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.

Development and validation of a novel prognostic lncRNA signature based on the APOBEC3 family genes in gastric cancer.

Introduction: Gastric Cancer (GC) refers to a prevalent malignant cancer accompanied by a weak prognosis. The APOBEC3 family genes and lncRNAs are linked with cancer progression. Nevertheless, there is still a scarcity of data concerning the prognostic value of APOBEC3-related lncRNAs in GC. Methods: We extracted the data from GC samples, including transcriptome as well as clinical data, obtained from the TCGA database. Then, we screened for lncRNAs that were correlated with the APOBEC3 family genes and constructed an APOBEC3-related lncRNA prognostic signature (LPS) by utilizing univariate Cox and lasso regression analysis. Furthermore, we validated our constructed signature and evaluated it thoroughly, including analysis of its function, immunity, mutations, and clinical applications via multiple methods, including Metascape, GSEA, and analyses including TIC and TME, immune checkpoints, CNV and SNPs, Kaplan-Meier survival curves, nomogram, decision tree and drug prediction analysis. Finally, we overexpressed LINC01094 to evaluate the impacts on the proliferation as well as migration with regards to KATO-2 cells. Results: We selected eight lncRNAs for our APOBEC3-related LPS, which is demonstrated as a valuable tool in predicting the individual GC patients' prognosis. Subsequently, we segregated the samples into subgroups of high-as well as low-risk relying on the risk score with regards to APOBEC3-related LPS. By performing functional analysis, we have shown that immune-as well as tumor-related pathways were enriched in high- and low-risk GC patients. Furthermore, immune analysis revealed a robust correlation between the APOBEC3-related LPS and immunity. We found that immune checkpoints were significantly associated with the APOBEC3-related LPS and were greatly exhibited in GC tumor and high-risk samples. Mutational analysis suggested that the mutational rate was greater in low-risk samples. Furthermore, we predicted small molecular drugs displayed greater sensitivity in patients categorized as high-risk. Moreover, the immune response was also better in high-risk patients. Of these drugs, dasatinib was significant in both methods and might be considered a potential novel drug for treating high-risk GC patients. Finally, we found that LINC01094 has the potential to enhance the migration, proliferation as well as inhibit apoptosis of KATO-2 in GC cells. And Dasatinib has an inhibitory effect on the migration as well as proliferation in GC cells. Conclusion: We created a novel APOBEC3-related LPS in predicting the prognosis with regards to individual GC patients. Importantly, this APOBEC3-related LPS was closely associated with immunity and might guide clinical treatment.

Efficacy of PD-1 Inhibitors in First-Line Treatment for Advanced Gastroesophageal Junction and Gastric Cancer by Subgroups: A Systematic Review and Meta-Analysis.

BACKGROUND: PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced gastric/gastroesophageal junction cancer still needs to be precisely determined. OBJECTIVE: This objective of this study is to evaluate the efficacy of anti-PD-1/PD-L1 therapy in advanced gastric/gastroesophageal junction adenocarcinoma patients through a systematic review and meta-analysis of relevant clinical trials. METHOD: The PubMed, Embase, and Cochrane Library electronic databases were searched up to August 1, 2022, for clinical trials of anti-PD-1/PD-L1 immunotherapy for the first-line treatment of advanced gastroesophageal cancer. Hazard ratios and 95% confidence intervals for overall survival, progression-free survival, and objective response rates were extracted and pooled for meta-analysis. Prespecified subgroups included the following: agent type, PD-L1 expression, and high microsatellite instability. RESULTS: This study analyzed 5 RCTs involving 3,355 patients. Compared with the chemotherapy group, the combined immunotherapy group had a significantly higher objective response rate (OR = 0.63, 95% CI: 0.55-0.72, p < 0.00001) and prolonged overall survival (HR = 0.82, 95% CI: 0.76-0.88, p < 0.00001) and progression-free survival (HR = 0.75, 95% CI: 0.69-0.82, p < 0.00001). The combination of immunotherapy and chemotherapy prolonged OS in both MSI-H (HR = 0.38, p = 0.002) and MSS (HR = 0.78, p < 0.00001) populations, but there was a significant difference between groups (p = 0.02). However, in improving ORR, the benefit of ICI combined with chemotherapy in the MSS group and MSI-H group was not significantly different between groups (p = 0.52). Combination therapy with ICIs was more effective than chemotherapy alone in prolonging OS in the subgroup with a high CPS, regardless of the CPS cutoff for PD-L1. However, when the cutoff of CPS was 1, the difference between subgroups did not reach statistical significance (p = 0.12), while the benefit ratio of the MSI-H group was higher when the cutoff was 10 (p = 0.004) than when the cutoff value was 5 (p = 0.002). CONCLUSIONS: For first-line treatment of advanced gastroesophageal cancer, an ICI combination strategy is more effective than chemotherapy. The subgroup of patients with a CPS ≥10 has a more significant benefit, and CPS ≥10 has the potential to be used as an accurate marker of the dominant population of immuno-combined therapy.

