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Circular RNAs (circRNAs) are important non-coding RNAs (ncRNAs) involved in the development of multiple human diseases, especially cancers. circRNA_0084043 is significantly involved in the progression of melanoma. However, whether circRNA_0084043 is associated with glioma remains unknown. In this study, the upregulation of circRNA_0084043 in glioma and the association between circRNA_0084043 and glioma grade were identified. Our results showed that circRNA_0084043 is significantly involved in the proliferative, migratory, and invasive capacities of glioma cells. The results obtained from starBase, luciferase reporter assays, RNA immunoprecipitation assays, and RNA pull-down assays demonstrated that circRNA_0084043 acts as a direct sponge for miR-577. TargetScan algorithm was used to identify potential miR-577 targets, it was found that sorting nexin 5 (SNX5) is a candidate bound to miR-577. Finally, cell experiments testified that circRNA_0084043 enhanced growth, migration and invasion of glioma through the regulation of miR-577-mediated SNX5. Taken together, we concluded that circRNA_0084043 in the miR-577/SNX5 axis can be used as a candidate target for glioma therapy.
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Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/metabolismo , Interferência de RNA , Neoplasias Encefálicas/tratamento farmacológico , Nanomedicina , Biomimética , RNA Interferente Pequeno , Hipóxia/tratamento farmacológico , Linhagem Celular TumoralRESUMO
PURPOSE: Glioma is the most common primary intracranial tumor and exhibits rapid growth and aggressiveness. TRPM8 channel-associated factor 2 (TCAF2), located in cell junctions and the plasma membrane, plays a key role in the pathogeneses of several cancers in humans. However, the role of TCAF2 in glioma has been elusive. METHODS: A combination of bioinformatic analysis using The Cancer Genome Atlas database and biological experiments, including 5-ethynyl-2'-deoxyuridine, transwell, and immunohistochemistry assays and xenotransplantation, was performed to analyze the expression level of TCAF2 and to mechanistically explore the relationship of TCAF2 with malignancy, prognosis, and the immune microenvironment in glioma. RESULTS: TCAF2 was upregulated in glioma, and its expression level correlated with tumor grade and clinical outcome. The role of TCAF2 in promoting glioma malignancy was characterized through in vitro and in vivo experiments. Additionally, we observed that TCAF2 can modulate the metabolic pathways and immune microenvironment. CONCLUSION: TCAF2 acts as an oncogene and may serve as a therapeutic target and prognostic marker in glioma.
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Neoplasias Encefálicas , Glioma , Humanos , Glioma/genética , Neoplasias Encefálicas/genética , Agressão , Membrana Celular , Biologia Computacional , Microambiente Tumoral/genética , Proteínas de MembranaRESUMO
OBJECTIVE: To investigate the surgical method and efficacy of the extended pterional approach in the resection of huge medial sphenoid ridge meningiomas (MSRMs). METHODS: Retrospective analysis of clinical data from 41 patients diagnosed with MSRMs (diameter ≥4.0 cm) from Nanjing Brain Hospital between January 2012 and February 2022 was conducted. Within 24 hours after surgery, head computed tomography and magnetic resonance imagingwere reviewed to evaluate the extent of tumor resection based on Simpson grading. Cranial magnetic resonance imagingwas repeated 3 to 60 months after surgery to assess tumor recurrence or progression. Preoperative, discharge, and follow-up Karnofsky functional status scores (KPS) were assessed to determine patients' functional status. Repeated-measures analysis of variance was utilized to compare KPS at preoperative, hospital discharge, and final follow-up. RESULTS: The 41 selected cases included 38 cases (92.7%) of Simpson I-III resection and 3 cases (7.3%) of Simpson IV resection. All the cases had typical pathological features and definite pathological diagnoses. There were 2 recurrent tumors and 4 progressed tumors when the patients were followed up from 3 months to 60 months after operations. The results demonstrated that the KPS score at the final follow-up (91.4 ± 9.6) was higher than at hospital discharge (85.3 ± 8.9) and preoperation (78.2 ± 8.5) (F = 69.46, P = 0.033). CONCLUSIONS: The use of the extended pterional approach in the resection of huge MSRMs appears to be an effective surgical method. Careful dissection and preservation of vascular and neural structures, as well as meticulous microsurgical techniques in managing cavernous sinus tumors, can lead to reduced surgical complications and improved treatment outcomes.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Meningioma/complicações , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Neoplasias Meníngeas/complicações , Estudos Retrospectivos , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/complicações , Resultado do Tratamento , Procedimentos Neurocirúrgicos/métodosRESUMO
