Association Between Neurodegenerative Diseases and an Increased Risk of Epilepsy Based on Single Nucleotide Polymorphisms: A Mendelian Randomization Study.

Epilepsy is a common neurological disorder characterized by transient brain dysfunction, attributed to a multitude of factors. The purpose of this study is to explore whether neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), have a causal effect on epilepsy. Mendelian randomization (MR) methods were used to analyze the causal association between neurodegenerative diseases (AD, PD, ALS, and MS) and epilepsy based on single nucleotide polymorphisms from genome-wide association studies, including inverse-variance weighted, weighted median, MR-Egger, and weighted mode methods. The reliability and stability of the MR analysis results were assessed by the MR-Egger intercept, MR-PRESSO, and heterogeneity tests. Forty-three SNPs were selected for the MR analysis of MS and epilepsy. The inverse-variance weighted method showed a significant causal association between MS and increased risk of epilepsy (odds ratio 1.046; 95% confidence interval 1.001-1.093; P = 0.043). However, AD (P = 0.986), PD (P = 0.894), and ALS (P = 0.533) were not causally associated with epilepsy. Sensitivity analysis showed that the results were robust. The MR study confirmed the causal relationship between genetically predicted MS and epilepsy but did not support the causal relationship between genetically predicted AD, PD, and ALS on epilepsy.

Late-onset epilepsy and the risk of dementia: a systematic review and meta-analysis.

BACKGROUND: Patients with dementia have higher risk of epilepsy. However, it remains not comprehensively evaluated if late-onset epilepsy (LOE) is associated with higher risk of dementia. We, therefore, performed a meta-analysis to systematically evaluate the association. METHODS: Relevant cohort studies were identified by search of electronic databases including PubMed, Embase, and Web of Science. A randomized-effect model incorporating the possible between-study heterogeneity was used to pool the results. RESULTS: Overall, seven cohort studies including 873,438 adults were included, and 16,036 (1.8%) of them had LOE. With a mean follow-up duration of 8.7 years, 33,727 of them were diagnosed as dementia. Pooled results showed that LOE was associated with a higher risk of dementia (risk ratio [RR] 2.39, 95% confidence interval [CI] 2.04-2.81, p < 0.001, I2 = 67%). Results of subgroup analysis showed that the association between LOE and the risk of dementia was stronger in hospital-derived participants (RR 4.23, 95% CI 2.67-6.70, p < 0.001) than that in community-derived population (RR 2.25, 95% CI 1.93-2.63, p < 0.001; p for subgroup difference = 0.01). Pooled results of three studies showed that LOE was associated with a higher risk of Alzheimer's disease (RR 2.35, 95% CI 1.08-5.08, p = 0.03, I2 = 85%). One study suggested a significant association between LOE and risk of vascular dementia (RR 2.0, 95% CI 1.77-2.26, p < 0.001). CONCLUSIONS: Evidence from cohort studies suggests that LOE may be a risk factor of dementia.

Surgical Treatment of Recurrent Spheno- Orbital Meningioma.

OBJECTIVE: The extensive bone infiltration and carpet-like growth characteristics of spheno-orbital meningioma (SOM) make it hard to remove entirely, and recurrence and proptosis are the main reasons for reoperation. The authors report 20 cases of surgical treatment for recurrence of SOM, including surgical technique and symptom improvement. METHODS: The clinical data and follow-up results of 20 cases of recurrent SOM at our institution from 2000 to 2017 were retrospectively analyzed. RESULTS: All of the 20 patients with recurrence had received at least one operation before admission, with a mean age of 56 years and 70% female. The mean follow-up time was 36 months (172 months). All patients mainly showed symptoms such as proptosis and headache, and were found to be affected by supraorbital fissure during the operation. in 17 patients with recurrence, the affected sphenoid wing became tumor-like hyperplasia. Patients with extraocular muscle involvement have obvious protrusion and are often accompanied by diplopia. After surgical removal of the tumor, the symptoms of proptosis in 19 patients were significantly improved. During the follow-up, only 3 cases of proptosis recurred. After 15 patients underwent Simpson grade IV resection, 4 patients (27%) relapsed again. Five patients underwent Simpson III resection, and only 1 patient (20%) had tumor recurrence 18th months after surgery, and no proptosis recurred. CONCLUSIONS: The complete surgical removal of recurrent SOM is practically impossible. The main direction of surgical treatment should be to improve the symptoms of proptosis.

