Construction of EMT related prognostic signature for kidney renal clear cell carcinoma, through integrating bulk and single-cell gene expression profiles.

Introduction: Kidney renal clear cell carcinoma (KIRC), as a main type of malignant kidney cancers, has a poor prognosis. Epithelial-mesenchymal transformation (EMT) exerts indispensable role in tumor progression and metastasis, including in KIRC. This study aimed to mine more EMT related details and build prognostic signature for KIRC. Methods: The KIRC scRNA-seq data and bulk data were downloaded from GEO and TCGA databases, respectively. The cell composition in KIRC was calculated using CIBERSORT. Univariate Cox regression analysis and LASSO Cox regression analysis were combined to determine the prognostic genes. Gene set variation analysis and cell-cell communication analysis were conducted to obtain more functional information. Additionally, functional analyses were conducted to determine the biological roles of si-LGALS1 in vitro. Results: We totally identified 2,249 significant differentially expressed genes (DEGs) in KIRC samples, meanwhile a significant distinct expression pattern was found in KIRC, involving Epithelial Mesenchymal Transition pathway. Among all cell types, significantly higher proportion of epithelial cells were observed in KIRC, and 289 DEGs were identified in epithelial cells. After cross analysis of all DEGs and 970 EMT related genes, SPARC, TMSB10, LGALS1, and VEGFA were optimal to build prognostic model. Our EMT related showed good predictive performance in KIRC. Remarkably, si-LGALS1 could inhibit migration and invasion ability of KIRC cells, which might be involved in suppressing EMT process. Conclusion: A novel powerful EMT related prognostic signature was built for KIRC patients, based on SPARC, TMSB10, LGALS1, and VEGFA. Of which, si-LGALS1 could inhibit migration and invasion ability of KIRC cells, which might be involved in suppressing EMT process.

Development and validation of a two glycolysis-related LncRNAs prognostic signature for glioma and in vitro analyses.

BACKGROUND: Mounting evidence suggests that there is a complex regulatory relationship between long non-coding RNAs (lncRNAs) and the glycolytic process during glioma development. This study aimed to investigate the prognostic role of glycolysis-related lncRNAs in glioma and their impact on the tumor microenvironment. METHODS: This study utilized glioma transcriptome data from public databases to construct, evaluate, and validate a prognostic signature based on differentially expressed (DE)-glycolysis-associated lncRNAs through consensus clustering, DE-lncRNA analysis, Cox regression analysis, and receiver operating characteristic (ROC) curves. The clusterProfiler package was applied to reveal the potential functions of the risk score-related differentially expressed genes (DEGs). ESTIMATE and Gene Set Enrichment Analysis (GSEA) were utilized to evaluate the relationship between prognostic signature and the immune landscape of gliomas. Furthermore, the sensitivity of patients to immune checkpoint inhibitor (ICI) treatment based on the prognostic feature was predicted with the assistance of the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Finally, qRT-PCR was used to verify the difference in the expression of the lncRNAs in glioma cells and normal cell. RESULTS: By consensus clustering based on glycolytic gene expression profiles, glioma patients were divided into two clusters with significantly different overall survival (OS), from which 2 DE-lncRNAs, AL390755.1 and FLJ16779, were obtained. Subsequently, Cox regression analysis demonstrated that all of these lncRNAs were associated with OS in glioma patients and constructed a prognostic signature with a robust prognostic predictive efficacy. Functional enrichment analysis revealed that DEGs associated with risk scores were involved in immune responses, neurons, neurotransmitters, synapses and other terms. Immune landscape analysis suggested an extreme enrichment of immune cells in the high-risk group. Moreover, patients in the low-risk group were likely to benefit more from ICI treatment. qRT-PCR results showed that the expression of AL390755.1 and FLJ16779 was significantly different in glioma and normal cells. CONCLUSION: We constructed a novel prognostic signature for glioma patients based on glycolysis-related lncRNAs. Besides, this project had provided a theoretical basis for the exploration of new ICI therapeutic targets for glioma patients.

Recent Insight on Regulations of FBXW7 and Its Role in Immunotherapy.

