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AIMS: Neutrophil extracellular traps (NETs) have been implicated in thrombotic diseases. There is no definitive explanation for how NETs form during acute ischemic strokes (AIS). The purpose of our study was to investigate the potential mechanism and role of NETs formation in the AIS process. METHODS: As well as 45 healthy subjects, 45 patients with AIS had ELISA tests performed to detect NET markers. Expression of high-mobility group box 1 (HMGB1) on platelet microvesicles (PMVs) was analyzed by flow cytometry in healthy subjects and AIS patients' blood samples. We established middle cerebral artery occlusion (MCAO) mice model to elucidate the interaction between PMPs and NETs. RESULTS: A significant elevation in NET markers was found in patient plasma in AIS patients, and neutrophils generated more NETs from patients' neutrophils. HMGB1 expression was upregulated on PMVs from AIS patients and induced NET formation. NETs enhanced Procoagulant activity (PCA) through tissue factor and via platelet activation. Targeting lactadherin in genetical and in pharmacology could regulate the formation of NETs in MCAO model. CONCLUSIONS: NETs mediated by PMVs derived HMGB1 exacerbate thrombosis and brain injury in AIS. Video Abstract.
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Lesiones Encefálicas , Trampas Extracelulares , Proteína HMGB1 , Accidente Cerebrovascular Isquémico , Trombosis , Animales , Ratones , Humanos , Trampas Extracelulares/metabolismo , Proteína HMGB1/metabolismo , Trombosis/metabolismo , Neutrófilos , Lesiones Encefálicas/metabolismoRESUMEN
Cancer-associated fibroblasts (CAFs) are an important component of the stroma. Studies showed that CAFs were pivotally in glioma progression which have long been considered a promising therapeutic target. Therefore, the identification of prognostic CAF markers might facilitate the development of novel diagnostic and therapeutic approaches. A total of 1333 glioma samples were obtained from the TCGA and CGGA datasets. The EPIC, MCP-counter, and xCell algorithms were used to evaluate the relative proportion of CAFs in glioma. CAF markers were identified by the single-cell RNA-seq datasets (GSE141383) from the Tumor Immune Single-Cell Hub database. Unsupervised consensus clustering was used to divide the glioma patients into different distinct subgroups. The least absolute shrinkage and selection operator regression model was utilized to establish a CAF-related signature (CRS). Finally, the prognostic CAF markers were further validated in clinical specimens by RTâqPCR. Combined single-cell RNA-seq analysis and differential expression analysis of samples with high and low proportions of CAFs revealed 23 prognostic CAF markers. By using unsupervised consensus clustering, glioma patients were divided into two distinct subtypes. Subsequently, based on 18 differentially expressed prognostic CAF markers between the two CAF subtypes, we developed and validated a new CRS model (including PCOLCE, TIMP1, and CLIC1). The nomogram and calibration curves indicated that the CRS was an accurate prognostic marker for glioma. In addition, patients in the high-CRS score group had higher immune infiltration and tumor mutation burden levels. Moreover, the CRS score had the potential to predict the response to immune checkpoint blockade (ICB) therapy and chemotherapy. Finally, the expression profiles of three CAF markers were verified by RTâqPCR. In general, our study classified glioma patients into distinct subgroups based on CAF markers, which will facilitate the development of individualized therapy. We also provided insights into the role of the CRS in predicting the response to ICB and chemotherapy in glioma patients.