IRF7 as an Immune-Related Prognostic Biomarker and Associated with Tumor Microenvironment in Low-Grade Glioma.

PURPOSE: Tumor microenvironment (TME) affects the occurrence and progression of low-grade glioma (LGG). The aim of this study is to identify TME-related genes that influence prognosis in LGG patients and to explore their function and role in tumor immunity. PATIENTS AND METHODS: The TME components of LGG samples in the Cancer Genome Atlas (TCGA) database were identified by the ESTIMATE method, and differentially expressed genes (DEGs) with significant differences in immune scores and stromal scores were screened out. The core genes of DEGs were screened out by protein-protein interaction (PPI) network. Furthermore, immune-related target genes significantly correlated with prognosis were identified. Survival analysis and correlation analysis showed the correlation between target genes and clinical features and prognosis. The expression differences of target genes were verified by external database Chinese Glioma Genome Atlas (CGGA). CIBERSORT software identified the proportion of tumor-infiltrating immune cells (TICs) that were significantly related to target genes. Gene set enrichment analysis (GSEA) could enrich the main functions related to high and low expression of target genes. RESULTS: A total of 1567 DEGs were screened out from 529 LGG samples in the TCGA database, and 146 immune-related genes affecting prognosis were found. A total of 403 core genes were obtained from PPI network. The target gene interferon regulatory factor 7 (IRF7) was significantly associated with prognosis and clinical features of the tumor. The CGGA database verified the relationship between high and low expression groups of IRF7 and prognosis. GSEA indicated that IRF7 was mainly enriched in immune-related activities, significantly correlated with T cells CD8, macrophages M1, macrophages M2 and monocytes. CONCLUSION: The IRF7 is involved in immune responses in TME of LGG, which in turn influenced tumor occurrence and progression. IRF7 can act as a potential biomarker for prognosis in patients with LGG and provide a target for tumor immunotherapy.

Circ_0000520 contributes to triple-negative breast cancer progression through mediating the miR-1296/ZFX axis.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high incidence of local recurrence and metastasis. Circular RNAs (circRNAs) are implicated in the pathomechanism of TNBC. Here, we investigated the function of circ_0000520 in TNBC and its associated mechanism. METHODS: Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were used to measure RNA and protein expression. Cell proliferation was analyzed by cell counting kit-8 (CCK8) assay, flow cytometry and colony formation assay. Cell apoptosis was assessed by flow cytometry. Cell migration ability was analyzed by transwell migration and wound healing assays. Transwell invasion assay was conducted to analyze the invasion ability. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pulldown assay were performed to verify the interaction between microRNA-1296 (miR-1296) and circ_0000520 or zinc finger protein X-linked (ZFX). Xenograft mice model was established to analyze the role of circ_0000520 in xenograft tumor growth in vivo. RESULTS: Circ_0000520 expression was upregulated in TNBC tissues and cell lines. Circ_0000520 knockdown suppressed the proliferation, migration, and invasion whereas induced the apoptosis of TNBC cells. miR-1296 was verified as a target of circ_0000520, and circ_0000520 silencing-mediated suppressive effects on the malignant potential of TNBC cells were partly overturned by miR-1296 knockdown. miR-1296 interacted with the 3' untranslated region (3'UTR) of ZFX, and ZFX overexpression partly reversed miR-1296 overexpression-mediated effects in TNBC cells. Circ_0000520 absence reduced ZFX expression by upregulating miR-1296 in TNBC cells. Circ_0000520 silencing suppressed xenograft tumor growth in vivo. CONCLUSIONS: Circ_0000520 contributed to TNBC development by binding to miR-1296 to induce ZFX expression.

Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p.

