An innovative prognostic model based on autophagy-related long noncoding RNA signature for low-grade glioma.

Autophagy is a highly conserved lysosomal degradation process essential in tumorigenesis. However, the involvement of autophagy-related long noncoding RNAs (lncRNAs) in low-grade glioma (LGG) remains unclear. In this study, we established an autophagy-related lncRNA prognostic signature for patients with LGG and assess its underlying functions. We used univariate Cox, least absolute shrinkage and selection operator and multivariate Cox regression models to establish an autophagy-related lncRNA prognostic signature. Kaplan-Meier survival analysis, receiver operating characteristic curve, nomogram, C-index, calibration curve and clinical decision-making curve were used to assess the predictive capability of the identified signature. A signature comprising nine autophagy-related lncRNAs (AL136964.1, ARHGEF26-AS1, PCED1B-AS1, AS104072.1, PRKCQ-AS1, LINC00957, AS125616.1, PSMB8-AS1 and AC087741.1) was identified as a prognostic model. Patients with LGG were divided into the high- and low-risk cohorts based on the median model-based risk score. The survival analysis revealed a 10-year survival rate of 9.3% (95% CI 1.91-45.3%) and 13.48% (95% CI 4.52-40.2%) in high-risk patients in the training and validation sets, respectively, and 48.4% (95% CI 24.7-95.0%) and 48.4% (95% CI 28.04-83.4%) in low-risk patients in the training and validation sets, respectively. This finding suggested a relatively low survival in high-risk patients. In addition, the lncRNA signature was independently prognostic and potentially associated with the progression of LGG. Therefore, the 9-autophagy-related-lncRNA signature may play a crucial role in the diagnosis and treatment of LGG, which may offer new avenues for tumour-targeted therapy.

siRNA-mediated silencing of bFGF gene inhibits the proliferation, migration, and invasion of human pituitary adenoma cells.

Human pituitary adenoma is one of the most common intracranial tumors with an incidence as high as 16.7%. Recent evidence has hinted a relationship between growth factors of pituitary or hypothalamic origin and proliferation of human pituitary adenoma cells. This study explores the effects of small interfering RNA-mediated silencing of basic fibroblast growth factor gene on the proliferation, migration, and invasion of human pituitary adenoma cells. Human pituitary adenoma tissues were collected to obtain human pituitary adenoma cells. The basic fibroblast growth factor silencing interference plasmid was constructed, and the human pituitary adenoma cells were transfected and assigned as basic fibroblast growth factor-small interfering RNA, negative control-small interfering RNA, and blank groups. The quantitative real-time polymerase chain reaction and Western blotting were carried out to detect the expression of basic fibroblast growth factor, pituitary tumor transforming gene, vascular endothelial growth factor, cluster of differentiation 147, and matrix metalloproteinase 9. Cell Counting Kit-8 assay was conducted to observe cell proliferation at 0, 24, 48, and 72 h. Flow cytometry was used to determine cell cycle. Transwell and scratch test were applied to detect the invasion and migration of pituitary adenoma cells. Protein kinase C activity was detected. In comparison with the blank group, the basic fibroblast growth factor-small interfering RNA group showed reduced messenger RNA and protein expression of basic fibroblast growth factor, reduced cell viability at 24, 48, and 72 h, increased cells in G0/G1 stage, declined cells in S and G2/M stages, decreased number of cell migration, shortened migrating distance, reduced protein kinase C activity, and decreased expression of pituitary tumor transforming gene, vascular endothelial growth factor, cluster of differentiation 147, and matrix metalloproteinase 9. However, the negative control-small interfering RNA group had no evident differences in basic fibroblast growth factor expression, cell viability, cell cycle, number of cell migration, migrating distance, protein kinase C activity, and expression of pituitary tumor transforming gene, vascular endothelial growth factor, cluster of differentiation 147, and matrix metalloproteinase 9 compared with the blank group. The study provides evidence that small interfering RNA-mediated silencing of basic fibroblast growth factor gene inhibits the proliferation, migration, and invasion of human pituitary adenoma cells.

N7-methylguanosin regulators-mediated methylation modification patterns and characterization of the immune microenvironment in lower-grade glioma.

