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INTRODUCTION: The triglyceride glucose index (TyG) is associated with cardiovascular diseases; however, its association with stroke remains unclear. This study aimed to elucidate this relationship by examining two extensive cohort studies using two-sample Mendelian randomization (MR). METHODS: Using data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) and the Medical Information Mart for Intensive Care (MIMIC)-IV, the correlation between TyG (continuous and quartile) and stroke was examined using multivariate Cox regression models and sensitivity analyses. Two-sample MR was employed to establish causality between TyG and stroke using the inverse variance weighting method. Genome-wide association study catalog queries were performed for single nucleotide polymorphism-mapped genes, and the STRING platform used to assess protein interactions. Functional annotation and enrichment analyses were also conducted. RESULTS: From the NHANES and MIMIC-IV cohorts, we included 740 and 589 participants with stroke, respectively. After adjusting for covariates, TyG was linearly associated with the risk of stroke death (NHANES: hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.41-0.99, P=0.047; Q3 vs. Q1, HR 0.62, 95%CI: 0.40-0.96, P=0.033; MIMIC-IV: HR 0.46, 95%CI: 0.27-0.80, P=0.006; Q3 vs. Q1, HR 0.32, 95%CI: 0.12-0.86; Q4 vs. Q1, HR 0.30, 95%CI: 0.10-0.89, P=0.030, P for trend=0.017). Two-sample MR analysis showed genetic prediction supported a causal association between a higher TyG and a reduced risk of stroke (odds ratio 0.711, 95%CI: 0.641-0.788, P=7.64e-11). CONCLUSIONS: TyG was causally associated with a reduced risk of stroke. TyG is a critical factor for stroke risk management.
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The cadherin family plays a pivotal role in orchestrating synapse formation in the central nervous system. Cadherin-related family member 1 (CDHR1) is a photoreceptor-specific calmodulin belonging to the expansive cadherin superfamily. However, its role in traumatic brain injury (TBI) remains largely unknown. CDHR1 expression across various brain tissue sites was analyzed using the GSE104687 dataset. Employing a summary-data-based Mendelian Randomization (SMR) approach, integrated analyses were performed by amalgamating genome-wide association study abstracts from TBI with public data on expressed quantitative trait loci and DNA methylation QTL from both blood and diverse brain tissues. CDHR1 expression and localization in different brain tissues were meticulously delineated using western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay. CDHR1 expression was consistently elevated in the TBI group compared to that in the sham group across multiple tissues. The inflammatory response emerged as a crucial biological mechanism, and pro-inflammatory and anti-inflammatory factors were not expressed in either group. Integrated SMR analyses encompassing both blood and brain tissues substantiated the heightened CDHR1 expression profiles, with methylation modifications emerging as potential contributing factors for increased TBI risk. This was corroborated by western blotting and immunohistochemistry, confirming augmented CDHR1 expression following TBI. This multi-omics-based genetic association study highlights the elevated TBI risk associated with CDHR1 expression coupled with putative methylation modifications. These findings provide compelling evidence for future targeted investigations and offer promising avenues for developing interventional therapies for TBI.
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Lesões Encefálicas Traumáticas , Caderinas , Animais , Humanos , Masculino , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Proteínas Relacionadas a Caderinas , Caderinas/genética , Caderinas/metabolismo , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genéticaRESUMO
BACKGROUND: Glioma is one of the most aggressive malignant brain tumors and is characterized by invasive growth and poor prognosis. TBC1D1, a member of the TBC family, is associated with the development of various malignancies. However, the role of TBC1D1 in glioma-genesis remains unclear. METHODS: The effect of TBC1D1 on the prognosis of glioma patients and related influencing factors were analyzed in the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. Expression of TBC1D1 in glioma cell lines was detected by western blotting. Cell viability and proliferation were measured by EdU and Colony formation assays, respectively. Transwell and wound healing assays were performed to determine the cell migration and invasion capacities. Immunofluorescence was used to observe actin morphology in the cytoskeleton. RESULTS: We discovered that high TBC1D1 expression in gliomas led to poor prognosis. Downregulation of TBC1D1 in glioma cells significantly inhibited multiple important functions, such as proliferation, migration, and invasion. We further demonstrated that the tumor-inhibitory effect of TBC1D1 might occur through the P-LIMK/cofilin pathway, destroying the cytoskeletal structure and affecting the depolymerization of F-actin, thereby inhibiting glioma migration. CONCLUSION: TBC1D1 affects the balance and integrity of the actin cytoskeleton via cofilin, thereby altering the morphology and aggressiveness of glioma cells. This study provides a new perspective on its role in tumorigenesis, thereby identifying a potential therapeutic target for the treatment of gliomas.