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BACKGROUND: Glioblastoma (GBM) is an aggressive and unstoppable malignancy. Natural killer T (NKT) cells, characterized by specific markers, play pivotal roles in many tumor-associated pathophysiological processes. Therefore, investigating the functions and complex interactions of NKT cells is great interest for exploring GBM. METHODS: We acquired a single-cell RNA-sequencing (scRNA-seq) dataset of GBM from Gene Expression Omnibus (GEO) database. The weighted correlation network analysis (WGCNA) was employed to further screen genes subpopulations. Subsequently, we integrated the GBM cohorts from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases to describe different subtypes by consensus clustering and developed a prognostic model by least absolute selection and shrinkage operator (LASSO) and multivariate Cox regression analysis. We further investigated differences in survival rates and clinical characteristics among different risk groups. Furthermore, a nomogram was developed by combining riskscore with the clinical characteristics. We investigated the abundance of immune cells in the tumor microenvironment (TME) by CIBERSORT and single sample gene set enrichment analysis (ssGSEA) algorithms. Immunotherapy efficacy assessment was done with the assistance of Tumor Immune Dysfunction and Exclusion (TIDE) and The Cancer Immunome Atlas (TCIA) databases. Real-time quantitative polymerase chain reaction (RT-qPCR) experiments and immunohistochemical profiles of tissues were utilized to validate model genes. RESULTS: We identified 945 NKT cells marker genes from scRNA-seq data. Through further screening, 107 genes were accurately identified, of which 15 were significantly correlated with prognosis. We distinguished GBM samples into two distinct subtypes and successfully developed a robust prognostic prediction model. Survival analysis indicated that high expression of NKT cell marker genes was significantly associated with poor prognosis in GBM patients. Riskscore can be used as an independent prognostic factor. The nomogram was demonstrated remarkable utility in aiding clinical decision making. Tumor immune microenvironment analysis revealed significant differences of immune infiltration characteristics between different risk groups. In addition, the expression levels of immune checkpoint-associated genes were consistently elevated in the high-risk group, suggesting more prominent immune escape but also a stronger response to immune checkpoint inhibitors. CONCLUSIONS: By integrating scRNA-seq and bulk RNA-seq data analysis, we successfully developed a prognostic prediction model that incorporates two pivotal NKT cells marker genes, namely, CD44 and TNFSF14. This model has exhibited outstanding performance in assessing the prognosis of GBM patients. Furthermore, we conducted a preliminary investigation into the immune microenvironment across various risk groups that contributes to uncover promising immunotherapeutic targets specific to GBM.
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Glioblastoma , Células T Asesinas Naturales , Humanos , Glioblastoma/genética , Pronóstico , Secuencia de Bases , RNA-Seq , Microambiente Tumoral/genéticaRESUMEN
m6A RNA methylation is an emerging epigenetic modification, and its potential role in immunity and stemness remains unknown. Based on 17 widely recognized m6A regulators, the m6A modification patterns and corresponding characteristics of immune infiltration and stemness of 1152 low-grade glioma samples were comprehensively analyzed. Machine-learning strategies for constructing m6AScores were trained to quantify the m6A modification patterns of individual samples. Here, we reveal a significant correlation between the multi-omics data of regulators and clinicopathological parameters. We identified two distinct m6A modification patterns (an immune-activated differentiation pattern and an immune-desert dedifferentiation pattern) and four regulatory patterns of m6A methylation on immunity and stemness. We show that the m6AScores can predict the molecular subtype of low-grade glioma, the abundance of immune infiltration, the enrichment of signaling pathways, gene variation and prognosis. The concentration of high immunogenicity and clinical benefits in the low-m6AScore group confirmed the sensitive response to radio-chemotherapy and immunotherapy in patients with high-m6AScore. The results of the pan-cancer analyses illustrate the significant correlation between m6AScore and clinical outcome, the burden of neoepitope, immune infiltration and stemness. The assessment of individual tumor m6A modification patterns will guide us in improving treatment strategies and developing objective diagnostic tools.