N7-methylguanosine (m7G) modification signature has recently emerged as a crucial regulator of tumor progression and treatment in cancer. However, there is limited information available on the genomic profile of lower-grade gliomas (LGGs) related to m7G methylation modification genes' function in tumorigenesis and progression. In this study, we employed bioinformatics methods to characterize m7G modifications in individuals with LGG from The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). We used gene set enrichment analysis (GSEA), single sample GSEA (ssGSEA), CIBERSORT algorithm, ESTIMATE algorithm, and TIDE to evaluate the association between m7G modification patterns, tumor microenvironment (TME) cell infiltration properties, and immune infiltration markers. The m7G scoring scheme using principal component analysis (PCA) was employed to investigate the m7G modification patterns quantitatively. We examined the m7G modification hub genes' expression levels in normal samples, refractory epilepsy samples, and LGG samples using immunohistochemistry, western-blotting, and qRT-PCR. Our findings revealed that individuals with LGG could be categorized into two groups based on m7G scores (high and low) according to the properties of m7G. Moreover, we observed that high m7G score was associated with significant clinical benefit and prolonged survival duration in the anti-PD-1 cohort, while low m7G score was associated with improved prognostic outcomes and increased likelihood of complete or partial response in the anti-PD-L1 cohort. Different m7G subtypes also showed varying Tumor Mutational Burden (TMB) and immune profiles and might have distinct responses to immunotherapy. Furthermore, we identified five potential genetic markers that were highly correlated with the m7G score signature index. These findings provide insight into the features and classification associated with m7G methylation modifications and may aid in improving the clinical outcome of LGG.

Genomic Profiling of Lower-Grade Gliomas Subtype with Distinct Molecular and Clinicopathologic Characteristics via Altered DNA-Damage Repair Features.

Lower WHO grade II and III gliomas (LGGs) exhibit significant genetic and transcriptional heterogeneity, and the heterogeneity of DNA damage repair (DDR) and its relationship to tumor biology, transcriptome, and tumor microenvironment (TME) remains poorly understood. In this study, we conducted multi-omics data integration to investigate DDR alterations in LGG. Based on clinical parameters and molecular characteristics, LGG patients were categorized into distinct DDR subtypes, namely, DDR-activated and DDR-suppressed subtypes. We compared gene mutation, immune spectrum, and immune cell infiltration between the two subtypes. DDR scores were generated to classify LGG patients based on DDR subtype features, and the results were validated using a multi-layer data cohort. We found that DDR activation was associated with poorer overall survival and that clinicopathological features of advanced age and higher grade were more common in the DDR-activated subtype. DDR-suppressed subtypes exhibited more frequent mutations in IDH1. In addition, we observed significant upregulation of activated immune cells in the DDR-activated subgroup, which suggests that immune cell infiltration significantly influences tumor progression and immunotherapeutic responses. Furthermore, we constructed a DDR signature for LGG using six DDR genes, which allowed for the division of patients into low- and high-risk groups. Quantitative real-time PCR results showed that CDK1, CDK2, TYMS, SMC4, and WEE1 were significantly upregulated in LGG samples compared to normal brain tissue samples. Overall, our study sheds light on DDR heterogeneity in LGG and provides insight into the molecular pathways of DDR involved in LGG development.

Safety and Efficacy of Cell Transplantation on Improving Motor Symptoms in Patients With Parkinson's Disease: A Meta-Analysis.

Background: The past four decades have seen the growing use of tissue or cell transplants in Parkinson's disease (PD) treatment. Parkinson's cell therapy is a promising new treatment; however, efficacy of cell transplantation for Parkinson's disease are entirely unclear. Objective: To conduct a meta-analysis and a systematic review of the efficacy of cell therapy in patients with PD. Methods: A systematic literature review and meta-analysis of 10 studies were performed to assess the efficacy of cell therapy in Parkinson's patients. To achieve this, we compared the change in Unified Parkinson's Disease Rating Scale (UPDRS) II and III scale scores to baseline and assessed the incidence of transplant-related adverse events. The MINORS score and the I2 index were applied to evaluate the quality of studies between-study heterogeneity, respectively. Results: The literature search yielded 10 articles (n = 120). The improvement in motor function based on the UPDRSIII assessment was -14.044 (95% CI: -20.761, -7.327) (p < 0.001), whereas improvement in daily living ability based on the UPDRSII assessment was -5.661 (95% CI: -7.632, -3.689) (p < 0.001). Conclusion: The present findings demonstrate important clues on the therapeutic effect of cell therapy in alleviating motor impairment and daily living ability in PD patients.

The need to be alert to complications of peri-lead cerebral edema caused by deep brain stimulation implantation: A systematic literature review and meta-analysis study.