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Neoplasias Encefálicas , Glioma , Humanos , Proliferação de Células/genética , Linhagem Celular Tumoral , Glioma/patologia , Neoplasias Encefálicas/patologia , Movimento Celular/genética , Actinas , Citoesqueleto de Actina/metabolismo , Fatores de Despolimerização de Actina/metabolismo , Fatores de Despolimerização de Actina/farmacologia , Proteínas Ativadoras de GTPase/genéticaRESUMO
BACKGROUND: Triglyceride glucose (TyG) is associated with stroke, atherosclerosis, and adverse clinical outcomes. However, its correlation with cerebrovascular disease (CVD) mortality remains unclear. This study aimed to investigate the relationship between TyG index and mortality in patients with CVD. METHODS: Patient data sourced from the Medical Information Mart for Intensive Care -IV database were categorized based on TyG quartiles. Kaplan-Meier survival analysis was used to estimate survival disparities among the TyG subgroups. Cox proportional risk modeling was used to examine the association between the TyG index and mortality. Generalized summation models were applied to fit the smoothed curves. log-likelihood ratio test were used to analyze the non-linear relationship. RESULTS: The study comprised 1,965 patients (50.18% were male). The 28-day and 90-day mortality rates were 20.10% and 24.48%, respectively. The TyG index exhibited a linear relationship with the 28-day mortality (Hazards ratio (HR), 1.16; 95% confidence interval (CI), 0.99-1.36) and the 90-day mortality (HR, 1.18; 95% CI, 1.02-1.37). In the TyG Q4 group, each 1 mg/dl increase was linked to a 35% rise in the risk of 28-day mortality and a 38% increase in the risk of 90-day mortality. Subgroup analyses highlighted a more substantial association between TyG index and 90-day mortality in the diabetic group. CONCLUSION: Our findings underscore the positive association between TyG and the 28- and 90-day mortality rates in patients with CVD. This insight may prove pivotal for identifying at-risk populations and enhancing risk prediction in the clinical management of CVD.
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BACKGROUND: The clinical effect of postoperative radiotherapy (PORT) in non-malignant meningioma (NMM) has not been well explored. METHODS: A total of 8629 patients with NMM (surgery alone group: n = 7716, postoperative radiotherapy group: n = 913) were obtained from the Surveillance, Epidemiology, and End Results database. Patient profiles were matched by 1:1 propensity score matching (PSM). Logistic regression analysis was performed to identify factors associated with PORT versus surgery alone (SA). Univariate and multivariate Cox regression analyses determined prognostic variables with overall survival (OS) in NMM. Subgroup analyses were performed with Cox proportional hazards regression models. RESULTS: All the SA (n = 7716) and PORT (n = 913) groups were included. Women with PORT (66.3%) and SA (70.9%) were almost twice as likely as men, and tumors with benign behaviors in the SA group were almost seven times more frequent than those with malignant characteristics. We explored the demographic, clinical characteristics, and prognostic factors in NMM. Laterality, surgery, tumor size, diagnosis year, age, and tumor behavior were associated with PORT versus SA. Patients treated with PORT had better OS than those treated with SA (p = 0.03). After PSM, PORT remained comparable to SA (hazard ratio 0.56, 95% confidence interval 0.35-0.88, p = 0.013). In the subgroup analysis of PORT treatment, borderline malignant behavior increased the death risk by 23%, while other variables did not have a significant clinical benefit (p > 0.05). CONCLUSIONS: Borderline malignant behavior should be considered seriously, and the PORT regimen should be actively implemented for patients with benign meningiomas.
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Neoplasias Meníngeas , Meningioma , Masculino , Humanos , Feminino , Meningioma/epidemiologia , Meningioma/radioterapia , Meningioma/cirurgia , Pontuação de Propensão , Estudos Retrospectivos , Radioterapia Adjuvante , Programa de SEER , Neoplasias Meníngeas/epidemiologia , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/cirurgiaRESUMO
Most spinal meningiomas (SM) are benign lesions of the thoracic spine and are usually treated surgically. This study aimed to explore treatment strategies and construct a nomogram for SM. Data on patients with SM from 2000 to 2019 were extracted from the Surveillance, Epidemiology, and End Results database. First, the distributional properties and characteristics of the patients were descriptively evaluated, and the patients were randomly divided into training and testing groups in a 6:4 ratio. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the survival predictors. Kaplan-Meier curves explained survival probability by different variables. The nomogram was constructed based on the results of LASSO regression. The predictive power of the nomogram was identified using the concordance index, time-receiver operating characteristics, decision curve analysis, and calibration curves. We recruited 1,148 patients with SM. LASSO results for the training group showed that sex (coefficient, 0.004), age (coefficient, 0.034), surgery (coefficient, -0.474), tumor size (coefficient, 0.008), and marital status (coefficient, 0.335) were prognostic factors. The nomogram prognostic model showed good diagnostic ability in both the training and testing groups, with a C-index of 0.726, 95% (0.679, 0.773); 0.827, 95% (0.777, 0.877). The calibration and decision curves suggested that the prognostic model had better diagnostic performance and good clinical benefit. In the training and testing groups, the time-receiver operating characteristic curve showed that SM had moderate diagnostic ability at different times, and the survival rate of the high-risk group was significantly lower than that of the low-risk group (training group: p = 0.0071; testing group: p = 0.00013). Our nomogram prognostic model may have a crucial role in predicting the six-month, one-year, and two-year survival outcomes of patients with SM and may be useful for surgical clinicians to formulate treatment plans.
