RESUMO
Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in â¼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.
Assuntos
Neoplasias Encefálicas , Éxons , Glioblastoma , Mutação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
circRNADisease v2.0 is an enhanced and reliable database that offers experimentally verified relationships between circular RNAs (circRNAs) and various diseases. It is accessible at http://cgga.org.cn/circRNADisease/ or http://cgga.org.cn:9091/circRNADisease/. The database currently includes 6998 circRNA-disease entries across multiple species, representing a remarkable 19.77-fold increase compared to the previous version. This expansion consists of a substantial rise in the number of circRNAs (from 330 to 4246), types of diseases (from 48 to 330) and covered species (from human only to 12 species). Furthermore, a new section has been introduced in the database, which collects information on circRNA-associated factors (genes, proteins and microRNAs), molecular mechanisms (molecular pathways), biological functions (proliferation, migration, invasion, etc.), tumor and/or cell line and/or patient-derived xenograft (PDX) details, and prognostic evidence in diseases. In addition, we identified 7 159 865 relationships between mutations and circRNAs among 30 TCGA cancer types. Due to notable enhancements and extensive data expansions, the circRNADisease 2.0 database has become an invaluable asset for both clinical practice and fundamental research. It enables researchers to develop a more comprehensive understanding of how circRNAs impact complex diseases.
Assuntos
Bases de Dados Genéticas , Neoplasias , RNA Circular , Humanos , Linhagem Celular , Neoplasias/genéticaRESUMO
Increasing evidences have found that the interactions between hypoxia, immune response and metabolism status in tumour microenvironment (TME) have clinical importance of predicting clinical outcomes and therapeutic efficacy. This study aimed to develop a reliable molecular stratification based on these key components of TME. The TCGA data set (training cohort) and two independent cohorts from CGGA database (validation cohort) were enrolled in this study. First, the enrichment score of 277 TME-related signalling pathways was calculated by gene set variation analysis (GSVA). Then, consensus clustering identified four stable and reproducible subtypes (AFM, CSS, HIS and GLU) based on TME-related signalling pathways, which were characterized by differences in hypoxia and immune responses, metabolism status, somatic alterations and clinical outcomes. Among the four subtypes, HIS subtype had features of immunosuppression, oxygen deprivation and active energy metabolism, resulting in a worst prognosis. Thus, for better clinical application of this acquired stratification, we constructed a risk signature by using the LASSO regression model to identify patients in HIS subtype accurately. We found that the risk signature could accurately screen out the patients in HIS subtype and had important reference value for individualized treatment of glioma patients. In brief, the definition of the TME-related subtypes was a valuable tool for risk stratification in gliomas. It might serve as a reliable prognostic classifier and provide rational design of individualized treatment, and follow-up scheduling for patients with gliomas.
Assuntos
Glioma , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Metabolismo Energético , Análise por Conglomerados , Glioma/diagnóstico , Glioma/genética , HipóxiaRESUMO
BACKGROUND: As a component of membrane lipids and the precursor of oxysterols and steroid hormones, reprogrammed cholesterol metabolism contributes to the initiation and progression of multiple cancers. Thus, we aim to further investigate the significances of cholesterol metabolism in lower-grade gliomas (LGGs). METHODS: The present study included 413 LGG samples from TCGA RNA-seq dataset (training cohort) and 172 LGG samples from CGGA RNA-seq dataset (validation cohort). The cholesterol metabolism-related signature was identified by the LASSO regression model. Bioinformatics analyses were performed to explore the functional roles of this signature in LGGs. Kaplan-Meier and Cox regression analyses were enrolled to estimate prognostic value of the risk signature. RESULTS: Our findings suggested that cholesterol metabolism was tightly associated clinicopathologic features and genomic alterations of LGGs. Bioinformatics analyses revealed that cholesterol metabolism played a key role in immunosuppression of LGGs, mainly by promoting macrophages polarization and T cell exhaustion. Kaplan-Meier curve and Cox regression analysis showed that cholesterol metabolism was an independent prognostic indicator for LGG patients. To improve the clinical application value of the risk signature, we also constructed a nomogram model to predict the 1-, 3- and 5-year survival of LGG patients. CONCLUSION: The cholesterol metabolism was powerful prognostic indicator and could serve as a promising target to enhance personalized treatment of LGGs.