SCFFBXW7 E3 ubiquitin ligase complex is a crucial enzyme of the ubiquitin proteasome system that participates in variant activities of cell process, and its component FBXW7 (F-box and WD repeat domain-containing 7) is responsible for recognizing and binding to substrates. The expression of FBXW7 is controlled by multiple pathways at different levels. FBXW7 facilitates the maturity and function maintenance of immune cells via functioning as a mediator of ubiquitination-dependent degradation of substrate proteins. FBXW7 deficiency or mutation results in the growth disturbance and dysfunction of immune cell, leads to the resistance against immunotherapy, and participates in multiple illnesses. It is likely that FBXW7 coordinating with its regulators and substrates could offer potential targets to improve the sensitivity and effects of immunotherapy. Here, we review the mechanisms of the regulation on FBXW7 and its tumor suppression role in immune filed among various diseases (mostly cancers) to explore novel immune targets and treatments.

Comprehensive Analysis of Prognostic Value and Immune Infiltration of IGFBP Family Members in Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The insulin-like growth factor-binding protein (IGFBP) family is involved in tumorigenesis and the development of multiple cancers. However, little is known about the prognostic value and regulatory mechanisms of IGFBPs in GBM. Oncomine, Gene Expression Profiling Interactive Analysis, PrognoScan, cBioPortal, LinkedOmics, TIMER, and TISIDB were used to analyze the differential expression, prognostic value, genetic alteration, biological function, and immune cell infiltration of IGFBPs in GBM. We observed that IGFBP1, IGFBP2, IGFBP3, IGFBP4, and IGFBP5 mRNA expression was significantly upregulated in patients with GBM, whereas IGFBP6 was downregulated; this difference in mRNA expression was statistically insignificant. Subsequent investigations showed that IGFBP4 and IGFBP6 mRNA levels were significantly associated with overall survival in patients with GBM. Functional Gene Ontology Annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that genes coexpressed with IGFBP4 and IGFBP6 were mainly enriched in immune-related pathways. These results were validated using the TIMER and TSMIDB databases. This study demonstrated that the IGFBP family has prognostic value in patients with GBM. IGFBP4 and IGFBP6 are two members of the IGFBP family that had the highest prognostic value; thus, they have the potential to serve as survival predictors and immunotherapeutic targets in GBM.

Prognostic Value of MEG3 and Its Correlation With Immune Infiltrates in Gliomas.

Accumulating evidence has revealed that dysregulated lncRNA expression contributes to the onset and progression of cancer. However, the mechanistic role of lncRNA in glioma progression and tumor immunology remains largely unknown. This study aimed to evaluate the significance of maternally expressed gene 3 (MEG3) in the prognosis of and its immune-related roles in gliomas. The expression levels of MEG3 were analyzed using Oncomine and TIMER database. As an important imprinted gene, the copy number variation (CNV) of MEG3 in both glioblastoma multiforme (GBM) and low-grade glioma (LGG) were analyzed using GSCALite database, whereas its prognostic significance was assessed using PrognoScan and GEPIA databases. The relationship between MEG3 and tumor-infiltrated immune cells was analyzed using TIMER. Results showed that MEG3 expression was lower in most of the human cancer tissues than in the normal tissues. We also found that heterozygous deletion of MEG3 occurred more frequent than heterozygous amplification in gliomas, and mRNA expression of MEG3 was significantly positively correlated with its CNV in both the GBM and LGG group. Survival analysis showed that the CNV level of MEG3 had significant correlation with overall survival (OS) and progression-free survival (PFS) compared with wild type in LGG. Lower MEG3 expression was related with poor prognosis. Further analysis showed that in GBM, MEG3 expression level was significantly positively correlated with that of infiltrating CD8+ T cells and significantly negatively correlated with that of infiltrating dendritic cells. In LGG, MEG3 expression level was significantly negatively correlated with levels of infiltrating B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Univariate Cox survival analysis demonstrated that only the level of infiltrating dendritic cells significantly affected the survival time of patients with GBM, while all six types of immune cells had a significant effect on the survival time of patients with LGG. Furthermore, MEG3 expression showed strong correlations with multiple immune markers in gliomas, especially in LGG. The current findings suggest that MEG3 expression might serve as a possible prognostic marker and potential immunotherapeutic target for gliomas.

Upregulated protein O-GlcNAcylation promoted functional and structural recovery of the contused spinal cord injury in rats by Thiamet-G treatment.