BACKGROUND: Long noncoding RNA OPA-interacting protein 5 antisense transcript 1 (OIP5-AS1) was confirmed to involve in the malignancy of breast cancer. However, whether exosomal OIP5-AS1 is implicated in trastuzumab resistance remains unclear. METHODS: The IC50 value of cells to trastuzumab, cell proliferation, migration, and apoptosis was analyzed by cell counting kit-8 assay, colony formation assay, transwell assay, or flow cytometry, respectively. The expression of OIP5-AS1 and microRNA (miR)-381-3p was detected using quantitative real-time polymerase chain reaction. Exosomes were isolated by ultracentrifugation and qualified by nanoparticle tracking analysis software. Western blot was used to detect the protein levels of tumor susceptibility gene 101 (TSG101), CD81, CD63, or high-mobility group protein B3 (HMGB3). The interaction between miR-381-3p and OIP5-AS1 or HMGB3 was confirmed by dual-luciferase reporter assay and pull-down assay. In vivo experiments were conducted using murine xenograft models. RESULTS: OIP5-AS1 was elevated in trastuzumab-resistant breast cancer cells, and OIP5-AS1 knockdown rescued trastuzumab sensitivity. Extracellular OIP5-AS1 was packaged into exosomes, which were secreted by trastuzumab-resistant cells, and could be absorbed by trastuzumab-sensitive cells in breast cancer. Importantly, intercellular transfer of OIP5-AS1 via exosomes enhanced trastuzumab resistance in vitro. OIP5-AS1 was a sponge of miR-381-3p; besides, miR-381-3p targeted HMGB3. Murine xenograft analysis showed exosomal OIP5-AS1 induced trastuzumab resistance in vivo. Exosomal OIP5-AS1 was dysregulated in the serum of breast cancer patients and might be a promising diagnostic biomarker in trastuzumab resistance. CONCLUSION: Intercellular transfer of OIP5-AS1 by exosomes enhanced trastuzumab resistance in breast cancer via miR-381-3p/HMGB3 axis, indicating a potential therapeutic strategy to boost the effectiveness of trastuzumab in resistant breast cancer patients.

Diagnostic nomogram model for predicting preoperative pathological grade of meningioma.

BACKGROUND: Meningioma is the most common primary tumor of the central nervous system. Preoperative diagnosis of high-grade meningioma is helpful for the selection of treatment options. The aim of our study is to establish a diagnostic nomogram model for preoperative prediction of the pathological grade of meningioma. METHODS: The predictive model was established from a cohort of 215 clinicopathologically confirmed meningioma between January 2012 and December 2017. Radiomic features were collected from preoperative magnetic resonance imaging (MRI) and computed tomography of patients with meningioma. The least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction and feature selection. Multivariate logistic regression was used to build a predictive model and presented as a nomogram. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. Internal validation was evaluated using bootstrapping validation. RESULTS: High-grade meningioma was observed in 47 patients (22%). The predictors included in the nomogram were tumor-brain interface, bone invasion, and tumor location. The final diagnostic model exhibited good calibration and discrimination with a C-index of 0.874 (95% confidence interval: 0.818-0.929) and a higher C-index of 0.868 in internal validation. Decision curve analysis (DCA) indicated that the nomogram is very useful in clinical practice. CONCLUSIONS: This study provides a nomogram model with tumor-brain interface, bone invasion, and tumor location that can effectively predict the preoperative pathological grading of patients with meningioma and thus help clinicians provide more reasonable treatment strategies for meningioma patients.

Suboptimal declines and delays in early breast cancer treatment after COVID-19 quarantine restrictions in China: A national survey of 8397 patients in the first quarter of 2020.

BACKGROUND: Cancer patients had been profoundly affected by the outbreak of COVID-19 especially after quarantine restrictions in China. We aimed to explore the treatment changes and delays of early breast cancer (EBC) during the first quarter of 2020. METHODS: We did this retrospective, multicentre, cohort study at 97 cancer centres in China. EBC patients who received treatment regardless of preoperative therapy, surgery or postoperative therapy during first quarter of 2020 were included. FINDINGS: 8397 patients were eligible with a median age of 50 (IQR 43-56). 0·2% (15/8397) of EBC patients were confirmed as COVID-19 infection. Only 5·2% of breast cancer diagnosis occurred after quarantine in Hubei compared with 15·3% in other provinces (OR= 0·30, 95%CI 0·24-0·38). postoperative endocrine therapy were least affected compared with different regions after quarantine (OR=0·37 [95%CI 0·19-0·73]). The proportion of surgery decreased from 16·4% in December last year to 2·6% in February in Hubei. Compared with intervals from diagnosis to treatment before quarantine restrictions, the average time increased with significance from 3·5 to 7·7 days in Hubei and 5·7 to 7·7 days in other provinces (p< 0·001). There were also 18·5 and 7·2 days delay in Hubei and other provinces respectively when calculating interval from surgery to postoperative therapy. INTERPRETATION: EBC from high risk regions had a comparative rate of COVID-19 infection. After implementation of COVID-19 quarantine restrictions, fewer diagnosis and surgery with significant delays were seen when compared with treatment before. FUNDING: Beijing Medical Award Foundation (YJ0120).