TRIM25 promotes glioblastoma cell growth and invasion via regulation of the PRMT1/c-MYC pathway by targeting the splicing factor NONO.

BACKGROUND: Ubiquitination plays an important role in proliferating and invasive characteristic of glioblastoma (GBM), similar to many other cancers. Tripartite motif 25 (TRIM25) is a member of the TRIM family of proteins, which are involved in tumorigenesis through substrate ubiquitination. METHODS: Difference in TRIM25 expression levels between nonneoplastic brain tissue samples and primary glioma samples was demonstrated using publicly available glioblastoma database, immunohistochemistry, and western blotting. TRIM25 knockdown GBM cell lines (LN229 and U251) and patient derived GBM stem-like cells (GSCs) GBM#021 were used to investigate the function of TRIM25 in vivo and in vitro. Co-immunoprecipitation (Co-IP) and mass spectrometry analysis were performed to identify NONO as a protein that interacts with TRIM25. The molecular mechanisms underlying the promotion of GBM development by TRIM25 through NONO were investigated by RNA-seq and validated by qRT-PCR and western blotting. RESULTS: We observed upregulation of TRIM25 in GBM, correlating with enhanced glioblastoma cell growth and invasion, both in vitro and in vivo. Subsequently, we screened a panel of proteins interacting with TRIM25; mass spectrometry and co-immunoprecipitation revealed that NONO was a potential substrate of TRIM25. TRIM25 knockdown reduced the K63-linked ubiquitination of NONO, thereby suppressing the splicing function of NONO. Dysfunctional NONO resulted in the retention of the second intron in the pre-mRNA of PRMT1, inhibiting the activation of the PRMT1/c-MYC pathway. CONCLUSIONS: Our study demonstrates that TRIM25 promotes glioblastoma cell growth and invasion by regulating the PRMT1/c-MYC pathway through mediation of the splicing factor NONO. Targeting the E3 ligase activity of TRIM25 or the complex interactions between TRIM25 and NONO may prove beneficial in the treatment of GBM.

Identifying PLAUR as a Pivotal Gene of Tumor Microenvironment and Regulating Mesenchymal Phenotype of Glioblastoma.

The mesenchymal (MES) phenotype of glioblastoma (GBM) is the most aggressive and therapy-resistant subtype of GBM. The MES phenotype transition during tumor progression results from both tumor-intrinsic genetic alterations and tumor-extrinsic microenvironmental factors. In this study, we sought to identify genes that can modulate the MES phenotype via both mechanisms. By integrating weighted gene co-expression network analysis (WGCNA) and the differential expression analysis of hypoxia-immunosuppression-related genes, we identified the plasminogen activator, urokinase receptor (PLAUR) as the hub gene. Functional enrichment analysis and GSVA analysis demonstrated that PLAUR was associated with the MES phenotype of glioma and the hypoxia-immunosuppression-related microenvironmental components. Single-cell sequencing analysis revealed that PLAUR mediated the ligand-receptor interaction between tumor-associated macrophages (TAMs) and glioma cells. Functional experiments in vitro with cell lines or primary glioma cells and xenograft models using BALB/c nude mice confirmed the role of PLAUR in promoting the MES phenotype of GBM. Our findings indicate that PLAUR regulates both glioma cells and tumor cell-extrinsic factors that favor the MES phenotype and suggest that PLAUR might be a potential target for GBM therapy.

Dynamic nomogram for predicting acute kidney injury in patients with acute ischemic stroke: A retrospective study.

Background: This study sought to develop and validate a dynamic nomogram chart to assess the risk of acute kidney injury (AKI) in patients with acute ischemic stroke (AIS). Methods: These data were drawn from the Medical Information Mart for Intensive Care III (MIMIC-III) database, which collects 47 clinical indicators of patients after admission to the hospital. The primary outcome indicator was the occurrence of AKI within 48 h of intensive care unit (ICU) admission. Independent risk factors for AKI were screened from the training set using univariate and multifactorial logistic regression analyses. Multiple logistic regression models were developed, and nomograms were plotted and validated in an internal validation set. Based on the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) to estimate the performance of this nomogram. Results: Nomogram indicators include blood urea nitrogen (BUN), creatinine, red blood cell distribution width (RDW), heart rate (HR), Oxford Acute Severity of Illness Score (OASIS), the history of congestive heart failure (CHF), the use of vancomycin, contrast agent, and mannitol. The predictive model displayed well discrimination with the area under the ROC curve values of 0.8529 and 0.8598 for the training set and the validator, respectively. Calibration curves revealed favorable concordance between the actual and predicted incidence of AKI (p > 0.05). DCA indicates the excellent net clinical benefit of nomogram in predicting AKI. Conclusion: In summary, we explored the incidence of AKI in patients with AIS during ICU stay and developed a predictive model to help clinical decision-making.

Global Trends and Hotspots in Trigeminal Neuralgia Research From 2001 to 2021: A Bibliometric Analysis.

