasso regression, 4 OS-SEs were identified and used to construct an effective prediction model (AUC: .904), whose risk score was proved to be an independent prognostic factor. Furthermore, Kruskal-Wallis test and Mann-Whitney-Wilcoxon test showed that an aberrant splicing type of aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) regulated by CDC-like kinase 1 (CLK1) was associated with the metastasis and stage of SKCM. Besides, the overlapped signal pathway for AIMP2 was galactose metabolism identified by the co-expression analysis. External database validation also confirmed that AIMP2, CLK1, and the galactose metabolism were associated with the metastasis and stage of SKCM patients. ChIP-seq and ATAC-seq methods further confirmed the transcription regulation of CLK1, AIMP2, and other key genes, whose cellular expression was detected by Single Cell Sequencing. In conclusion, we proposed that CLK1-regulated AIMP2-78704-ES might play a critical role in the tumorigenesis and metastasis of SKCM via galactose metabolism. Besides, we established an effective model with MTMR14-63114-ES, URI1-48867-ES, BATF2-16724-AP, and MED22-88025-AP to predict the metastasis and prognosis of SKCM patients.

Ral GEF with the PH Domain and SH3 Binding Motif 1 Regulated by Splicing Factor Junction Plakoglobin and Pyrimidine Metabolism Are Prognostic in Uterine Carcinosarcoma.

Uterine carcinosarcoma (UCS) is a highly invasive malignant tumor that originated from the uterine epithelium. Many studies suggested that the abnormal changes of alternative splicing (AS) of pre-mRNA are related to the occurrence and metastasis of the tumor. This study investigates the mechanism of alternative splicing events (ASEs) in the tumorigenesis and metastasis of UCS. RNA-seq of UCS samples and alternative splicing event (ASE) data of UCS samples were downloaded from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases, several times. Firstly, we performed the Cox regression analysis to identify the overall survival-related alternative splicing events (OSRASEs). Secondly, a multivariate model was applied to approach the prognostic values of the risk score. Afterwards, a coexpressed network between splicing factors (SFs) and OSRASEs was constructed. In order to explore the relationship between the potential prognostic signaling pathways and OSRASEs, we fabricated a network between these pathways and OSRASEs. Finally, validations from multidimension platforms were used to explain the results unambiguously. 1,040 OSRASEs were identified by Cox regression. Then, 6 OSRASEs were incorporated in a multivariable model by Lasso regression. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was 0.957. The risk score rendered from the multivariate model was corroborated to be an independent prognostic factor (P < 0.001). In the network of SFs and ASEs, junction plakoglobin (JUP) noteworthily regulated RALGPS1-87608-AT (P < 0.001, R = 0.455). Additionally, RALGPS1-87608-AT (P = 0.006) showed a prominent relationship with distant metastasis. KEGG pathways related to prognosis of UCS were selected by gene set variation analysis (GSVA). The pyrimidine metabolism (P < 0.001, R = -0.470) was the key pathway coexpressed with RALGPS1. We considered that aberrant JUP significantly regulated RALGPS1-87608-AT and the pyrimidine metabolism pathway might play a significant part in the metastasis and prognosis of UCS.

Construction and validation of nomograms for non-metastatic Ewing sarcoma: A prognostic factor analysis based on the SEER database.

Ewing sarcoma is the second most common osseous disease in children and adolescents. It presents with a poor prognosis due to the high degree of malignancy and distant metastasis. In order to predict the disease prognosis and investigate a suitable therapeutic strategy for Ewing sarcoma, the present study aimed to describe the clinical characteristics, and to construct and validate nomograms for patients with non-metastatic Ewing sarcoma. A total of 627 cases of non-metastatic Ewing sarcoma were retrospectively collected from the Surveillance, Epidemiology, and End Results database between 2005 and 2014. Survival analysis and a machine learning model were used to identify independent prognostic variables and establish nomograms to estimate overall survival (OS) and cause-specific survival (CSS). The nomograms were bootstrap internally validated and externally validated using non-metastatic Ewing sarcoma cases from the First Affiliated Hospital of Zhengzhou University. The accuracy was also assessed by comparing with current American Joint Committee on Cancer (AJCC) staging systems. The total series consisted of 627 patients with non-metastatic Ewing sarcoma with a mean age of 20.14 years. Age, tumor extension, sex, International Classification of Diseases for Oncology, 3rd Edition histology, surgery and chemotherapy were identified as independent risk factors for OS and CSS. The aforementioned outcomes were incorporated to construct the nomograms, and the concordance indices (C-indices) for internal validation of OS and CSS prediction were 0.791 and 0.813, which were higher than those for AJCC sixth edition (OS, 0.531; CSS, 0.534) and seventh edition (OS, 0.547; CSS, 0.561), while the C-indices for external validation of OS and CSS prediction were 0.834 and 0.825, respectively. In conclusion, age, sex, tumor extension and surgery were independent prognostic factors for both OS and CSS. In addition, with regard to OS, the Ewing sarcoma subtype was a poor factor and chemotherapy was a favorable one. Nomograms based on reduced Cox models attained a satisfactory accuracy in predicting the survival of patients with non-metastatic Ewing sarcoma and could assist clinicians in evaluating survival more accurately.