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Adenosina/análogos & derivados , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Metilación de ADN/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Glioma/genética , Glioma/inmunología , Inmunidad Innata , Metiltransferasas/genética , Proteínas de Unión al ARN/genética , Adenosina/genética , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Variaciones en el Número de Copia de ADN , Epigénesis Genética , Glioma/patología , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Aprendizaje Automático , Tasa de Mutación , Fenotipo , Pronóstico , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate a Robust Prognostic Model for IDH wild-type GBM (COVPRIG) for the prediction of overall survival using a novel metric, gene-gene (G × G) interaction, and explore molecular and cellular underpinnings. METHODS: Univariate and multivariate Cox regression of four independent trans-ethnic cohorts containing a total of 800 samples. Prediction efficacy was comprehensively evaluated and compared with previous models by a systematic literature review. The molecular underpinnings of COVPRIG were elucidated by integrated analysis of bulk-tumor and single-cell based datasets. RESULTS: Using a Cox-ph model-based method, six of the 93,961 G × G interactions were screened to form an optimal combination which, together with age, comprised the COVPRIG model. COVPRIG was designed for RNA-seq and microarray, respectively, and effectively identified patients at high risk of mortality. The predictive performance of COVPRIG was satisfactory, with area under the curve (AUC) ranging from 0.56 (CGGA693, RNA-seq, 6-month survival) to 0.79 (TCGA RNAseq, 18-month survival), which can be further validated by decision curves. Nomograms were constructed for individual risk prediction for RNA-seq and microarray-based cohorts, respectively. Besides, the prognostic significance of COVPRIG was also validated in GBM including the IDH mutant samples. Notably, COVPRIG was comprehensively evaluated and externally validated, and a systemic review disclosed that COVPRIG outperformed current validated models with an integrated discrimination improvement (IDI) of 6-16%. Moreover, integrative bioinformatics analysis predicted an essential role of METTL1+ neural-progenitor-like (NPC-like) malignant cell in driving unfavorable outcome. CONCLUSION: This study provided a powerful tool for the outcome prediction for IDH wild-type GBM, and preliminary molecular underpinnings for future research.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/patología , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Pronóstico , Nomogramas , MetiltransferasasRESUMEN
Spontaneous intracerebral hemorrhage (ICH) accounts for 10-20% of all strokes and contributes to higher mortalities and severe disabilities. The aims of this study were, therefore, to characterize novel biomarkers, metabolic disruptions, and mechanisms involving ICH. A total 30 ICH patients and 30 controls were enrolled in the study, and their clinical characteristics were analyzed. Nontargeted metabolomic analysis was conducted using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF). Multivariate statistical analysis and receiver operating characteristic curve analysis were used for screening and evaluating the predictive ability of biomarkers. ICH patients showed significantly higher systolic blood pressure, diastolic blood pressure, blood glucose levels, white blood cell counts, neutrophil count, percentage of neutrophils and globulin and a lower albumin/globin ratio when compared with controls. In sum, 11 important metabolites were identified, which were associated with disruption of fatty acid oxidation and sphingolipid and phospholipid metabolism, as well as increased inflammation, oxidative stress, and vascular pathologies. Further multiple logistic regression analyses of these metabolites showed that l-carnitine and phosphatidylcholine (20:3/22:6) have potential as biomarkers of ICH, and the area under the curve, sensitivity, specificity were 0.974, 90%, and 93%, respectively. These findings provide insights into the pathogenesis, early prevention, and diagnosis of ICH.
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Hemorragia Cerebral , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas/métodos , Metaboloma/fisiología , Metabolómica/métodos , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Hemorragia Cerebral/sangre , Hemorragia Cerebral/metabolismo , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Curva ROC , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Glioma (GM) is a highly lethal human cancer. Circular RNAs (circRNAs) act as an imperative factor in oncogenesis. We aimed to investigate the biological functions and mechanisms of circ-CDC45 in GM. circ-CDC45 expression in GM specimens and cell lines was measured by real-time quantitative reverse transcription polymerase chain reaction. Fisher's exact test and Kaplan-Meier curves further analyzed its clinical implications. A gain/loss-of-function study was conducted to investigate the role of circ-CDC45 in GM. Additionally, luciferase reporter and rescue assays were performed to unravel the mechanisms of circ-CDC45. High circ-CDC45 expression was found in GM specimens and cells, which was tightly related to a larger tumor size, higher world health organization (WHO) stages, and worse survival for patients with GM. Functionally, manipulation of circ-CDC45 expression strongly affected cell growth, apoptosis, migration and invasion, which suggests the oncogenic function of circ-CDC45 in GM oncogenesis. Stepwise mechanism studies indicated that circ-CDC45 sponged and regulated the expression of miR-516b and miR-527 to promote cell growth and invasion. Briefly, the regulatory network of circ-CDC45/miR-516b/miR-527 plays a pivotal role in GM tumorigenesis and may act as a potential target for GM treatment.