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BACKGROUND: Cervical cancer is a malignant tumor that affects females and remains the cause of the highest morbidity and mortality among women worldwide. Currently, gene-targeted therapy is a novel treatment option for clinicians. Furthermore, fatty acid synthase (FASN) plays a therapeutic role in various cancers. Nonetheless, the mechanism of action of this enzyme in cervical squamous cell carcinoma and cervical duct adenocarcinoma (CESC) has not yet been reported. METHODS: RNA (ribonucleic acid) sequencing data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). The expression levels of FASN were obtained from Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Human Protein Atlas (HPA). Univariate and multivariate Cox regression analyses were utilized to assess independent prognostic factors associated with survival. A nomogram and receiver operating characteristic curve (ROC) were employed to evaluate survival and predictive power. In vitro experiments and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) were conducted to identify cell interference efficiency. MTS, monoclonal formation, and EDU assays were used to determine cell viability. Wound healing and invasion assays (transwell assay) were used to evaluate cell migration and invasion. Finally, Hoechst 33342, propidium iodide (PI) staining and Annexin V-FITC staining were used to assess apoptosis and the cell cycle, while western blotting was utilized to determine the protein expression levels. RESULTS: FASN was aberrantly expressed in various cancers, including CESC, where it was highly expressed. Kaplan-Meier, univariate, multivariate Cox regression analyses and ROC curve indicated that FASN is a potential key indicator of survival prognosis among CESC patients and demonstrated good predictive ability and efficacy. Complementary in vitro experiments confirmed that FASN is an important target for CESC therapy. CONCLUSION: The current study validated the biological and clinical significance of FASN in CESC prognosis, suggesting that FASN knockdown may exert antitumor activity against cervical cancer through the Akt/mTOR signaling pathway.
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Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Feminino , Humanos , Carcinoma de Células Escamosas/genética , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Neoplasias do Colo do Útero/genéticaRESUMO
Objective: Glioblastoma is one of the most common and fatal malignancies in adults. Current treatment is still not optimistic. Glioblastoma (GBM) transports RNA to platelets in the blood system via microvesicles, suggesting that platelet RNA can be a potential diagnostic and therapeutic target. The roles of specific platelet RNAs in treatment of GBM are not well understood. Methods: Platelet RNA profiling of 8 GBM and 12 normal samples were downloaded from the GEO database. Differentially expressed genes (DEGs) were identified between tumors and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to elucidate the functions of up- and downregulated genes. miRNA was predicted by miRTarBase, TargetScan, and miRDB databases. circBase and circBank were used for circRNA prediction. ceRNA (circRNA-mRNA-miRNA) network was constructed to investigate the potential interactions. Results: 22 genes were upregulated and 9 genes were downregulated. There are only two genes (CCR7 and FAM102A) that connect to miRNAs (hsa-let-7a-5p, hsa-miR-1-3p). We assessed the overall survival rates by Kaplan-Meier plotter, and relative expression of GBM and subtypes for overlapped mRNA (CCR7 and FAM102A) were evaluated, and further, we obtained circRNAs (has-circ-0015164, hsa-circ-0003243) by circBank and circBase and bind sites through the CSCD database. Finally, a ceRNA network (circRNA-mRNA-miRNA) was constructed based on 2 miRNAs, 2 mRNAs, and 2 circRNAs by Cytoscape. This study focused on potential mRNA and ceRNA biomarkers to targeted treatment of GBM and provided ideas for clinical treatment through the combination of hematology and oncology. Conclusion: The findings of this study contribute to better understand the relationship between GBM and the blood system (platelets) and might lay a solid foundation for improving GBM molecule and gene diagnosis and prognosis.