Monitoring the therapeutic efficacy of CA4P in the rabbit VX2 liver tumor using dynamic contrast-enhanced MRI.

PURPOSE: The present work aims to evaluate whether dynamic contrast-enhanced magnetic resonance Imaging (DCE-MRI) can monitor non-invasively the blocking effect on microvessels of the Combretastatin-A4-phosphate (CA4P) and assess the therapeutic efficacy. METHODS: Forty rabbits were implanted the VX2 tumors specimens. Two weeks later, serial MRI (T1 weighted image, T2 weighted image and DCE) were performed at 0 h, 4 h, 24 h, 3 d and 7 d after CA4P (10 mg/kg) or saline treatment. The parameters of DCE (Ktrans, Kep, Ve and iAUC60) of enhancement tumor portions were measured. Then all the tumor samples were stained to count microvessel density (MVD). At last, two-way repeated measures ANOVA was used to analyze the difference between and within groups. The correlation between the Ktrans, Kep, Ve, iAUC60 and MVD was analyzed by using the Pearson correlation analysis and Spearman's rank correlation. RESULTS: The Ktrans and iAUC60 in the CA4P group were lower than the values of the control group at 4 h after treatment, which have significant differences (D-value: -0.133 min-1, 95%CI: -0.169~-0.097 min-1，F = 59.109, p < 0.001 for Ktrans; D-value: -10.533 mmol/sec, 95%CI: -17.147~-3.919 mmol/sec，F = 11.110, and p = 0.003 for iAUC60). In the CA4P group, the Ktrans and iAUC60 reached the minimum values at 4 h. There were significant differences between 4 h and other different time points of the Ktrans and iAUC60 in the treatment group (all p < 0.01). The parameters Ktrans (r = 0.532, P = 0.016 and r = 0.681, P = 0.001, respectively) and iAUC60 (r = 0.580, P = 0.007 and r = 0.568, P = 0.009, respectively) of 7 days showed correlation with MVD in both groups, while Kep and Ve did not show correlation with MVD (P > 0.05). CONCLUSION: The blocking effect of microvessels after CA4P treatment can be evaluated by DCE-MRI, and the parameters of quantitative Ktrans and semi- quantitative iAUC60 can assess the change of the tumor angiogenesis noninvasively.

The Roles of Magnetic Resonance-Guided Focused Ultrasound in Pain Relief in Patients With Bone Metastases: A Systemic Review and Meta-Analysis.

OBJECTIVE: Cancer pain, the most common skeleton-related event of bone metastases, significantly disturbs patients' life. MRI-guided focused ultrasound (MRgFUS) is a therapeutic option to relieve pain; however, its efficacy and safety have not been fully explored. Therefore, we aim to conduct a meta-analysis on studies reporting MRgFUS for patients with bone metastases. METHODS: Randomized controlled trials (RCT) and non-RCTs on MRgFUS treatment for patients with bone metastases were collected using PubMed, MEDLINE In-Process (US National Library of Medicine), National Institutes of Health (US National Library of Medicine), Embase (Elsevier), Web of Science, CINAHL, and the Cochrane Library between August 2007 and September 2019. Data on quantitative pain assessment before/after MRgFUS, response rate, and complication were extracted and analyzed. RESULTS: Fifteen eligible studies with 362 patients were selected in this meta-analysis. The average pain score was 6.74 (95% CI: 6.30-7.18) at baseline, 4.15 (95% CI: 3.31-4.99) at 0-1 week, 3.09 (95% CI: 2.46-3.72) at 1-5 weeks, and 2.28 (95% CI: 1.37-3.19) at 5-14 weeks. Compared with baseline, the pain improvement at 0-1 week was 2.54 (95% CI: 1.92-3.16, p < 0.01), at 1-5 weeks was 3.56 (95% CI: 3.11-4.02, p < 0.01), and at 5-14 weeks was 4.22 (95% CI: 3.68-4.76, p < 0.01). Change from baseline in OMEDD at 2 weeks after treatment was -15.11 (95% CI: -34.73, 4.50), at 1 month after treatment was -10.87 (95% CI: -26.32, 4.58), and at 3 months after treatment was -5.53 (95% CI: -20.44, 9.38). The overall CR rate was 0.36 (95% CI: 0.24-0.48), PR rate was 0.47 (95% CI: 0.36-0.58), and NR rate was 0.23 (95% CI: 0.13-0.34). Among 14 studies including 352 patients, 93 (26.4%) patients with minor complications and 5 (1.42%) patients with major complications were recorded. CONCLUSION: This meta-analysis identifies MRgFUS as a reliable therapeutic option to relieve cancer pain for patients with metastatic bone tumors with controllable related complications.