Assuntos
Glioma , Humanos , Metabolismo dos Lipídeos , Cognição , Biologia Computacional , ColesterolRESUMO
Polymerase I and transcript release factor (PTRF) plays a role in the regulation of gene expression and the release of RNA transcripts during transcription, which have been associated with various human diseases. However, the role of PTRF in glioma remains unclear. In this study, RNA sequencing (RNA-seq) data (n = 1022 cases) and whole-exome sequencing (WES) data (n = 286 cases) were used to characterize the PTRF expression features. Gene ontology (GO) functional enrichment analysis was used to assess the biological implication of changes in PTRF expression. As a result, the expression of PTRF was associated with malignant progression in gliomas. Meanwhile, somatic mutational profiles and copy number variations (CNV) revealed the glioma subtypes classified by PTRF expression showed distinct genomic alteration. Furthermore, GO functional enrichment analysis suggested that PTRF expression was associated with cell migration and angiogenesis, particularly during an immune response. Survival analysis confirmed that a high expression of PTRF is associated with a poor prognosis. In summary, PTRF may be a valuable factor for the diagnosis and treatment target of glioma.
Assuntos
Variações do Número de Cópias de DNA , Glioma , Humanos , Linhagem Celular Tumoral , Glioma/genética , Análise de SobrevidaRESUMO
BACKGROUND: Age is a powerful prognostic factor of high-grade glioma (HGG). However, the underlying genetic mechanisms of the discrepant prognosis among different age groups remain elusive. METHODS: A total of 953 and 559 HGG patients from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts were enrolled and assigned as young, intermediate, elderly groups. The data of clinicopathological characteristics, mRNA, mutation, copy number alteration was analyzed. RESULTS: Transcriptomic analysis revealed that diverse biological processes including immune response are altered between the young and elderly groups. Combined with the analysis of infiltrating immune cells and immune checkpoints, our results suggest an immune suppression status in the elderly group. Patients from different age groups exhibit different mutation and copy number alteration profiles. CONCLUSIONS: A multi-omics analysis is conducted to explore the biological basis of HGG patients of different age groups. This study suggests an immune-suppressive environment in elderly patients.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Transcrição Gênica/genética , Adulto , Neoplasias Encefálicas/patologia , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Feminino , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , RNA Mensageiro/genéticaRESUMO
Standard treatment regimen of gliomas has almost reached a bottleneck in terms of survival benefit. Immunotherapy has been explored and applied in glioma treatment. Immunosuppression, as a hallmark of glioma, could be alleviated by inhibiting certain abnormally expressed biomarkers. Here, transcriptome data of 325 whole grade gliomas were collected from the CGGA database. The TCGA RNA sequencing database was used for validation. Western blot was used to verify the expression level of VAT1 on cellular level. The results showed that the expression of VAT1 was positively correlated with the grades of glioma as classified by WHO. A higher expression level of VAT1 was observed in the mesenchymal subtype of gliomas. The area under the curve suggested that the expression level of VAT1 might be a potential prognostic marker of mesenchymal subtype. In survival analysis, we found that patients with high VAT1 expression level tended to have shorter overall survival, which indicated the prognostic value of VAT1 expression. The results of gene ontology analysis showed that most biological processes of VAT1-related genes were involved in immune and inflammatory responses. The results of GSEA analysis showed a negative correlation between VAT1 expression and immune cells. We also identified that the expression of immune checkpoints increased with VAT1 expression. Therefore, the high expression level of VAT1 in patients with glioma was a potential indicator of a lower survival rate for patients with gliomas. Remarkably, VAT1 contributed to glioma-induced immunosuppression and might be a novel target in glioma immunotherapy.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/imunologia , Imunomodulação , Proteínas de Transporte Vesicular/genética , Biomarcadores Tumorais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Glioma/patologia , Humanos , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Mutação , Gradação de Tumores , Prognóstico , Curva ROCRESUMO
Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower-grade diffuse gliomas were profiled. Subtype-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS-related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas.