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Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Glioma/patología , MicroARNs/genética , ARN Circular/genética , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Glioma/genética , Glioma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
BACKGROUND Recent literature has revealed that LINC01207 plays a vital part in tumorigenesis and malignancy progression. However, the potential mechanisms of LINC01207 in malignant glioma are still unknown. MATERIAL AND METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to analyze LINC01207 mRNA levels in malignant glioma cell lines and tissue samples. The correlation between LINC01207 mRNA levels and clinical characteristics was explored, and the relative survival rate was observed using the Kaplan-Meier method. To examine the function of LINC01207, we performed cell viability, EdU assay, cell cycle assay, Transwell assay, and wound-healing assay to analyze relative cell proliferation, migration/invasion ability. Finally, qRT-PCR and western blot were used to investigate the potential mechanisms. RESULTS LINC01207 mRNA was lowly expressed in malignant glioma cells and cancer tissue samples. Low expression of LINC01207 was associated with Karnofsky performance score (KPS), invasion condition, and tumor grade. Moreover, multivariate analysis confirmed LINC01207 expression and tumor grade were significant independent predictors of poor survival in malignant glioma. LINC01207 markedly inhibited cellar proliferation and viability via inducing G0/G1 phase cell cycle arrested and repressed cell metastasis through restraining epithelial-to-mesenchymal procession in vivo. In addition, we detected a reduction in the protein levels of ß-catenin and p-GSK-3ß, while GSK-3ß expression was upregulated. CONCLUSIONS In summary, LINC01207 served as a tumor-related tumor suppress gene for malignant glioma through inhibiting of GSK-3ß/ß-catenin signaling pathway.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , ARN Largo no Codificante/genética , beta Catenina/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica/genética , Metástasis de la Neoplasia , Transducción de SeñalRESUMEN
Sonodynamic therapy (SDT) has shown great potential as an approach for cancer treatment, and hyperthermotherapy (HT) is also a promising cancer therapy. Here, we investigate whether HT could improve the efficacy of SDT and to make a preliminary exploration on potential mechanism. Xenograft tumor was established in nude mice model, and SNB19 and U87MG glioma cell lines were utilized for in vitro experiment. Alamar blue assay was performed to assess cell viability. Optical microscope was used to characterize the morphology changes of the glioma cells induced by SDT and HT treatments. Apoptotic rate, mitochondrial membrane potential (MMP), and intracellular production of reactive oxygen species (ROS) were examined by flow cytometer. The cell apoptosis of tumor tissues were detected by TUNEL assay. Furthermore, the expression of apoptosis-related proteins was detected with Western blot in vitro and immunohistochemistry in vivo. SDT plus HT group could significantly reduce the cell viability with circular-cell morphological change, compared with SDT group, and cell viability was decreased depending on raise of 5-ALA concentration, ultrasound exposure time, and temperature. The results also indicate that HT increased a conspicuous apoptosis, ROS production, and a remarkable loss in MMP induced by 5-ALA-SDT in vitro. Meanwhile, our data also demonstrated that the combined treatment could significantly induce apoptosis and delay tumor growth in vivo. Furthermore, in both in vitro and in vivo experiments, SDT plus HT group expressed significantly higher protein levels of Bax and cleaved caspase-3, 8, and 9 compared to SDT, HT, and control groups and significantly lower protein level of bcl-2 than the other three groups, while the expression of these proteins was unchanged between HT and control groups. HT may provide an important promotion on 5-ALA-SDT and further propose that SDT in combination with HT is a new potential application for the treatment of human glioma.