Identification of prognostic and bone metastatic alternative splicing signatures in bladder cancer.

Bladder cancer (BLCA), originating from the epithelium of the urinary bladder, was the second most common malignancy in the urinary system with a high metastasis rate and poor post-metastasis prognosis. Alternative splicing events (ASEs) were regarded as important markers of tumor progression and prognosis, however, their roles in bladder cancer bone metastasis have not been recognized. In this study, we constructed a predictive model based on ASEs and explored the molecular mechanism of ASEs in BLCA bone metastasis, based on data from the Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. We proposed the hypothesis that the splicing events of ITGB4 was regulated by the splicing factor JUP, and this regulation might play a key role in BLCA bone metastasis through the glycosphingolipid biosynthesis ganglio series pathway.

A comparative integrated multi-omics analysis identifies CA2 as a novel target for chordoma.

BACKGROUND: Chordoma is a rare mesenchymal malignancy, with a high recurrence rate and unclear tumorigenic mechanism. Genetic alterations, epigenetic regulators, and chromatin spatial organization play crucial roles in the initiation and progression of chordoma. In the current study, we aim to uncover the novel therapeutical targets for chordoma via using integrated multi-omics analysis. METHODS: The RNA-sequencing (RNA-seq), assay for transposable accessible chromatin by high-throughput sequencing (ATAC-seq), and Hi-C were performed between chordoma and human nucleus pulposus (HNP), along with imageological examination and clinical information. The expressions of identified targets were validated by clinical samples and their functions were further evaluated by cell and animal experiments via gene knockdown and inhibitors. RESULTS: The integrated multi-omics analysis revealed the important roles of bone microenvironment in chordoma tumorigenesis. By comparing the hierarchical structures, CA2 (carbonic anhydrase II) and THNSL2 (threonine synthase-like 2) were identified in the switched compartments, cell-specific boundaries, and loops. Additionally, CA2 was highly expressed in chordoma but barely found in HNP. The cell growth and migration of chordoma cells were dramatically suppressed via inhibition of CA2 either with genetic deletion or pharmaceutical treatment with Dorzolamide HCl. Furthermore, Dorzolamide HCl also regulated the bone microenvironment by blocking the osteoclast differentiation of bone marrow monocytes. CONCLUSION: This study uncovers the roles of bone microenvironment in the chordoma tumorigenesis and identifies CA2 as a novel therapeutic target for chordoma. Besides, our findings suggest Dorzolamide HCl as a promising therapeutic option for chordoma.

Identification of prognostic and bone metastasis​-related alternative splicing signatures in mesothelioma.

Mesothelioma (MESO) is an infrequent tumor derived from mesothelial cells of pleura, peritoneum, pericardium, and tunica vaginalis testis. Despite advancement in technologies and better understanding of tumor progression mechanism, the prognosis of MESO remains poor. The role of alternative splicing events (ASEs) in the oncogenesis, tumor metastasis and drug resistance has been widely discussed in multiple cancers. But the prognosis and potential therapeutic value of ASEs in MESO were not clearly studied by now. We constructed a prognostic model using RNA sequencing data and matched ASE data of MESO patients obtained from the TCGA and TCGASpliceSeq database. A total of 3,993 ASEs were identified associated with overall survival using Cox regression analysis. Eight of them were finally figured out to institute the model by lasso regression analysis. The risk score of the model can predict the prognosis independently. Among the identified 390 splicing factors (SF), HSPA1A and DDX3Y was significantly associated with 43 OS-SEs. Among these OS-SEs, SNX5-58744-AT (p = 0.048) and SNX5-58745-AT (p = 0.048) were significantly associated with bone metastasis. Co-expression analysis of signal pathways and SNX5-58744-AT, SNX5-58745-AT was also depicted using GSVA. Finally, we proposed that splicing factor (SF) HSPA1A could regulate SNX5-58744-AT (R = -0.414) and SNX5-58745-AT (R = 0.414) through the pathway "Class I MHC mediated antigen processing and presentation" (R = 0.400). In this way, tumorigenesis and bone metastasis of MESO were controlled.