Single-Cell Profiling of Tumor Immune Microenvironment Reveals Immune Irresponsiveness in Gastric Signet-Ring Cell Carcinoma.

BACKGROUND & AIMS: Gastric cancer (GC) is a major cancer type characterized by high heterogeneity in both tumor cells and the tumor immune microenvironment (TIME). One intractable GC subtype is gastric signet-ring cell carcinoma (GSRCC), which is associated with poor prognosis. However, it remains unclear what the GSRCC TIME characteristics are and how these characteristics may contribute to clinical outcomes. METHODS: We enrolled 32 patients with advanced GC of diverse subtypes and profiled their TIME using an immune-targeted single-cell profiling strategy, including (1) immune-targeted single-cell RNA sequencing (n = 20 patients) and (2) protein expression profiling by a targeted antibody panel for mass cytometry (n = 12 patients). We also generated matched V(D)J (variable, diversity, and joining gene segments) sequencing of T and B cells along CD45+ immunocytes. RESULTS: We found that compared to non-GSRCC, the GSRCC TIME appears to be quiescent, where both CD4+ and CD8+ T cells are difficult to be mobilized, which further impairs the proper functions of B cells. CXCL13, mainly produced by follicular helper T cells, T helper type 17, and exhausted CD8+ T cells, is a central coordinator of this transformation. We show that CXCL13 expression can predict the response to immune checkpoint blockade in GC patients, which may be related to its effects on tertiary lymphoid structures. CONCLUSIONS: Our study provides a comprehensive molecular portrait of immune cell compositions and cell states in advanced GC patients, highlighting adaptive immune irresponsiveness in GSRCC and a mediator role of CXCL13 in TIME. Our targeted single-cell transcriptomic and proteomic profiling represents a powerful approach for TIME-oriented translational research.

Pan-cancer analysis reveals interleukin-17 family members as biomarkers in the prediction for immune checkpoint inhibitor curative effect.