Assuntos
Processamento Alternativo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioma/diagnóstico , Glioma/genética , Biomarcadores Tumorais/genética , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Mutação , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sequência de RNA , Transdução de SinaisRESUMO
As the core element of material and energy metabolism pathways, the biological functions and prognostic significance of ATP metabolism in diffuse gliomas have so far remained unclear. Based on comprehensive analysis of ATP metabolism-related gene expression profiles, we constructed an ATP metabolism-related risk signature to determine the role of ATP metabolism. We found that this ATP metabolism-related gene expression profile could divide patients into 2 robust groups with distinct clinical characteristics and prognosis. Patients in the high-risk group tended to be predicted as malignant entities, indicating that the activation of ATP metabolism may promote the malignant progress of diffuse gliomas. Cox regression and Kaplan-Meier analyses suggested that this risk signature was an independent predictor for prognosis. Furthermore, we constructed an individualized prognosis prediction model through nomogram and time-dependent receiver operating characteristic (ROC) curve analyses. Functional analysis suggested that, in addition to material and energy metabolism, ATP metabolism also played an essential role in the regulation of the tumor immune microenvironment. In brief, the ATP metabolism-related signature was tightly associated with regulation of the tumor immune microenvironment and could serve as an independent prognostic biomarker in diffuse gliomas.
Assuntos
Trifosfato de Adenosina/metabolismo , Biomarcadores Tumorais , Glioma/etiologia , Glioma/metabolismo , Metaboloma , Microambiente Tumoral/imunologia , Adulto , Biologia Computacional/métodos , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Glioma/mortalidade , Glioma/patologia , Humanos , Metabolômica/métodos , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Gradação de Tumores , Prognóstico , Regiões Promotoras Genéticas , Curva ROC , Microambiente Tumoral/genéticaRESUMO
Tumor-associated macrophages (TAMs) are regarded as the most abundantly infiltrating immune cells around the tumor microenvironment in gliomas, which plays an important role in tumorgenesis and immunosuppression. A total of 216 patients diagnosed with primary glioma were obtained from the Chinese Glioma Genome Atlas of which the RNA sequencing data was used as training set. RNA sequencing from the Cancer Genome Atlas was applicated for validation. We found that mesenchymal subtype showed strong positive correlation with macrophage-related genes (MRGs) expression. Survival analysis showed that high expression level of MRG predicted poor prognosis. A TAM-based nine-gene signature was constructed, which divided the samples into high- and low-risk of unfavorable outcome. The result of Cox regression analysis showed that the risk score was an independent prognostic factor in gliomas. Hence, the expression of TAMs was correlated with patient survival. The nine-TAM-related gene signature can predict patient survival efficiently.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Macrófagos Associados a Tumor/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de RNA/métodos , Análise de Sobrevida , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Gliomas are the most common and malignant brain tumors. The standard therapy is surgery combined with radiotherapy, chemotherapy, and/or other comprehensive methods. However, the emergence of chemoresistance is the main obstacle in treatment and its mechanism is still unclear. METHODS: We firstly developed a multi-gene signature by integrated analysis of cancer stem cell and drug resistance related genes. The Chinese Glioma Genome Atlas (CGGA, 325 samples) and The Cancer Genome Atlas (TCGA, 699 samples) datasets were then employed to verify the efficacy of the risk signature and investigate its significance in glioma prognosis. GraphPad Prism, SPSS and R language were used for statistical analysis and graphical work. RESULTS: This signature could distinguish the prognosis of patients, and patients with high risk score exhibited short survival time. The Cox regression and Nomogram model indicated the independent prognostic performance and high prognostic accuracy of the signature for survival. Combined with a well-known chemotherapy impact factor-MGMT promoter methylation status, this risk signature could further subdivide patients with distinct survival. Functional analysis of associated genes revealed signature-related biological process of cell proliferation, immune response and cell stemness. These mechanisms were confirmed in patient samples. CONCLUSIONS: The signature was an independent and powerful prognostic biomarker in glioma, which would improve risk stratification and provide a more accurate assessment of personalized treatment. Additional file 8 Video abstract.