BACKGROUND: The compatibility of deep brain stimulation (DBS) hardware and MRI scans has greatly improved the diagnostic rate of postoperative peri-lead edema (PLE). However, the etiology, incidence, and prognostic outcomes of this complication have not been established. OBJECTIVE: The incidence of PLE and associated symptoms, the process of occurrence and progression of this complication, as well as treatment strategies were evaluated. METHODS: We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses compliant systematic review of all studies that reported on incidences of PLE and associated symptoms after DBS implantation. Through systematic literature review, we evaluated its causes, neuropsychiatric symptoms, duration, treatment methods, and prognostic outcomes. RESULTS: Our search retrieved 10 articles, including 5 articles on PLE and 10 articles on symptomatic PLE. The incidence of PLE was 35.8% (95% CI: 17.0%-54.6%), while the incidence of symptomatic PLE was 3.1% (95% CI: 1.5%-4.7%) accounting for 8.7% of PLE. CONCLUSIONS: This complication is not as rare as previously reported. Therefore, it requires significant attention after DBS implantation. The correlation between its causes, duration, symptoms, and the area involved in edema should be assessed in long-term prospective clinical studies with large sample sizes.

N6-methyladenosine RNA methylation regulator-related alternative splicing gene signature as prognostic predictor and in immune microenvironment characterization of patients with low-grade glioma.

Background: N6-methyladenosine (m6A) RNA methylation is an important epigenetic modification affecting alternative splicing (AS) patterns of genes to regulate gene expression. AS drives protein diversity and its imbalance may be an important factor in tumorigenesis. However, the clinical significance of m6A RNA methylation regulator-related AS in the tumor microenvironment has not been investigated in low-grade glioma (LGG). Methods: We used 12 m6A methylation modulatory genes (WTAP, FTO, HNRNPC, YTHDF2, YTHDF1, YTHDC2, ALKBH5, YTHDC1, ZC3H13, RBM15, METTL14, and METTL3) from The Cancer Genome Atlas (TCGA) database as well as the TCGA-LGG (n = 502) dataset of AS events and transcriptome data. These data were downloaded and subjected to machine learning, bioinformatics, and statistical analyses, including gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Univariate Cox, the Least Absolute Shrinkage and Selection Operator (LASSO), and multivariable Cox regression were used to develop prognostic characteristics. Prognostic values were validated using Kaplan-Maier survival analysis, proportional risk models, ROC curves, and nomograms. The ESTIMATE package, TIMER database, CIBERSORT method, and ssGSEA algorithm in the R package were utilized to explore the role of the immune microenvironment in LGG. Lastly, an AS-splicing factor (SF) regulatory network was examined in the case of considering the role of SFs in regulating AS events. Results: An aggregate of 3,272 m6A regulator-related AS events in patients with LGG were screened using six machine learning algorithms. We developed eight AS prognostic characteristics based on splice subtypes, which showed an excellent prognostic prediction performance. Furthermore, quantitative prognostic nomograms were developed and showed strong validity in prognostic prediction. In addition, prognostic signatures were substantially associated with tumor immune microenvironment diversity, ICB-related genes, and infiltration status of immune cell subtypes. Specifically, UGP2 has better promise as a prognostic factor for LGG. Finally, splicing regulatory networks revealed the potential functions of SFs. Conclusion: The present research offers a novel perspective on the role of AS in m6A methylation. We reveal that m6A methylation regulator-related AS events can mediate tumor progression through the immune-microenvironment, which could serve as a viable biological marker for clinical stratification of patients with LGG so as to optimize treatment regimens.

Case Report: Bilateral Deep Brain Stimulation Implantation on Different Targets for a Parkinson's Disease Patient With a Bullet in the Brain.

Patients requiring deep brain stimulation due to intracerebral metallic foreign substances have not been reported elsewhere in the world. Additionally, the long-term effects of metallic foreign bodies on deep brain stimulation (DBS) are unknown. A 79-year-old man with a 5-year history of Parkinson's disease (PD) reported that, 40 years ago, while playing with a pistol, a metallic bullet was accidentally discharged into the left brain through the edge of the left eye, causing no discomfort other than blurry vision in the left eye. DBS was performed due to the short duration of efficacy for oral medication. Because the bullet was on the left subthalamic nucleus (STN) electrode trajectory and the patient's right limb was primarily stiff, the patient received globus pallidus interna (GPi)-DBS implantation in the left hemisphere and STN-DBS implantation in the right hemisphere. During a 6-month postoperative follow-up, the patient's PD symptoms were effectively managed with no noticeable discomfort.