Rechallenge of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) after PD-1 blockade failure was an effective therapy for non-small cell lung cancer (NSCLC) patients with resistance to EGFR-TKIs. The third-generation TKIs, like osimertinib and furmonertinib, can reach higher concentration in the cerebrospinal fluid (CSF) than other TKIs, and exhibit a beneficial effect in NSCLC patients with leptomeningeal metastases (LM) harboring sensitive EGFR mutation. Here, we report that two-stage IV pulmonary adenocarcinoma patients with LM harboring an EGFR L858R mutation benefit from the third-generation EGFR-TKIs rechallenge after immune checkpoint inhibitor (ICI) and anti-angiogenic agent combination therapy. Complete response (CR) to partial response (PR) of central nervous system (CNS) response was achieved immediately after the administration of furmonertinib and osimertinib. We conducted next-generation sequencing (NGS) and IHC to elucidate the evolution of driver mutations and the immune microenvironment. In conclusion, these two cases might provide a therapeutic strategy for further clinical practice. More research was needed to elucidate the resistance mechanisms and improve current treatment strategies in EGFR-mutated patients with LM.
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BACKGROUND: Interferons (IFNs) have been implemented as anti-tumor immunity agents in clinical trials of glioma, but only a subset of glioblastoma (GBM) patients profits from it. The predictive role of IFNs stimulated genes in GBM needs further exploration to investigate the clinical role of IFNs. METHODS: This study screened 526 GBM patients from three independent cohorts. The transcriptome data with matching clinical information were analyzed using R. Immunohistochemical staining data from the Human Protein Atlas and DNA methylation data from MethSurv were used for validation in protein and methylation level respectively. RESULTS: We checked the survival effect of all 491 IFNs response genes, and found 54 genes characterized with significant hazard ratio in overall survival (OS). By protein-protein interaction analysis, 10 hub genes were selected out for subsequent study. And based on the expression of these 10 genes, GBM patients could be divided into two subgroups with significant difference in OS. Furthermore, the least absolute shrinkage and selection operator cox regression model was utilized to construct a multigene risk signature, including STAT3, STAT2 and SOCS3, which could serve as an independent prognostic predictor for GBM. The risk model was validated in two independent GBM cohorts. The GBM patients with high risk scores mainly concentrated in the GBM Mesenchymal subtype. The higher risk group was enriched in hypoxia, angiogenesis, EMT, glycolysis and immune pathways, and had increased Macrophage M2 infiltration and high expression of immune checkpoint CD274 (namely PD-L1). CONCLUSIONS: Our findings revealed the three-gene risk model could be an independent prognostic predictor for GBM, and they were crucial participants in immunosuppressive microenvironment of GBM.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Interferons/genética , Interferons/metabolismo , Análise de Sobrevida , Microambiente TumoralRESUMO
Anaplastic lymphoma kinase ( ALK ) rearrangement defines a unique nonsmall cell lung cancer (NSCLC) molecular subtype, of which the patients could potentially benefit from anti- ALK therapies. So far, the outcomes of the canonical echinoderm microtubule-associated protein-like ( EML-ALK ) patients subjected to ALK inhibitors are well established. However, given the increasing complexity of ALK fusion partners, as detected by high-throughput sequencing, the responses of those with rare ALK fusion events remain to be explored. Here, we report a lung adenocarcinoma patient with brain metastasis harboring an ARHGAP5 downstream intergenic region ALK fusion, as detected by using DNA-based next-generation sequencing, who experienced a partial response to alectinib treatment. While whole- transcriptome RNA sequencing (RNA-seq) failed to identify potential ALK fusion transcripts, subsequent targeted deep RNA-seq revealed the expression of EML4-ALK transcripts in the tumor tissue. Given the increasing application of the ALK-tyrosine kinase inhibitors (TKIs), it is extremely crucial to define the patients who could be suitable for this treatment in clinic. The present case has provided supporting evidence that noncanonical ALK rearrangements on the genomic level are often functionally relevant and targetable by ALK-TKI, particularly in cases with sub-optimal quantity and quality for RNA validation.