Objectives-Elevated protein O-GlcNAcylation could benefit cell survival and promote organ functional recovery. Thiamet-G (O-GlcNAcase inhibitor) could upregulate protein O-GlcNAcylation level to improve dyskinesia in models of neurodegenerative diseases without any obvious detrimental side-effects. Therefore, we conducted this study to investigate the effects of protein O-GlcNAcylation upregulation by Thiamet-G on the spinal cord injury (SCI) in rats. Methods-We randomly assigned 74 rats to three groups: sham-operated group (Sham) with no lesion (n = 22), injured control group (SCI+SS) with saline solution (n = 26), and Thiamet-G treated group (SCI+Thiamet-G) (n = 26). We assessed Locomotor behavior using the Basso, Beattice, and Bresnahan (BBB) scale and evaluated histopathological alterations by morphometry and histochemistry. We also assessed potential inflammatory effects by microglia/macrophages immunohistochemistry, and potential apoptosis effects by caspase-3 western blot. Results-Thiamet-G treatment improved hindlimb motor functional recovery by inducing elevated protein O-GlcNAcylation, and mitigated the severity, reduced the lesion size and promoted the structural recovery of the injured spinal cord. Thiamet-G treatment also inhibited microglia/macrophages infiltration at the injury sites and the caspase-3 mediated apoptosis pathway. Discussion-We conclude that Thiamet-G induced elevated protein O-GlcNAcylation to ameliorate acute SCI, which could provide a potential novel therapeutic approach for SCI treatment.

Socioeconomic inequities in health care utilization in China.

The study assessed the present degree of inequity in health care utilization as well as the contributions of the main determinants in the context of expending health insurance coverage in China. Data were obtained from the 2008 National Health Services Survey (NHSS) in China. A concentration index was used to quantify the degree of income-related inequity in health care utilization. The need-standardized concentration indexes of outpatient care and inpatient care were 0.015 and 0.197, respectively. Income made the largest contribution to inequity favoring the better-off in the use of health care. The impacts of health insurance schemes on overall inequity varied according to the insurance memberships as well as types of services. The study revealed a pro-rich distribution of the probability of health care across income groups in China. Increased financial protection ability of medical insurance system remains a vital cornerstone to tackle the health care utilization inequity.

Spinal duraplasty with two novel substitutes restored locomotor function after acute laceration spinal cord injury in rats.

A dural tear is a common complication after acute laceration spinal cord injury (ALSCI). An unrepaired dural tear is associated with poor locomotor functional recovery. Spinal duraplasty with biomaterials may promote functional recovery in ALSCI. However, an ideal dural substitute has not yet been found. In this work, we investigated the possibility of using a denuded human amniotic membrane (DHAM) or DHAM seeded on bone marrow stromal cells (DHAM-BMSCs) as duraplasty biomaterials. We patched broken dura with the two novel substitutes in an ALSCI rat model. At the end of the eighth week, we observed that the neural motor function was recovered according to the Basso-Beattie-Bresnahan scale, and the neural loop was successfully reestablished between the ends of the lesions by motor-evoked potentials in the duraplasty groups. Moreover, the DHAM-BMSCs repaired the dura and resulted in a significant reduction in the total lesion and cystic volumes by nearly 10-fold versus the control group (p < 0.01). The levels of neurotrophic factors and NF-200-positive fibers were also improved in the duraplasty groups, compared to the control group. Our data suggest that the two novel substitutes may be promising grafts for patching dural defects to improve locomotor function after ALSCI.

Microsurgical anatomy of the greater superficial petrosal nerve.

OBJECTIVE: To clarify the orientation, classification, and relationships of the greater superficial petrosal nerve (GSPN), and to provide a detailed description on the microsurgical anatomic features and some landmarks to its identification. METHODS: A microsurgical anatomic dissection of the GSPN was studied in 40 specimens obtained from 20 adult cadaveric heads fixed in formalin. The course of the GSPN and its relationship to neighboring anatomic structures were observed. RESULTS: The GSPN could be divided into four segments: intrapetrosal, suprapetrosal, of foramen lacerum, and of pterygoid canal. About 17.5% (7/40) of GSPNs had communication with the glossopharyngeal nerve (GN). According to communication between the GSPN, internal carotid plexus, and GN, the segment of the foramen lacerum could be divided into five types. The middle meningeal artery and internal maxillary artery were the major blood suppliers of the GSPN. The GSPN usually ran parallel with the lesser petrosal nerve, but sometimes they were at angle to each other. CONCLUSIONS: The relationships between the GSPN and its surrounding structures were studied. The vulnerability of the GSPN is attributed to diverse factors. We confirmed the communication branches between the GSPN and the GN. Our study is important to the understanding of the relationship of the GSPN with adjacent structures and will improve further information during skull base operations.