Background: In recent years, there have been an increasing number of studies on trigeminal neuralgia (TN). However, a scientific and comprehensive study of the current situation and trends in the field of TN research is lacking. The purpose of this study is to summarize and visualize the development, research hotspots, and future trends in TN based on a bibliometric approach. Methods: Studies on TN published from 2001 to 2021 were obtained from the Web of Science Core Collection (WoSCC). Bibliometrics, CiteSpace, and VOSviewer tools were used for bibliometric analysis and visualization. Results: In total, 4,112 documents were searched. The number of research articles in the field is generally on an upward trend, with the fastest growth in the number of articles from 2017 to 2020. Shanghai Jiao Tong University, Pittsburgh University, and Mayo Clinic are the three institutions with the most publications. Shiting Li and Zakrzewska JM are the most prolific author and top co-cited authors, respectively. The Journal of Neurosurgery is the most influential journal. The top 5 keywords in that time frame are TN, microvascular decompression, facial pain, stereotactic radiosurgery, and neuropathic pain. Conclusion: This is the first comprehensive scientific bibliometric analysis of the global research field on TN over the past 21 years, providing a meaningful reference for further exploration of topical issues and research trends in the field.

Crosstalk Between the Oxidative Stress and Glia Cells After Stroke: From Mechanism to Therapies.

Stroke is the second leading cause of global death and is characterized by high rates of mortality and disability. Oxidative stress is accompanied by other pathological processes that together lead to secondary brain damage in stroke. As the major component of the brain, glial cells play an important role in normal brain development and pathological injury processes. Multiple connections exist in the pathophysiological changes of reactive oxygen species (ROS) metabolism and glia cell activation. Astrocytes and microglia are rapidly activated after stroke, generating large amounts of ROS via mitochondrial and NADPH oxidase pathways, causing oxidative damage to the glial cells themselves and neurons. Meanwhile, ROS cause alterations in glial cell morphology and function, and mediate their role in pathological processes, such as neuroinflammation, excitotoxicity, and blood-brain barrier damage. In contrast, glial cells protect the Central Nervous System (CNS) from oxidative damage by synthesizing antioxidants and regulating the Nuclear factor E2-related factor 2 (Nrf2) pathway, among others. Although numerous previous studies have focused on the immune function of glial cells, little attention has been paid to the role of glial cells in oxidative stress. In this paper, we discuss the adverse consequences of ROS production and oxidative-antioxidant imbalance after stroke. In addition, we further describe the biological role of glial cells in oxidative stress after stroke, and we describe potential therapeutic tools based on glia cells.

Case Report: A Pregnant Woman Diagnosed as ALK-Rearrangement Lung Large Cell Neuroendocrine Cancer With Brain Metastasis.

Concomitant malignant tumors and pregnancy present many difficult questions to both clinicians and patients. Due to no specific guidelines, each aspect of clinical management requires special considerations. This current report presents a rare case of a 38-year-old pregnant woman at gestational age 33 weeks with complaints of weakness of her right limbs for 2 weeks. After successive cesarean section and craniotomy, a diagnosis of lung large cell neuroendocrine carcinoma (LCNEC) metastatic to the brain was eventually made. Next generation sequencing (NGS) showed ALK-EML4 gene fusion. Immediately afterwards she was started on the targeted therapy with the ALK inhibitor alectinib. Ten months later, all known lesions exhibited a rapid regression, and no new brain metastases were found. Consequently, the therapeutic effect was considered as a partial response. Then, we review the previous literature using PubMed on maternal malignant brain tumors diagnosed during pregnancy, or lung LCNEC associated with ALK fusion, or ALK inhibitors treatment among the pregnant women, eventually, and discuss the concerns of dealing with these patients.

Matricellular protein tenascin C: Implications in glioma progression, gliomagenesis, and treatment.

Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.

Assessing rupture risk by hemodynamics, morphology and plasma concentrations of the soluble form of tyrosine kinase receptor Axl in unruptured intracranial aneurysms.

OBJECTIVE: This study investigated the relationship between morphology, hemodynamic parameters, and plasma concentrations of the soluble form of tyrosine kinase receptor Axl (sAxl) and their potential role in assessing the intracranial aneurysm rupture risk. METHODS: Thirty-nine patients were retrospectively recruited and these patients were divided into low and high rupture risk groups based on the PHASES score. Plasma levels of sAxl were measured using an enzyme-linked immunosorbent assay-based method. Computational fluid dynamics were used to calculate the morphological and hemodynamic parameters. Differences between clinical data, morphological-hemodynamic parameters and sAxl level were initially determined using univariate analysis. The variables (p ＜ 0.05) were included in a logistic regression model, and the specificity and sensitivity of the selected parameters were evaluated both graphically and statistically using receiver operating characteristic (ROC) curve methods. RESULTS: Aneurysm size ratio (p = 0.023), and normalized wall shear stress (WSS) (p = 0.02) showed significant differences between the two groups. Plasma concentrations of sAXL with a high rupture risk were significantly higher than the low rupture risk (8.47 ± 4.43 ng/ml vs. 5.37 ± 3.21 ng/ml; p = 0.016). Binary logistic regression analysis indicated that the concentration of sAxl was an independent determinant of high rupture risk (odds ratio=1.41, 95%CI=1.08-1.83, p = 0.011). The combination of sAxl + size ration (SR) + WSS achieved the highest area under the curve (0.849) for predicting rupture risk. CONCLUSIONS: Unruptured intracranial aneurysms with a higher rupture risk had a larger SR, lower WSS, and higher plasma sAxl concentration. Combining sAxl, SR, and WSS could help estimate the rupture risk of intracranial saccular aneurysm.