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Carbazóis , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Intergênico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Associadas aos Microtúbulos/genética , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , RNARESUMO
Human glioblastoma (GBM), the most aggressive brain tumor, comprises six major subtypes of malignant cells, giving rise to both inter-patient and intra-tumor heterogeneity. The interaction between different tumor subtypes and non-malignant cells to collectively shape a tumor microenvironment has not been systematically characterized. Herein, we sampled the cellular milieu of surgically resected primary tumors from 7 GBM patients using single-cell transcriptome sequencing. A lineage relationship analysis revealed that a neural-progenitor-2-like (NPC2-like) state with high metabolic activity was associated with the tumor cells of origin. Mesenchymal-1-like (MES1-like) and mesenchymal-2-like (MES2-like) tumor cells correlated strongly with immune infiltration and chronic hypoxia niche responses. We identified four subsets of tumor-associated macrophages/microglia (TAMs), among which TAM-1 co-opted both acute and chronic hypoxia-response signatures, implicated in tumor angiogenesis, invasion, and poor prognosis. MES-like GBM cells expressed the highest number of M2-promoting ligands compared to other cellular states while all six states were associated with TAM M2-type polarization and immunosuppression via a set of 10 ligand-receptor signaling pathways. Our results provide new insights into the differential roles of GBM cell subtypes in the tumor immune microenvironment that may be deployed for patient stratification and personalized treatment.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Hipóxia/genética , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
HOXC cluster antisense RNA 3 (HOXC-AS3) is a long noncoding RNA (lncRNA) that plays a crucial role in various tumors; nevertheless, its role in glioma and its mechanism have not been completely elucidated. In this research, we discovered that HOXC-AS3 was over-expression in glioma cells and tissues and was associated with prognosis. Next, we determined that HOXC-AS3 targeted miR-216 as a sponge and that the F11 receptor (F11R) was the target of miR-216 by online databases analysis, qRT-PCR, and luciferase reporter assay. In addition, the rescue experiments confirmed that HOXC-AS3 regulated the expression of F11R by competitively binding miR-216 and functioning as a competing endogenous RNA (ceRNA). The intracranial glioblastoma mouse model suggested that HOXC-AS3 could promote glioma malignant progression in vivo. In summary, our study shows that the HOXC-AS3/miR-216/F11R axis plays an important role in the malignant progression of glioma, and may provide new ideas for the treatment of glioma.
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Glioma is a pervasive malignancy and the main cause of cancer-related deaths worldwide. Circular RNA is an important subject of cancer research, and its role and function in glioma are poorly understood. This study demonstrated that hsa_circ_0091581 is upregulated in glioma tissues and cells. The results of the CCK-8, EdU, and transwell assays indicated that hsa_circ_0091581 promotes proliferation, migration, and invasion of glioma cells. The results of the luciferase reporter and RNA immunoprecipitation assays indicated that the mechanism of the effects of hsa_circ_0091581 on glioma cells involves sponging miR-1243-5p to regulate RMI1. The results of the rescue experiments indicated that hsa_circ_0091581 regulates proliferation, migration, and invasion of glioma cells by targeting RMI1 in a miR-1243-5p dependent manner. The results of the nude mice xenograft assays showed that knockdown of hsa_circ_0091581 inhibits glioma growth in vivo. Thus, our study determined the role of hsa_circ_0091581/miR-1243-5p/RMI1 in glioma and suggests that this axis may be a novel therapeutic target in glioma.