Co-expression Analysis of Genes and Tumor-Infiltrating Immune Cells in Metastatic Uterine Carcinosarcoma.

Uterine carcinosarcoma (UCS) is a malignant tumor with a high tendency to invasion and metastasis. However, the underlying invasion and metastasis mechanisms of UCS remain poorly understood. Genetic alteration and tumor-infiltrating immune cells play important roles in tumorigenesis, progression, and metastasis. To better understand the underlying mechanisms of UCS, we screened tumor-infiltrating immune cells by applying CIBERSORT algorithm and constructed nomograms to predict the prognosis of UCS patients based on metastasis-specific tumor-infiltrating immune cells and genes, and demonstrated their utility by the high AUC values. Combining gene co-expression and experimental validation results, we propose a potential mechanism of AK8, MPZ, and mast cells activated might play important parts in UCS metastasis.

The Clinical Characteristics and Prediction Nomograms for Primary Spine Malignancies.

BACKGROUND: Primary spine malignancies (PSMs) are relatively rare in bone tumors. Due to their rarity, the clinical characteristics and prognostic factors are still ambiguous. In this study, we aim to identify the clinical features and proposed prediction nomograms for patients with PSMs. METHODS: Patients diagnosed with PSMs including chordoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, and malignant giant cell tumor of bone (GCTB) between 1975 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The patient and tumor characteristics were described based on clinical information. The significant prognostic factors of overall survival (OS) and cancer-specific survival (CSS) were identified by the univariate and multivariate Cox analysis. Then, the nomograms for OS and CSS were established based on the selected predictors and their accuracy was explored by the Cox-Snell residual plot, area under the curve (AUC) of receiver operator characteristic (ROC) and calibration curve. RESULTS: The clinical information of 1,096 patients with PSMs was selected from the SEER database between 1975 and 2016. A total of 395 patients were identified with full survival and treatment data between 2004 and 2016. Chordoma is the commonest tumor with 400 cases, along 172 cases with osteosarcoma, 240 cases with chondrosarcoma, 262 cases with Ewing sarcoma and 22 cases with malignant GCTB. The univariate and multivariate analyses revealed that older age (Age > 60), distant metastasis, chemotherapy, and Surgery were independent predictors for OS and/or CSS. Based on these results, the nomograms were established with a better applicability (AUC for CSS: 0.784; AUC for OS: 0.780). CONCLUSIONS: This study provides the statistics evidence for the clinical characteristics and predictors for patients with PSMs based on a large size population. Additionally, precise prediction nomograms were also established with a well-applicability.

Prognostic Factors for Survival in Patients with Malignant Giant Cell Tumor of Bone: A Risk Nomogram Analysis Based on the Population.

BACKGROUND Malignant giant cell tumor of bone (MGCTB) is a rare histological type of malignant tumor that has a high tendency for local relapse and distant metastasis and ultimately leads to a poor prognosis. The purpose of this study was to describe the epidemiological features, identify the prognostic factors, and construct nomograms for patients with MGCTB. MATERIAL AND METHODS Patients with MGCTB that was histologically diagnosed between 1973 and 2014 were selected from the Surveillance, Epidemiology, and End Results (SEER) database as a training set. Survival analysis, Lasso regression, and random forests were used to identify the prognostic variables and establish the nomograms for patients with MGCTB, while an external cohort of 37 patients from our own institution and an external cohort of 163 patients from the SEER database in 2016 were used to validate the generalization performance of the nomograms. RESULTS In total, univariate and multivariable analysis indicated that age, International Classification of Diseases for Oncology, historical stage, primary site, surgery information, radiotherapy, and chemotherapy were independent prognostic variables for overall survival or cause-specific survival. Nomograms based on the multivariable models were built to predict survival, and we achieved a higher C-index in subsequent multidimensional validation. CONCLUSIONS Age, historical stage, and chemotherapy were independent prognostic variables for overall survival and cause-specific survival of MGCTB patients, and radiotherapy and primary site were independent prognostic variables for overall survival. Nomograms based on significant clinicopathological features and clinical experience can be effective in predicting the probability of survival for MGCTB patients.