Background: The interleukin-17 (IL-17) family contains six homologous genes, IL-17A to IL-17F. Growing evidence indicates that dysregulated IL-17 family members act as major pathogenic factors in the early and late stages of cancer development and progression. However, the prevalence and predictive value of IL-17 for immune checkpoint inhibitor (ICI) therapeutic effectiveness in multiple tumor types remain largely unknown, and the associations between its expression levels and immunotherapy-associated signatures also need to be explored. Methods: The pan-cancer dataset in The Cancer Genome Atlas (TCGA) was downloaded from UCSC Xena (http://xena.ucsc.edu/). The immunotherapeutic cohorts included IMvigor210, which were obtained from the Gene Expression Omnibus database and included in a previously published study. Other datasets, namely, the GEO dataset and PRECOG, GEO, and METABRIC databases, were also included. In 33 TCGA tumor types, a pan-cancer analysis was carried out including their expression map, clinical risk assessment, and immune subtype analysis, along with their association with the stemness indices, tumor microenvironment (TME) in pan-cancer, immune infiltration analysis, ICI-related immune indicators, and drug sensitivity. RT-PCR was also carried out to verify the gene expression levels among MCF-10A and MCF-7 cell lines. Results: The expression of the IL-17 family is different between tumor and normal tissue in most cancers, and consistency has been observed between gene activity and gene expression. RT-PCR results show that the expression differences in the IL-17 family of human cell (MCF-10A and MCF-7) are consistent with the bioinformatics differential expression analysis. Moreover, the expression of the IL-17 family can be a sign of patients' survival prognosis in some tumors and varies in different immune subtypes. Moreover, the expression of the IL-17 family presents a robust correlation with immune cell infiltration, ICI-related immune indicators, and drug sensitivity. High expression of the IL-17 family is significantly related to immune-relevant pathways, and the low expression of IL-17B means a better immunotherapeutic response in BLCA. Conclusion: Collectively, IL-17 family members may act as biomarkers in predicting the prognosis of the tumor and the therapeutic effects of ICIs, which provides new guidance for cancer treatment.

Enhanced Antibacterial and Osteogenic Properties of Graphene Oxide Loaded with Berberine on Biomedical Titanium.

Internal implants are widely used in most orthopedic surgeries, of which titanium and its alloys are most widely used owing to the excellent corrosiveness resistance, low elastic modulus and good biocompatibility. However, implant failure still occurs for that titanium and its alloys themselves do not own antibacterial and osteogenic properties. In this work, we successfully fabricated berberine-loaded graphene oxide (GO) on the surface of biomedical titanium and systematically investigated its capabilities of antibacteria and osteogenesis. In vitro results showed that berberine had low antibacterial activity, but GO loaded with berberine on titanium (Ber&GO@Ti) exhibited superior antibacterial activity against Staphylococcus aureus (S. aureus) with the synergistic effect of GO and berberine. Meanwhile, Ber&GO@Ti performed satisfactory cytocompatibility and was capable of promoting osteogenic differentiation of MC3T3-E1 cells. In the vivo experiment, Ber&GO@Ti showed excellent antibacterial properties and inflammatory cells e.g., neutrophils had seldom been found. No visceral toxicity had been found. This multifunctional coating showed great potential in orthopedic implants.

Using a Machine Learning Approach to Identify Key Biomarkers for Renal Clear Cell Carcinoma.

Background: The most common and deadly subtype of renal carcinoma is kidney renal clear cell carcinoma (KIRC), which accounts for approximately 75% of renal carcinoma. However, the main cause of death in KIRC patients is tumor metastasis. There are no obvious clinical features in the early stage of kidney cancer, and 25-30% of patients have already metastasized when they are first diagnosed. Moreover, KIRC patients whose local tumors have been removed by nephrectomy are still at high risk of metastasis and recurrence and are not sensitive to chemotherapy and radiotherapy, leading to poor prognosis. Therefore, early diagnosis and treatment of this disease are very important. Methods: KIRC-related patient datasets were downloaded from the GEO database and TCGA database. DEG screening and GO, KEGG and GSEA enrichment analysis was firstly conducted and then the LASSO and support vector machine (SVM) RFE algorithms were adopted to identify KIRC-associated key genes in training sets and validate them in the test set. The clinical prognostic analysis including the association between the expression of key genes and the overall survival, stage, grade across KIRC, the immune infiltration difference between normal samples and cancer samples, the correlation between the key genes and immune cells, immunomodulator, immune subtypes of KIRC were investigated in this research. Results: We finally screened out 4 key genes, including ACPP, ANGPTL4, SCNN1G, SLC22A7. The expression of key genes show difference among normal samples and tumor samples, SCNN1G and SLC22A7 could be predictor of prognosis of patients. The expression of key genes was related with the abundance of tumor infiltration immune cells and the gene expression of immune checkpoint. Conclusion: This study screened the 4 key genes, which contributed to early diagnosis, prognosis assessment and immune target treatment of patients with KIRC.