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BACKGROUND: Glioma is the most common primary brain tumor with a poor prognosis. Key genes that are negatively related to prognosis may provide the therapy targets to cure glioma. To clarify the role of CD44 in glioma, we explored its function at bulk-transcriptome, spatial and single-cell transcriptome levels. METHODS: In total, expression profiles with survival data of whole-grade glioma from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), RNA-seq data with anatomic information of glioblastoma (GBM) from the Ivy Glioblastoma Atlas Project, RNA-sequencing (RNA-seq) data from recurrent GBM receiving adjuvant anti-PD-1 immunotherapy accessed through GSE121810, and single-cell RNA-seq data of GBM under accession GSE103224 were enrolled in this study. CD44-specific findings were further analyzed by R language. RESULTS: CD44 is positively correlated with WHO grade of malignancy and is negatively related to prognosis in glioma. Meanwhile, CD44 predominantly expresses in GBM mesenchymal subtype, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses reveal that CD44 positively coexpressed genes are closely related to glioma immunity. Moreover, CD44+ cells mainly distribute in perinecrotic region with high expression of immune factors. At single-cell resolution, only malignant tumor cells, tumor-associated macrophages (TAMs), and T cells express CD44 in GBM. CD44+ malignant tumor cells are in mesenchymal-1-like (MES1-like) cellular state, and CD44+ TAMs are in M2 phenotype. CD44+ T cells have high expression of both PD-1 and PD-L1. CD44 and its directly interacted inhibitory immunomodulators are upregulated in patients with nonresponder recurrent GBM treated with PD-1 blockade therapy. CONCLUSION: Our work demonstrates that CD44, a new M2 TAM biomarker, is involved in immune suppressor and promote glioma progression in glioma microenvironment. These results expand our understanding of CD44-specific clinical and immune features in glioma.
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Reactive oxygen species (ROS) modulator 1 (Romo1) is a mitochondrial membrane protein that is essential for the regulation of mitochondrial ROS production and redox sensing. Although the physiological functions of Romo1 have been studied for the past few years, the role of Romo1 in cancer remained unclear. In this study, we found that the high expression of Romo1 is associated with the poor prognosis of glioblastoma patients. Further study revealed that Romo1 is highly expressed in macrophages, indicating that the overexpression of Romo1 may participate in the function of macrophages and contribute to the progression of glioblastoma. Through the glioblastoma mouse model, we found that the overexpression of Romo1 in bone marrow cells significantly inhibited the immune response within tumor microenvironment, and that the overexpression of Romo1 resulted in the M2 polarization of bone marrow derived macrophages (BMDMs) through mTORC1 signaling pathway. In addition, the inhibition of Romo1 combining with anti-PD-1 immunotherapy significantly improved the survival outcome of glioblastoma in mouse model. Collectively, our study highlights the important role of Romo1 in immune response especially the function of macrophages, and implicates it as a potential target of immunotherapy for glioblastoma.
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Glioblastoma/etiologia , Glioblastoma/metabolismo , Imunidade , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Linhagem Celular Tumoral , Suscetibilidade a Doenças , Metabolismo Energético , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Proteínas de Membrana/genética , Camundongos , Proteínas Mitocondriais/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Background: The presence of glioma stem cells (GSCs) is thought to be a key factor responsible for development of the incurable glioblastoma multiforme (GBM). GSCs are often displayed during chemotherapy resistance, except for demethoxycurcumin (DMC), a component of curcumin, which has been previously confirmed to inhibit GSCs proliferation and induce apoptosis. Purpose: The objective of this study was to identify the main mechanism underlying anti-GSCs resistance by DMC. Patients and methods: qRT-PCR was used to determine the expression of miR-145 in glioma patients and GSCs, and GSCs were transfected with miR-145 overexpressed vectors. Then, functional analyses (in vitro and in vivo) were performed to confirm the role of miR-145 and DMC in GSCs. Finally, related proteins were tested by immunohistochemistry and Western blot. Results: miR-145 was atypically low-expressed miRNA in GSCs, and could enhance GSC chemosensitivity to DMC both in vitro and in vivo. Upregulation of miR-145 in GSCs resulted in increased cell growth inhibition and apoptosis to DMC. Further research on the mechanism demonstrated that the combined effects of miR-145 and DMC were involved in the miR-145/SOX2-Wnt/ß-catenin pathway. Overexpression of SOX2 reduced GSC resistance to growth inhibition by miR-145+ DMC treatment. Conclusion: Our data strongly support an important role for miR-145 in enhancing GSC chemosensitivity to DMC by targeting the SOX2-Wnt/ß-catenin axis.