Assuntos
Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Ontologia Genética , Glioma/tratamento farmacológico , Glioma/imunologia , Humanos , Modelos Biológicos , Análise Multivariada , Nomogramas , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Transdução de Sinais/genética , Análise de SobrevidaRESUMO
1p/19q codeletion, which leads to the abnormal expression of 1p19q genes in oligodendroglioma, is associated with chemosensitivity and favorable prognosis. Here, we aimed to explore the clinical implications of 1p19q gene expression in 1p/19q non-codel gliomas. We analyzed expression of 1p19q genes in 668 1p/19q non-codel gliomas obtained from The Cancer Genome Atlas (n = 447) and the Chinese Glioma Genome Atlas (n = 221) for training and validation, respectively. The expression of 1p19q genes was significantly correlated with the clinicopathological features and overall survival of 1p/19q non-codel gliomas. Then, we derived a risk signature of 25 selected 1p19q genes that not only had prognosis value in total 1p/19q non-codel gliomas but also had prognosis value in stratified gliomas. The prognosis value of the risk signature was superior than known clinicopathological features in 1p/19q non-codel gliomas and was also highly associated with the following features: loss of CDKN2A/B copy number in mutant-IDH-astrocytoma; telomerase reverse transcriptase (TERT) promoter mutation, combined chromosome 7 gain/chromosome 10 loss and epidermal growth factor receptor amplification in wild-type-IDH-astrocytoma; classical and mesenchymal subtypes in glioblastoma. Furthermore, genes enriched in the biological processes of cell division, extracellular matrix, angiogenesis significantly correlated to the signature risk score, and this is also supported by the immunohistochemistry and cell biology experiments. In conclusion, the expression profile of 1p19q genes is highly associated with the malignancy and prognosis of 1p/19q non-codel gliomas. A 25-1p19q-gene signature has powerfully predictive value for both malignant molecular pathological features and prognosis across distinct subgroups of 1p/19q non-codel gliomas.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Movimento Celular , Proliferação de Células , Seguimentos , Glioma/genética , Glioma/cirurgia , Humanos , Pessoa de Meia-Idade , Prognóstico , RNA-Seq , Taxa de Sobrevida , Transcriptoma , Células Tumorais Cultivadas , Adulto JovemRESUMO
The methylation status of the promoter of MGMT gene is a crucial factor influencing clinical decision-making in patients with gliomas. MGMT pyrosequencing results are often dichotomized by a cut-off value based on an average of several tested CpGs. However, this method frequently results in a "gray zone", representing a dilemma for physicians. We therefore propose a novel analytical model for MGMT methylation pyrosequencing. MGMT CpG heterogeneity was investigated in 213 glioma patients in two tested cohorts: cohort A in which CpGs 75-82 were tested and cohort B in which CpGs 72-78 were tested. The predictive performances of the novel and traditional averaging models were compared in 135 patients who received temozolomide using receiver operating characteristic curves and Kaplan-Meier curves, and in patients stratified according to isocitrate dehydrogenase gene mutation status. The results were validated in an independent cohort of 65 consecutive patients with high-grade gliomas from the Chinese Glioma Genome Atlas database. Heterogeneity of MGMT promoter CpG methylation level was observed in most gliomas. The optimal cut-off value for each individual CpG varied from 4-16%. The current analysis defined MGMT promoter methylation as occurring when at least three CpGs exceeded their respective cut-off values. This novel analysis could accurately predict the prognosis of patients in the methylation "gray zone" according to the standard averaging method, and improved the area under the curves from 0.67, 0.76, and 0.67 to 0.70, 0.84, and 0.72 in cohorts A, B, and the validation cohort, respectively, demonstrating superiority of this analytical method in all three cohorts. Furthermore, the advantages of the novel analysis were retained regardless of WHO grade and isocitrate dehydrogenase gene mutation status. In conclusion, this novel analytical model offers an improved clinical predictive performance for MGMT pyrosequencing results and is suitable for clinical use in patients with gliomas.
Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas Supressoras de Tumor/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Resectioning of giant maxillofacial tumors has been shown to cause facial depression deformity, representing a persistent challenge for surgeons. Here, the authors review their experience using autologous free fat grafts to repair total parotidectomy defects. This review aims to encourage the surgical field to pay more attention to this century-old treatment technique. METHODS: Patients were included who underwent free fat transfer for tissue reconstruction after total parotidectomy at the Affiliated Stomatology Hospital of China Medical University between 2012 and 2018. Patients with bleeding disease or postoperative follow-up less than 6 months were excluded. RESULTS: Twenty-three patients between the ages of 35 and 68 were included in this analysis. Ten patients (6 males, 4 females) underwent fat grafting at the time of total parotidectomy, and a control group of 13 patients (9 males, 4 females) underwent total parotidectomy without correction of concave deformities. There were significant differences between fat graft group and control group in terms of age (44.9â±â9.0117 years versus 56.385â±â8.9586 years; Pâ=â0.006), Frey syndrome questionnaire score (1â±â0 versus 2.385â±â1.0439; Pâ=â0.00), blood loss (195.7â±â54.8777âmL versus 107.769â±â22.8916âmL; Pâ=â0.001), postoperative drainage (319.8â±â103.1803âmL versus 230.385â±â53.5701âmL; Pâ=â0.027), duration of postoperative drainage (122.4â±â23.8663âhours versus 90.462â±â22.2434âhours; Pâ=â0.003), and satisfaction questionnaire score (8.5â±â0.8498 versus 3â±â1.1547; Pâ=â0.00). The difference in operation time between the fat graft group and control group was not significant (417â±â108.0062âmin versus 351.538â±â91.7475âmin; Pâ=â0.131). CONCLUSION: Autologous free fat grafting resulted in more blood loss as well as an increased volume and duration of postoperative drainage. Remarkably, however, patients had superior satisfaction, lower Frey syndrome scores, and similar operation times with use of free fat grafting after parotidectomy. The authors recommend such grafting be utilized to repair concave deformities secondary to total parotidectomy.
Assuntos
Tecido Adiposo/transplante , Face/cirurgia , Neoplasias Parotídeas/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Adulto , Idoso , Perda Sanguínea Cirúrgica , Drenagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Tempo , Transplante AutólogoRESUMO
BACKGROUND: Increasing evidence has shown that long non-coding RNAs (lncRNAs) are important prognostic biomarkers and epigenetic regulators with critical roles in cancer initiation and progression. However, the expression and clinical prognostic value of antisense lncRNAs in diffuse glioma patients remain unknown. METHODS: Here, we profiled differentially expressed antisense lncRNAs in glioma using RNA sequencing data from Chinese Glioma Genome Atlas database. Cox regression was performed to evaluate the prognostic value. Gene oncology (GO) and gene set enrichment analysis (GSEA) were used for functional analysis of antisense LncRNAs. RESULTS: Expression profiling identified 169 aberrantly expressed antisense lncRNAs between lower grade glioma (LGG) (grade II and III) and glioblastoma multiforme (GBM), 113 antisense lncRNAs between LGG IDH-wt and IDH-mut samples, and 70 antisense lncRNAs between GBM IDH-wt and IDH-mut samples, respectively. Among them, three antisense lncRNAs (WDFY3-AS2, MCM3AP-AS1 and LBX2-AS1) were significantly associated with prognosis and malignant progression of patients. WDFY3-AS2, the top one of downregulated antisense lncRNAs in GBM with fold change of 0.441 (P < 0.001), showed specific decreased expression in classical, mesenchymal, LGG IDH-wt, GBM IDH-wt or MGMT promoter unmethylated stratified patients. Chi square test found that WDFY3-AS2 was significantly associated with the clinical and molecular features of glioma. Univariate and multivariate Cox regression analysis indicated that WDFY3-AS2 was independently correlated with overall survival (OS) of patients. Kaplan-Meier analysis found that patients with high WDFY3-AS2 expression had longer OS than the low expression ones in the stratified cohorts. Additionally, GO and GSEA showed that gene sets correlated with WDFY3-AS2 expression were involved in regulation of synaptic transmission, glutamate receptor and TNF signaling pathway. CONCLUSION: Our findings provided convincing evidence that WDFY3-AS2 is a novel valuable prognostic biomarker for diffuse glioma.