ITGB2 as a prognostic indicator and a predictive marker for immunotherapy in gliomas.

PURPOSE: Glioma is the most common primary tumor in the brain, accounting for 81% of intracranial malignancies. Nowadays, cancer immunotherapy has become a novel and revolutionary treatment for patients with advanced, highly aggressive tumors. However, to date, there are no effective biomarkers to reflect the response of glioma patients to immunotherapy. In this study, we aimed to assess the clinical predictive value of ITGB2 in patients with glioma. METHODS: The correlation between ITGB2 expression levels and glioma progression was explored and validated using data from CGGA, TCGA, GEO datasets, and patient samples from our hospital. Univariate and multivariate cox regression models were developed to determine the predictive role of ITGB2 on the prognosis of patients with glioma. The relationship between ITGB2 and immune activation was then analyzed. Finally, we predicted the immunotherapy response in both high and low ITGB2 expression subgroups. RESULTS: ITGB2 was significantly elevated in gliomas with higher malignancy and predicted poor prognosis. In multivariate analysis, the hazard ratio for ITGB2 expression (low versus high) was 0.71 with 95% CI (0.59-0.85) (P < 0.001). Furthermore, we found that ITGB2 stratified glioma patients into high and low ITGB2 expression subgroups, exhibiting different clinical outcomes and immune activation status. At last, we demonstrated that glioma patients with high ITGB2 expression levels had better immunotherapy response. CONCLUSIONS: This study demonstrated ITGB2 as a novel predictor for clinical prognosis and response to immunotherapy in gliomas. Assessing expression levels of ITGB2 is a promising method to discover patients that may benefit from immunotherapy.

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.

Establishment of a nomogram with EMP3 for predicting clinical outcomes in patients with glioma: A bi-center study.

AIM: To demonstrate the clinical value of epithelial membrane protein 3 (EMP3) with bioinformatic analysis and clinical data, and then to establish a practical nomogram predictive model with bicenter validation. METHODS: The data from CGGA and TCGA database were used to analyze the expression of EMP3 and its correlation with clinical prognosis. Then, we analyzed EMP3 expression in samples from 179 glioma patients from 2013 to 2017. Univariate and multivariate cox regression were used to predict the prognosis with multiple factors. Finally, a nomogram to predict poor outcomes was formulated. The accuracy and discrimination of nomograms were determined with ROC curve and calibration curve in training and validation cohorts. RESULTS: EMP3 was significantly higher in higher-grade glioma and predicted poor prognosis. In multivariate analysis, high expression of EMP3 (HR = 2.842, 95% CI 1.984-4.071), WHO grade (HR = 1.991, 95% CI 1.235-3.212), and IDH1 mutant (HR = 0.503, 95% CI 0.344-0.737) were included. The nomogram was constructed based on the above features, which represented great predictive value in clinical outcomes. CONCLUSION: This study demonstrated EMP3 as a novel predictor for clinical progression and clinical outcomes in glioma. Moreover, the nomogram with EMP3 expression represented a practical approach to provide individualized risk assessment for glioma patients.

Retraction Notice to: Application of Inorganic Nanocomposite Hydrogels in Bone Tissue Engineering.

[This retracts the article DOI: 10.1016/j.isci.2020.101845.].

Application of Inorganic Nanocomposite Hydrogels in Bone Tissue Engineering.

Bone defects caused by trauma and surgery are common clinical problems encountered by orthopedic surgeons. Thus, a hard-textured, natural-like biomaterial that enables encapsulated cells to obtain the much-needed biophysical stimulation and produce functional bone tissue is needed. Incorporating nanomaterials into cell-laden hydrogels is a straightforward tactic for producing tissue engineering structures that integrate perfectly with the body and for tailoring the material characteristics of hydrogels without hindering nutrient exchange with the surroundings. In this review, recent developments in inorganic nanocomposite hydrogels for bone tissue engineering that are of vital importance but have not yet been comprehensively reviewed are summarized.