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Ácido Aminolevulínico/uso terapéutico , Glioma/terapia , Hipertermia Inducida , Terapia por Ultrasonido , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido Aminolevulínico/farmacología , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Terapia Combinada , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/terapia , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Protoporfirinas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Sodium-hydrogen exchanger isoform 1 (NHE1) plays a role in survival and migration/invasion of several cancers and is an emerging new therapeutic target. However, the role of NHE1 in glioblastoma and the interaction of NHE1 expression and function in glioblastoma cells with cytotoxic temozolomide (TMZ) therapy remain unknown. In this study, we detected high levels of NHE1 protein only in primary human glioma cells (GC), glioma xenografts and glioblastoma, but not in human neural stem cells or astrocytes. GC exhibited an alkaline resting pHi (7.46±0.04) maintained by robust NHE1-mediated H(+) extrusion. GC treatment with TMZ for 2-24h triggered a transient decrease in pHi, which recovered by 48h and correlated with concurrent upregulation of NHE1 protein expression. NHE1 protein was colocalized with ezrin at lamellipodia and probably involved in GC migration. The TMZ-treated GC exhibited increased migration and invasion, which was attenuated by addition of NHE1 inhibitor HOE-642. Most importantly, NHE1 inhibition prevented prosurvival extracellular signal-regulated kinase activation and accelerated TMZ-induced apoptosis. Taken together, our study provides the first evidence that GC upregulate NHE1 protein to maintain alkaline pHi. Combining TMZ therapy with NHE1 inhibition suppresses GC migration and invasion, and also augments TMZ-induced apoptosis. These findings strongly suggest that NHE1 is an important cytoprotective mechanism in GC and presents a new therapeutic strategy of combining NHE1 inhibition and TMZ chemotherapy.
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Antineoplásicos Alquilantes/farmacología , Proteínas de Transporte de Catión/genética , Movimiento Celular , Supervivencia Celular , Dacarbazina/análogos & derivados , Resistencia a Antineoplásicos , Intercambiadores de Sodio-Hidrógeno/genética , Equilibrio Ácido-Base , Animales , Apoptosis , Astrocitos/metabolismo , Transporte Biológico , Proteínas de Transporte de Catión/metabolismo , Línea Celular Tumoral , Dacarbazina/farmacología , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Células-Madre Neurales/metabolismo , Intercambiador 1 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , Temozolomida , Regulación hacia ArribaRESUMEN
OBJECTIVE: The aim of this study was to investigate the effect of bumetanide on peri-tumor edema caused by photodynamic therapy (PDT) of intraparenchymal C6 glioma xenografts. METHODS: Seven days after inoculation with C6 cells, rats with MRI-confirmed glioma received hematoporphyrin monomethyl ether (HMME)-mediated PDT, injection of bumetanide or a combination of the two treatments. After treatment, tumor volume, tumor weight, brain water content, microvessel density, expression of NKCC-1, Zonula occludens-1 (ZO-1), and animal survival time were examined. RESULTS: In the PDT group, tumor growth was significantly inhibited and survival prolonged. Bumetanide enhanced the efficacy of PDT and reduced PDT-induced peri-tumor edema in the combined PDT + bumetanide treatment group where NKCC-1 expression in response to PDT was significantly suppressed. ZO-1 expression was significantly suppressed in the PDT-only group. This suppression was not observed in the combined PDT + bumetanide treatment group. CONCLUSION: PDT, in combination with bumetanide was seen to significantly inhibit the growth of C6 glioma, relieve peri-tumor edema caused by PDT alone and prolong survival. These results suggest that PDT, in combination with bumetanide, may be a useful and promising strategy in the treatment of human glioma.