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Glioma is a primary malignancy in central nervous system. Radiotherapy has been used as one of the standard treatments for glioma for decades. Since radioresistance can reduce the curative efficacy of radiotherapy in glioma, investigating the cause of radioresistance and predicting the tumour radiosensibility appeared particularly important. We previously reported that CFL1 and PGK1 are over-expressed in radioresistant U251 glioma cells. In this study, the level of CFL1 and PGK1 of 113 glioma tissues were measured by ELISA method. The relevance of the expression of these two proteins to radiosensibility was analyzed by mean test and multivariate logistic regression. The survival analysis was carried out in 85 irradiated patients and 105 followed-up patients respectively. The relationship between protein expression and clinical parameters was explored in overall 113 patients, and the correlation between CFL1 and PGK1 were determined as well. Our results showed that the expression of CFL1 and PGK1 were significantly higher (P < 0.001) in radioresistant patients than others. The multivariate Logistic regression demonstrated that the expression of CFL1 (p < 0.001) and PGK1 (p < 0.001) were associated with radioresistance in glioma. The multivariate Cox regression in overall survival suggested that CFL1 level or PGK1 level could be the independent prognosis factor for poor prognosis in 113 glioma patients. In addition, CFL1 expression was positively correlated with PGK1 expression in glioma. The results suggested that as promising indicators, CFL1 and PGK1 could be used to evaluate glioma radiosensibility and prognosis. These two proteins could also be the potential therapeutic targets of glioma.
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We compared the surgical efficacy of the supraorbital key-hole approach (SKA) to conventional unilateral frontotemporal craniotomy (UFTC) for the treatment of patients with unilateral-dominant bilateral frontal contusions (BFCs). A retrospective analysis of 62 patients with unilateral-dominant BFCs who underwent surgery at our institute between 2014 and 2017 was performed. There were 26 patients who underwent SKA (group A) and 36 who underwent UFTC (group B). Postoperative computed tomography scans showed satisfactory evacuation of the frontal cerebral contusions in both groups (p > 0.05). There was less intraoperative blood loss in group A than group B (17.1 ± 4.55 vs. 67.6 ± 10.28 mL, p < 0.05). The operative time was also shorter in group A (82.7 ± 13.73 vs. 132.4 ± 9.17 min, p < 0.05). Postoperative bleeding occurred in three cases in group A and in only one case in group B (p > 0.05). The average length of hospitalization was shorter in group A than group B (7.3 ± 1.09 vs. 12.9 ± 1.71 days, p < 0.05). No differences in the Glasgow Outcome Scale were observed between the two groups after 6 months of follow-up (p > 0.05). Thus, compared to UFTC, SKA is associated with shorter operation times and less trauma to the surrounding brain tissue.
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Contusão Encefálica/patologia , Contusão Encefálica/cirurgia , Lobo Frontal/patologia , Adulto , Idoso , Biomarcadores , Contusão Encefálica/diagnóstico , Craniotomia/métodos , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
We explored differences in postoperative pain relief achieved through decompression of the trigeminal nerve compressed by arteries and veins. Clinical characteristics, intraoperative findings, and postoperative curative effects were analyzed in 72 patients with trigeminal neuralgia who were treated by microvascular decompression. The patients were divided into arterial and venous compression groups based on intraoperative findings. Surgical curative effects included immediate relief, delayed relief, obvious reduction, and invalid result. Among the 40 patients in the arterial compression group, 32 had immediate pain relief of pain (80.0%), 5 cases had delayed relief (12.5%), and 3 cases had an obvious reduction (7.5%). In the venous compression group, 12 patients had immediate relief of pain (37.5%), 13 cases had delayed relief (40.6%), and 7 cases had an obvious reduction (21.9%). During 2-year follow-up period, 6 patients in the arterial compression group experienced recurrence of trigeminal neuralgia, but there were no recurrences in the venous compression group. Simple artery compression was followed by early relief of trigeminal neuralgia more often than simple venous compression. However, the trigeminal neuralgia recurrence rate was higher in the artery compression group than in the venous compression group.