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Glioblastoma , MicroRNAs , Adulto , Biomarcadores/metabolismo , Biologia Computacional , Redes Reguladoras de Genes/genética , Glioblastoma/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR7/genéticaRESUMO
Intracranial aneurysm (IA) can cause fatal subarachnoid hemorrhage (SAH) after rupture, and identifying patients with unruptured IAs is essential for reducing SAH fatalities. The epithelial-mesenchymal transition (EMT) may be vital to IA progression. Here, identified key EMT-related genes in aneurysms and their pathogenic mechanisms via bioinformatic analysis. The GSE13353, GSE75436, and GSE54083 datasets from Gene Expression Omnibus were analyzed with limma to identify differentially expressed genes (DEGs) among unruptured aneurysms, ruptured aneurysms, and healthy samples. The results revealed that three EMT-related DEGs (ADIPOQ, WNT11, and CCL21) were shared among all groups. Coexpression modules and hub genes were identified via weighted gene co-expression network analysis, revealing two significant modules (red and green) and 14 EMT-related genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggested that cytokine interactions were closely related. Gene set enrichment analysis revealed that unruptured aneurysms were enriched for the terms "inflammatory response" and "vascular endothelial growth". Protein-protein interaction analysis identified seven key genes, which were evaluated with the GSE54083 dataset to determine their sensitivity and specificity. In the external validation set, we verified the differential expression of seven genes in unruptured aneurysms and normal samples. Together, these findings indicate that FN1, and SPARC may help distinguish normal patients from patients with asymptomatic IAs.
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Aneurisma Roto/genética , Transição Epitelial-Mesenquimal , Aneurisma Intracraniano/genética , Aneurisma Roto/fisiopatologia , Quimiocina CCL21/genética , Perfilação da Expressão Gênica , Humanos , Aneurisma Intracraniano/fisiopatologia , Osteonectina/genética , Transcriptoma , Proteínas Wnt/genéticaRESUMO
OBJECTIVE: To explore the predictive value of milk fat globule epidermal growth factor 8 (MFG-E8) in the occurrence of delayed cerebral ischemia (DCI) after an aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We recruited 32 patients with aSAH as the case group and 24 patients with unruptured aneurysms as the control group. Serum MFG-E8 levels were measured by western blot and enzyme-linked immunosorbent assay. We analyzed the relationship between MFG-E8 levels and the risk of DCI. RESULTS: The levels of serum MFG-E8 in the case group (mean = 11160.9 pg/mL) were significantly higher than those in the control group (mean = 3081.0 pg/mL, p < 0.001). MFG-E8 levels highly correlated with the World Federation of Neurosurgical Societies (WFNS) and modified Fisher scores (r = -0.691 and - 0.767, respectively, p < 0.001). In addition, MFG-E8 levels in patients with DCI (5882.7 ± 3162.4 pg/mL) were notably higher than those in patients without DCI (15818.2 ± 3771.6 pg/mL, p < 0.001). A receiver operating characteristic curve showed that the occurrence of DCI could effectively be predicted by MFG-E8 (area under the curve = 0.976, 95%CI = 0.850-1.000). Kaplan-Meier survival analysis showed a remarkable decrease in the incidence of DCI in case group individuals with high levels of MFG-E8 (≥11160.9 pg/mL, p < 0.001). CONCLUSION: MFG-E8 may be a useful predictive marker for DCI after an aSAH and could be a promising surrogate end point.
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Antígenos de Superfície/metabolismo , Isquemia Encefálica/metabolismo , Infarto Cerebral/metabolismo , Proteínas do Leite/metabolismo , Hemorragia Subaracnóidea/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROCRESUMO
PURPOSE: Arctigenin (ARG) is a natural lignan compound extracted from Arctium lappa and has displayed anticancer function and therapeutic effect in a variety of cancers. Arctigenin is mainly from Arctium lappa extract. It has been shown to induce autophagy in various cancers. However, as for whether arctigenin induces autophagy in gliomas or not, the specific mechanism is still worth exploring. METHODS: Using CCK8, the monoclonal experiment was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. PI/RNase and FITC-conjugated anti-annexin V were used to detect the cell cycle and apoptosis. Western blotting was used to determine the specified protein level, and constructed LC3B-GFP plasmid was used for analysis of autophagy. RESULTS: Our research showed that ARG inhibited the growth and proliferation and invasion and migration of glioma cells in a dose-dependent manner (U87MG and T98G) and arrested the cell cycle and induced apoptosis. Interestingly, ARG induced autophagy in a dose-dependent manner. We applied Western blotting to measure the increase in the key autophagy protein LC3B, as well as some other autophagy-related proteins (increase in Beclin-1 and decrease in P62). In order to further explore the mechanism that ARG passed initiating autophagy to inhibit cell growth, we further found by Western blotting that AKT and mTOR phosphorylation proteins (P-AKT, P-mTOR) were reduced after ARG treatment, and we used AKT agonists to rescue, and the phosphorylated proteins of AKT and mTOR increased, and we found that the autophagy-related proteins were also reversed. And interestingly, the protein of apoptosis was also reversed along with autophagy. CONCLUSIONS: We thought ARG inhibited the proliferation of glioma cells by inducing autophagy and apoptosis through the AKT/mTOR pathway.