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Neoplasias Encefálicas/tratamiento farmacológico , Bumetanida/uso terapéutico , Diuréticos/uso terapéutico , Edema/tratamiento farmacológico , Glioma/tratamiento farmacológico , Fotoquimioterapia/efectos adversos , Animales , Biomarcadores/metabolismo , Línea Celular Tumoral , Edema/inducido químicamente , Edema/metabolismo , Hematoporfirinas/efectos adversos , Hematoporfirinas/uso terapéutico , Masculino , Fármacos Fotosensibilizantes/efectos adversos , Fármacos Fotosensibilizantes/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Wistar , Trasplante Heterólogo , Resultado del TratamientoRESUMEN
Pseudouridine widely affects the stability and function of RNA. However, our knowledge of pseudouridine properties in tumors is incomplete. We systematically analyzed pseudouridine synthases (PUSs) expression, genomic aberrations, and prognostic features in 10907 samples from 33 tumors. We found that the pseudouridine-associated pathway was abnormal in tumors and affected patient prognosis. Dysregulation of the PUSs expression pattern may arise from copy number variation (CNV) mutations and aberrant DNA methylation. Functional enrichment analyses determined that the PUSs expression was closely associated with the MYC, E2F, and MTORC1 signaling pathways. In addition, PUSs are involved in the remodeling of the tumor microenvironment (TME) in solid tumors, such as kidney and lung cancers. Particularly in lung cancer, increased expression of PUSs is accompanied by increased immune checkpoint expression and Treg infiltration. The best signature model based on more than 112 machine learning combinations had good prognostic ability in ACC, DLBC, GBM, KICH, MESO, THYM, TGCT, and PRAD tumors, and is expected to guide immunotherapy for 19 tumor types. The model was also effective in identifying patients with tumors amenable to etoposide, camptothecin, cisplatin, or bexarotene treatment. In conclusion, our work highlights the dysregulated features of PUSs and their role in the TME and patient prognosis, providing an initial molecular basis for future exploration of pseudouridine. Studies targeting pseudouridine are expected to lead to the development of potential diagnostic strategies and the evaluation and improvement of antitumor therapies.
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Previous studies proposed that isocitrate dehydrogenase 1 (IDH1) mutation was associated with improved survival in patients with glioblastoma, but those studies reported varying estimates and yielded inconclusive results. The purpose of the present study was to determine the effect of IDH1 mutation on the prognosis of patients with glioblastoma by performing a meta-analysis. Pubmed and Embase databases were searched for eligible studies. Studies reporting overall survival by IDH1 mutation in patients with glioblastoma were considered potentially eligible for the meta-analysis. For the quantitative aggregation of the survival results, the IDH mutation effect was measured by the pooled hazard ratio (HR) with its 95% confidence interval (95%CI). Nine studies with a total of 1,669 patients with glioblastoma were finally included into this meta-analysis. Overall, the IDH1 mutation was associated with improved survival in patients with glioblastoma (random effects model HR = 0.45, 95%CI 0.29-0.69, P < 0.001). Sensitivity analysis further showed that the pooled estimates were stable in this meta-analysis. Therefore, the findings from this meta-analysis suggest that IDH1 mutation is associated with improved overall survival in patients with glioblastoma.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Isocitrato Deshidrogenasa/genética , Mutación , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Glioblastoma/patología , Humanos , Análisis Multivariante , Pronóstico , Análisis de SupervivenciaRESUMEN
Extra-neural spread of glioblastoma (GBM) is extremely rare. We report a case of postoperative intracranial GBM spreading to the subcutaneous tissue via the channel of craniotomy defect in a 73-year-old woman. Radiological images and histopathology indicate that the tumor microenvironment of the subcutaneous tumor is clearly different from the intracranial tumor. We also model the invasion of GBM cells through the dura-skull defect in mouse. The retrospective analysis of GBM with scalp metastases suggests that craniectomy is a direct cause of subcutaneous metastasis in patients with GBM. Imaging examinations of other sites for systemic screening is also recommended to look for metastases outside the brain when GBM invades the scalp or metastasizes to it.