Identification and validation of a novel eight mutant-derived long non-coding RNAs signature as a prognostic biomarker for genome instability in low-grade glioma.

Long non-coding RNAs (lncRNAs) comprise an integral part of the eukaryotic transcriptome. Alongside proteins, lncRNAs modulate lncRNA-based gene signatures of unstable transcripts, play a crucial role as antisense lncRNAs to control intracellular homeostasis and are implicated in tumorigenesis. However, the role of genomic instability-associated lncRNAs in low-grade gliomas (LGG) has not been fully explored. In this study, lncRNAs expression and somatic mutation profiles in low-grade glioma genome were used to identify eight novel mutant-derived genomic instability-associated lncRNAs including H19, FLG-AS1, AC091932.1, AC064875.1, AL138767.3, AC010273.2, AC131097.4 and ISX-AS1. Patients from the LGG gene mutagenome atlas were grouped into training and validation sets to test the performance of the signature. The genomic instability-associated lncRNAs signature (GILncSig) was then validated using multiple external cohorts. A total of 59 novel genomic instability-associated lncRNAs in LGG were used for least absolute shrinkage and selection operator (Lasso), single and multifactor Cox regression analysis using the training set. Furthermore, the independent predictive role of risk features in the training and validation sets were evaluated through survival analysis, receiver operating feature analysis and construction of a nomogram. Patients with IDH1 mutation status were grouped into two different risk groups based on the GILncSig score. The low-risk group showed a relatively higher rate of IDH1 mutations compared with patients in the high-risk group. Furthermore, patients in the low-risk group had better prognosis compared with patients in the high-risk group. In summary, this study reports a reliable prognostic prediction signature and provides a basis for further investigation of the role of lncRNAs on genomic instability. In addition, lncRNAs in the signature can be used as new targets for treatment of LGG.

Integrated Gene Expression and Methylation Analyses Identify DLL3 as a Biomarker for Prognosis of Malignant Glioma.

Glioma is one of the most common neurological malignancies worldwide. Delta-like ligand 3 (DLL3), an inhibitory ligand-driven activation of the Notch pathway, has been shown to be significantly associated with overall survival in patients with glioma. Therefore, the purpose of this study was to determine whether DLL3 as a biomarker in glioma is associated with patients' clinicopathological features and prognosis. We identified differences in transcriptome and promoter methylation in the Chinese Glioma Genome Atlas (CGGA) in patients with malignant glioma with shorter (less than 1 year) and longer (greater than 3 years) survival time. Further analysis of The Cancer Genome Atlas (TCGA) revealed that four genes (DLL3, TSPAN15, RTN1, PAK7) are highly associated with patient prognosis and play an indispensable role in evolution. We chose the expression level of DLL3 in glioma patients for our study. Patients were divided into groups with low and high expression of DLL3 according to the cutoff values obtained, and Kaplan-Meier and Cox analysis were used to examine the correlation between DLL3 gene expression and patient survival. We then performed a gene set enrichment analysis (GSEA) to identify significantly enriched signaling pathways. Our results confirmed that the overall survival of patients with low DLL3 expression was significantly shorter than that of patients with high DLL3 expression. GSEA showed that the signaling pathways of the immune process and immune response, among others, were enhanced with the DLL3 low-expression phenotype. Collectively, our findings signify that DLL3 is a potent prognostic factor for glioma, which can provide a viable approach for glioma prognostic assessment and valuable insights for anti-tumor immune-targeted therapies.

Efficacy of 11C-2ß-carbomethoxy-3ß-(4-fluorophenyl) tropane positron emission tomography combined with 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of early Parkinson disease: A protocol for systematic review and meta analysis.

BACKGROUND: Parkinson's disease (PD) has a high incidence in the elderly, and the late stage seriously affects the daily life of the patients. Most of the initial symptoms of PD are not obvious or atypical, which brings difficulties to the early diagnosis. Replacement therapy and neuroprotection after early diagnosis can significantly improve the prognosis and quality of life of patients. More and more evidence shows that 11C-2ß-carbomethoxy-3ß-(4-fluorophenyl) tropane positron emission tomography ( 11C-CFT PET) combined with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) can effectively improve the accuracy of early diagnosis. However, there is no consistent conclusion at present. The purpose of this study is to evaluate the efficacy of 11C-CFT PET combined with 18F-FDG PET in the diagnosis of early PD. METHODS: We will search 7 electronic databases (PubMed, EMBASE, Web of Science, Cochrane library, PsycINFO, AMED, Scopus), ongoing trials and grey literature to collect related randomized controlled trials and will use Review Manager Software 5.2 and STATA Software 16.0 for analysis and synthesis. RESULTS: We will integrate the existing randomized controlled trials to evaluate the value of 11C-CFT PET combined with 18F-FDG PET in the diagnosis of early PD. CONCLUSION: Our study may prove that 11C-CFT PET combined with 18F-FDG PET can effectively diagnose early PD. REGISTRATION NUMBER: International Prospective Register of Systematic Reviews (PROSPERO): CRD42020203442.