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Cirurgia de Descompressão Microvascular , Manejo da Dor , Neuralgia do Trigêmeo/terapia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Cirurgia de Descompressão Microvascular/efeitos adversos , Cirurgia de Descompressão Microvascular/métodos , Pessoa de Meia-Idade , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Complicações Pós-Operatórias , Recidiva , Resultado do TratamentoRESUMO
PURPOSE: Intracranial bleeding and inflammatory reactions are common consequences of traumatic brain injury (TBI). Neutrophil gelatinase-associated lipocalin (NGAL), an iron-handling and acute phase protein, may participate in the pathogenesis of TBI. Therefore, we hypothesize that NGAL may be of high diagnostic and therapeutic relevance in the prognosis of TBI. METHODS: 74 subjects were recruited in this study. 30 TBI patients receiving emergent operation were designated as severe TBI group (sTBI), 24 TBI patients receiving conservative treatment as mild TBI group (mTBI), while 20 age-matched healthy volunteers as healthy controls (CNT). We detected the expression and localization of NGAL in brain tissue by Q-PCR, western blotting, and immunofluorescence. Serum NGAL was evaluated by ELISA. Clinical manifestations and outcomes were measured by Glasgow Score (GCS), Trauma score (TS), Revised Trauma score (RTS), APACHEII, Sequential Organ Failure Assessment (SOFA), and Abbreviated Injury Scale (AIS) 85 at admission. Glasgow outcome score (GOS) and Karnofsky Performance Score (KPS) were documented at discharge. RESULTS: NGAL mRNA and protein levels in brain tissue from sTBI group were profoundly higher than control tissue. Double labeled NGAL with GFAP, NeuN and Iba-1 by immunofluroscence demonstrated that increased NGAL was mainly located in neurons. Compared to CNT and mTBI groups, serum NGAL were significantly increased in sTBI group (sTBI: 532.6±71.77ng/ml vs. mTBI: 230.5±29.59ng/ml, p<0.01; sTBI: 532.6±71.77ng/ml vs. CNT 178.0±19.83ng/ml, p<0.01). Linear regression analysis indicated that there was a negative correlation between the NGAL levels and GCS (r=-0.427, p=0.033), TS (r=-0.429, p=0.032), RTS (r=-0.413, p=0.040) in sTBI group. However, NGAL levels did not correlated with GOS and KPS scores. The NAGL cut-off value of 244.13ng/ml yielded good sensitivity at 84% and specificity at 78.9%. CONCLUSION: NGAL may be a novel biomarker reflecting TBI severity, which increased obviously and negatively correlated with GCS, TS, and RTS scores; additionally, this characteristic of NGAL may be helpful in guiding clinical TBI therapeutic strategies.
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Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/fisiopatologia , Regulação da Expressão Gênica/fisiologia , Lipocalina-2/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Contagem de Leucócitos , Lipocalina-2/genética , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estatística como Assunto , Índices de Gravidade do TraumaRESUMO
The Ras-related C3 botulinum toxin substrate 1 (Rac1)-WASP-family verprolin-homologous protein-2 (WAVE2)-actin-related protein 2/3 (Arp2/3) signaling pathway has been identified to be involved in cell migration and invasion in various types of cancer cell. Cofilin1 (CFL1), which is regulated by the Rac1WAVE2Arp2/3 signaling pathway, may promote radioresistance in glioma. Therefore, the present study aimed to investigate the potential role of the Rac1WAVE2Arp2/3 signaling pathway in radioresistance in U251 human glioma cells and elucidate its affect on CFL1 expression. Western blot analysis was performed to evaluate the protein expression of CFL1. In the present study, Rac1 was inhibited by NSC 23766, WAVE2 was inhibited by transfection with short hairpin (sh)RNAWAVE2 using Lipofectamine™ 2000 and Arp2/3 was inhibited by CK666. Cell viability was measured using the 3(4,5dimethylthiazol2yl)-2,5diphenyltetrazolium bromide assay, the cell migration ability was examined by a woundhealing assay, and the cell invasion ability was assessed using a Transwell culture chamber system. The results showed that inhibition of the Rac1WAVE2Arp2/3 signaling pathway using NSC 23766, shRNAWAVE2 or CK666 reduced the cell viability, migration and invasion abilities in U251 human glioma cells, concordant with a reduced expression of CFL1. Furthermore, the expression of CFL1 was significantly increased in radioresistant U251 glioma cells when compared with normal U251 human glioma cells. These findings indicate that inhibition of the Rac1WAVE2Arp2/3 signaling pathway may promote radiosensitivity, which may partially result from the downregulation of CFL1 in U251 human glioma cells.