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Coagulopathy contributes to the majority of deaths and disabilities associated with traumatic brain injury (TBI). Whether neutrophil extracellular traps (NETs) contribute to an abnormal coagulation state in the acute phase of TBI remains unknown. Our objectives were to demonstrate the definitive role of NETs in coagulopathy in TBI. We detected NET markers in 128 TBI patients and 34 healthy individuals. Neutrophil-platelet aggregates were detected in blood samples from TBI patients and healthy individuals using flow cytometry and staining for CD41 and CD66b. Endothelial cells were incubated with isolated NETs and we detected the expression of vascular endothelial cadherin, syndecan-1, thrombomodulin, von Willebrand factor, phosphatidylserine, and tissue factor. In addition, we established a TBI mouse model to determine the potential role of NETs in TBI-associated coagulopathy. NET generation was mediated by high mobility group box 1 (HMGB1) from activated platelets and contributed to procoagulant activity in TBI. Furthermore, coculture experiments indicated that NETs damaged the endothelial barrier and caused these cells to assume a procoagulant phenotype. Moreover, the administration of DNase I before or after brain trauma markedly reduced coagulopathy and improved the survival and clinical outcome of mice with TBI.
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Trastornos de la Coagulación Sanguínea , Lesiones Traumáticas del Encéfalo , Trampas Extracelulares , Animales , Ratones , Trampas Extracelulares/metabolismo , Células Endoteliales , Trastornos de la Coagulación Sanguínea/etiología , Neutrófilos/metabolismo , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/metabolismoRESUMEN
Intra-tumoral necrosis (ITN) is reported to be an independent prognostic factor in glioma. However, knowledge of ITN is mainly limited to pseudopalisadwe, while its other aspects were neglected. Therefore, a deeper understanding of ITN could be valuable for understanding its exact role in glioma. The only reliable ITN model was time-dependently achieved with the GL261 syngeneic mouse model. The ITN-associated expression pattern was enriched from RNA sequencing. TCGA glioma samples were clustered into a high-expression group (HEG) and a low-expression group (LEG) based on their pattern and their association with prognosis, clinical status, immune status, and therapeutic responsiveness were compared. Mouse glioma with ITN demonstrated invasive histology. Cytokine signaling was significantly enriched in necrotic mouse glioma compared with non-necrotic glioma tissues. Nine pro-inflammatory (IL6, PPBP, IL1A, TNFSF11, CXCL11, CXCL9, CXCL10, CXCL3, and CCL8) and two anti-inflammatory cytokine (IL1RN and IL10) genes were found to be related to ITN-associated cytokine patterns. Comparative analysis showed that HEG had a significantly shorter survival time, five differentially distributed clinical statuses, more infiltrated immune cells, greater expression of immune checkpoints, and better therapeutic responsiveness than LEG. In conclusion, the ITN-associated cytokine pattern is characteristically expressed in glioma with ITN and might indicate necrosis missed in histology diagnosis. Its expression pattern could predict the prognosis, tumor grade, immune status, and therapeutic responsiveness of glioma patients.
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Necroptosis is a programmed form of necrotic cell death that serves as a host gatekeeper for defense against invasion by certain pathogens. Previous studies have uncovered the essential role of necroptosis in tumor progression and implied the potential for novel therapies targeting necroptosis. However, no comprehensive analysis of multi-omics data has been conducted to better understand the relationship between necroptosis and tumor. We developed the necroptosis index (NI) to uncover the effect of necroptosis in most cancers. NI not only correlated with clinical characteristics of multiple tumors, but also could influence drug sensitivity in glioma. Based on necroptosis-related differentially expressed genes, the consensus clustering was used to classify glioma patients into two NI subgroups. Then, we revealed NI subgroup I were more sensitive to immunotherapy, particularly anti-PD1 therapy. This new NI-based classification may have prospective predictive factors for prognosis and guide physicians in prioritizing immunotherapy for potential responders.
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Background: Photodynamic therapy (PDT) promotes significant tumor regression and extends the lifetime of patients. The actual operation of PDT often relies on the subjective judgment of experienced neurosurgeons. Patients can benefit more from precisely targeting PDT's key operating zones. Methods: We used magnetic resonance imaging scans and created 3D digital models of patient anatomy. Multiple images are aligned and merged in STL format. Neurosurgeons use HoloLens to import reconstructions and assist in PDT execution. Also, immunohistochemistry was used to explore the association of hyperperfusion sites in PDT of glioma with patient survival. Results: We constructed satisfactory 3D visualization of glioma models and accurately localized the hyperperfused areas of the tumor. Tumor tissue taken in these areas was rich in CD31, VEGFA and EGFR that were associated with poor prognosis in glioma patients. We report the first study using MR technology combined with PDT in the treatment of glioma. Based on this model, neurosurgeons can focus PDT on the hyperperfused area of the glioma. A direct benefit was expected for the patients in this treatment. Conclusion: Using the Mixed Reality technique combines multimodal imaging signatures to adjuvant glioma PDT can better exploit the vascular sealing effect of PDT on glioma.