Short-term efficacy of pipeline embolization device for treating complex intracranial aneurysms.

OBJECTIVE: To observe the short-term efficacy of Pipeline embolization divice (PED) for the treatment of complex intracranial aneurysms. METHODS: The clinical data of 29 consecutive patients with 32 intracranial aneurysms treated with PED between April 2015 to September 2016 were analyzed retrospectively. There were 3 small aneurysm, 15 large aneurysms, 8 giant aneurysms, 5 fusiform ayneurysms and 1 recidivation. The vessels include 25 anterior circulation and 4 posterior circulation. RESULTS: We treated 31 aneurysms with 30 PEDs and all of the stents were implanted successfully. 1 case of single aneurysm was multiple divices implanted and 1 case of 3 aneurysms were treated by single PED. 12 of the 29 patients were implanted PED only, 17 were implanted PED with coils, 2 underwent balloon remodeling after the PED implanted. The ostia of 19 ophthalmic arteries, 10 posterior communicating arteries, 4 posterior inferior cerebellar arteries and 1 anterior cerebral artery were covered by PED during procedures; 1 ophthalmic arteries and 1 posterior communicating artery disappeared, no branch vessels occlusion and parent artery stenosis occurred.Hemorrhagic complacations occurred in 2 patients, 2 hours and 5 days after procedure respectively. Radiographic follow-up examnations were carried out in 24 patients and revealed complete occlusion in 21 patients, uncomplete occlusion in 3 patients. No neurological injure occurred in 27 patients who received a clinical follow-up. CONCLUSION: PED provide a safe and effective methord for the treatment of intracranial complex aneurysms like wide-neck aneurysms, fusiform aneurysms, giant aneurysms in low risk of procedural complications and high rates of aneurysm occlusion.

MicroRNA-145 inhibits the activation of the mTOR signaling pathway to suppress the proliferation and invasion of invasive pituitary adenoma cells by targeting AKT3 in vivo and in vitro.

PURPOSE: This study was designed to explore how miR-145 regulates the mTOR signaling pathway in invasive pituitary adenoma (IPA) by targeting AKT3. METHODS: A total of 71 cases of IPA tissues and 66 cases of non-IPA tissues were obtained in this study. In vitro, the IPA cells were assigned into blank control, empty plasmid, miR-145 mimic, miR-145 inhibitor, miR-145 mimic + rapamycin, miR-145 inhibitor + rapamycin and rapamycin groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to detect the protein expressions of PI3K, AKT3, mTOR mRNA and the mRNA expression of miR-145 both in vivo and in vitro. Additionally, the S6K and RPS6 mRNA and protein expressions as well as the relative phosphorylation levels were determined in vitro. MTT assay, flow cytometry and transwell assay were used to testify the cell proliferation, apoptosis and invasion ability, respectively. RESULTS: The IPA tissues exhibited significantly lower expression of miR-145 but higher PI3K, AKT3 and mTOR mRNA and protein expressions when compared with the non-IPA tissues. Compared with the blank control and empty plasmid groups, the miR-145 mimic group showed significantly decreased PI3K, AKT3, mTOR, S6K and RPS6 mRNA and protein expressions as well as phosphorylation levels; besides, the IPA cell proliferation, migration and invasion ability were strongly inhibited, accompanied with the increased number of apoptotic cells. In the miR-145 inhibitor group, the PI3K, AKT3, mTOR, S6K and RPS6 mRNA and protein expressions as well as the phosphorylation levels were significantly increased; cell proliferation, migration and invasion ability were remarkably elevated, accompanied with reduced apoptotic cell number. CONCLUSION: The study demonstrates that miR-145 inhibits the mTOR signaling pathway to suppress the IPA cell proliferation and invasion and promotes its apoptosis by targeting AKT3.