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Complexo 2-3 de Proteínas Relacionadas à Actina/biossíntese , Cofilina 1/biossíntese , Regulação para Baixo/efeitos da radiação , Raios gama , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioma/metabolismo , Proteínas de Neoplasias/biossíntese , Tolerância a Radiação , Transdução de Sinais/efeitos da radiação , Família de Proteínas da Síndrome de Wiskott-Aldrich/biossíntese , Proteínas rac1 de Ligação ao GTP/biossíntese , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Linhagem Celular Tumoral , Cofilina 1/genética , Glioma/genética , Glioma/patologia , Glioma/radioterapia , Humanos , Proteínas de Neoplasias/genética , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética , Proteínas rac1 de Ligação ao GTP/genéticaRESUMO
BACKGROUND: Currently published studies investigating the association between brain tumors and venous thromboembolism (VTE) risk have yielded inconsistent findings. To provide a more precise estimate for this association, we firstly performed a meta-analysis by pooling all currently available data. METHODS: Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were calculated by use of STATA 12.0 software. All eligible studies were identified by a comprehensive literature search in databases of PubMed, Embase, Web of Science, and Google scholar. RESULTS: According to the inclusion criteria, 9 independent studies were finally included into this study. Individuals with brain tumors were at an increased risk of VTE (RR=1.66, 95% CI 1.31-2.12, P<0.001), particularly those undergoing surgery (RR=1.68, 95% CI 1.44-1.98, P<0.001). Stratified analysis by type of tumor showed that the risk of VTE was significantly associated with glioma (RR=1.68, 95% CI 1.44-1.98, P<0.001), high-grade glioma (RR=1.70, 95% CI 1.29-2.23, P<0.001), and glioblastoma multiforme (RR=1.74, 95% CI 1.43-2.12, P<0.001). CONCLUSIONS: The present meta-analysis suggests increased risk of VTE in patients with brain tumors, particularly those undergoing surgery.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/epidemiologia , Glioma/diagnóstico , Glioma/epidemiologia , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Neoplasias Encefálicas/cirurgia , Causalidade , Comorbidade , Feminino , Humanos , Incidência , Masculino , Medição de RiscoRESUMO
BACKGROUND: Acute post-traumatic cerebral hemispheric brain swelling (ACHS) is a serious disorder that occurs after traumatic brain injury, and it often requires immediate treatment. The aim of our clinical study was to assess the effects of stepwise intracranial decompression combined with external ventricular drainage (EVD) catheters on the prognosis of ACHS patients. METHODS: A retrospective study was performed on 172 cases of severe craniocerebral trauma patients with ACHS. The patients were divided into two groups: unilateral stepwise standard large trauma craniectomy (S-SLTC) combined with EVD catheter implants (n = 86) and unilateral routine frontal temporal parietal SLTC (control group, n = 86). RESULT: No significant differences in age, sex, or pre-operative Glasgow Coma Scale score were observed between groups (P < 0.05). There were no significant differences in the ipsilateral subdural effusion incidence rates between the S-SLTC + EVD treatment group and the routine SLTC group. However, the incidence rates of intraoperative acute encephalocele and contralateral epidural and subdural hematoma in the S-SLTC + EVD group were significantly lower than those in the SLTC group (17.4 and 3.5 vs. 37.2 and 23.3%, respectively). The mean intracranial pressure (ICP) values of patients in the S-SLTC + EVD group were also lower than those in the SLTC group at days 1 through 7 (P < 0.05). A positive neurological outcome [Glasgow Outcome Scale (GOS) score 4-5, 50.0%] and decreased mortality (15.1%) was observed in the S-SLTC + EVD group compared to the neurological outcome (GOS score 4-5, 33.8%; 36.0%) in the SLTC group (P < 0.05). CONCLUSION: Our data suggest that S-SLTC + EVD is more effective for controlling ICP, improving neurological outcome, and decreasing mortality rate compared with routine SLTC.