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This study aims to construct a Macrophage-Related Gene Prognostic Index (MRGPI) for glioblastoma (GBM) and explore the underlying molecular, metabolic, and immunological features. Based on the GBM dataset from The Cancer Genome Atlas (n = 156), 13 macrophage-related hub genes were identified by weighted gene co-expression network (WGCNA) analysis. 5 prognostic genes screened by Kaplan-Meire (K-M) analysis and Cox regression model were used to construct the MRGPI, including GPR84, NCF2, HK3, LILRB2, and CCL18. Multivariate Cox regression analysis found that the MRGPI was an independent risk factor (HR = 2.81, CI95: 1.13-6.98, p = 0.026), leading to an unfavorable outcome for the MRGPI-high group, which was further validated by 4 validation GBM cohorts (n = 728). Thereafter, the molecular, metabolic, and immune features and the clinical implications of the MRGPI-based groups were comprehensively characterized. Gene set enrichment analysis (GSEA) found that immune-related pathways, including inflammatory and adaptive immune response, and activated eicosanoid metabolic pathways were enriched in the MRGPI-high group. Besides, genes constituting the MRGPI was primarily expressed by monocytes and macrophages at single-cell scope and was associated with the alternative activation of macrophages. Moreover, correlation analysis and receiver operating characteristic (ROC) curves revealed the relevance between the MRGPI with the expression of immune checkpoints and T cell dysfunction. Thus, the responsiveness of samples in the MRGPI-high group to immune checkpoint inhibitors (ICI) was detected by algorithms, including Tumor Immune Dysfunction and Exclusion (TIDE) and Submap. In contrast, the MRGPI-low group had favorable outcome, was less immune active and insensitive to ICI. Together, we have developed a promising biomarker to classify the prognosis, metabolic and immune features for GBM, and provide references for facilitating the personalized application of ICI in GBM.
Asunto(s)
Glioblastoma , Glioblastoma/patología , Humanos , Inhibidores de Puntos de Control Inmunológico , Macrófagos , Pronóstico , Linfocitos T/metabolismoRESUMEN
BACKGROUND: photodynamics therapy (PDT) induces tumor cell death through oxidative stress and is closely associated with the expression of hypoxia inducible factor-1a (HIF1a), which activates multiple downstream survival signaling pathways. Therefore, the purpose of this study was to investigate the expression levels of HIF1a proteins in PDT-treated GBM cells and to determine whether inhibition of HIF1a reduces survival signals to enhance the efficacy of PDT. RESULTS: PDT combined with Acriflavine (ACF, PA) decreased the expression of HIF1a and regulated the downstream expression of GLUT-1, GLUT-3, HK2 and other gluconeogenic pathway proteins. PA group significantly suppressed tumor growth to improve the efficacy of PDT. METHODS: We first performed the correlation of HIF1a, GLUT-1, GLUT-3, and HK2, and quantified the expression of HIF1a on tumor grades and IDH mutation classification by TCGA and CGGA databases. Then, we used immunohistochemistry method to detect four gene expression levels in human GBM tissues. Besides, we examined the effects of different treatments on the proliferation, migration and invasion ability of GBM cell lines by CCK8, wound healing and transwell assays. ACF, a HIF1a/HIF1ß dimerization inhibitor, was used to evaluate its adjuvant effect on the efficacy of PDT. CONCLUSION: HIF1a is activated in GBM cell lines and contributes to the survival of tumor cells after PDT in vitro and in vivo. PA group inhibited HIF1a expression and improved PDT efficacy in the treatment of recalcitrant GBM.