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BACKGROUND: RNA editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines (A-to-I) in RNA, that alters gene expression and generates protein diversity. Dysregulation of A-to-I editing has been found associated with a number of nervous system diseases. However, the role of ADAR3, a brain specific high expression adenosine deaminase, in gliomas has rarely been investigated. In this study we illuminated the clinical significance and molecular features of ADAR3 in patients with glioma. METHODS: 309 glioma samples from Chinese Glioma Genome Atlas were enrolled into this study. In validation sets, 601 glioma samples in TCGA, 410 glioma samples in REMBRANDT and 258 glioma samples in GSE16011 were obtained. Relationships between ADAR3 expression and prognosis-related genomic alteration, outcome and gene ontology analysis were investigated. Moreover, the characteristic of GRIA2Q607R editing in gliomas has been investigated. Graphpad Prism 5.0, SPSS 16.0 and R language were used to perform statistical analysis and graphical work. RESULTS: ADAR3 expression was down regulated along with glioma grade progression in CGGA dataset. ADAR3 was characteristically highly expressed in neural subtype and IDH1/2 mutant preference. Moreover, high expression of ADAR3 predicted a better prognosis in lower-grade glioma (LGG) patients and multivariate analysis suggested ADAR3 expression was an independent prognostic indicator. The results of the three other validation datasets showed similar findings. Bioinformatics analyses suggested that ADAR3 may play a role in the malignant transformation of glioma cells by affecting cell proliferation, angiogenesis or cell adhesion. Furthermore, the editing level of GRIA2Q607R was significantly correlated with ADAR3 expression. CONCLUSIONS: Our study demonstrated the clinical and molecular characterization of ADAR3 in glioma development and progression. ADAR3 expression was negatively associated with tumor malignant in the overall glioma patients. And it was a favorable independent prognostic indicator of LGG patients. ADAR3 appeared to act as a tumor suppressor in glioma cells. Therefore, ADAR3 represented a potential therapeutic target and useful prognostic factor for glioma patients.
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This study demonstrates the application of DBR structure into the remote phosphor structure to improve the angular correlated color temperature (CCT) deviation in white light-emitting diodes (WLEDs). In the experiment, the LED device with DBR structure yielded a higher luminous efficiency than a conventional structure. The CCT deviation can be improved from 1758K to 280K in a range of -70 to 70 degree and the luminous flux increases more than 10% due to the enhancement of the light extraction of the blue light. Moreover, the reflectance of the different DBR structures is analyzed with different angles to reveal the reasons of such improvements. As the result, this LED device with DBR structure shows the great potential to use as the next generation lighting source.
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Chromosomal instability is a hallmark of human cancers and is closely linked to tumorigenesis. The prognostic value of molecular signatures of chromosomal instability (CIN) has been validated in various cancers. However, few studies have examined the relationship between CIN and glioma. Histone deacetylases (HDACs) regulate chromosome structure and are linked to the loss of genomic integrity in cancer cells. In this study, the prognostic value of HDAC4 expression and its association with markers of CIN were investigated by analyzing data from our own and four other large sample databases. The results showed that HDAC4 expression is downregulated in high- as compared to low-grade glioma and is associated with a favorable clinical outcome. HDAC4 expression and CIN were closely related in glioma from both functional and statistical standpoints. Moreover, the predictive value of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status-a widely used glioma marker-was refined by HDAC4 expression level, which was significantly related to CIN in our study. In conclusion, we propose that HDAC4 expression, a prognostic and CIN marker, enhances the predictive value of MGMT promoter methylation status for identifying patients who will most benefit from radiochemotherapy.
Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Glioma/metabolismo , Histona Desacetilases/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cromatina/metabolismo , Progressão da Doença , Glioma/diagnóstico , Humanos , Gradação de Tumores , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: The aim of this study was to investigate the efficacy of bevacizumab (Bev) in reducing peritumoral brain edema (PTBE) after stereotactic radiotherapy (SRT) for lung cancer brain metastases. METHODS: A retrospective analysis was conducted on 44 patients with lung cancer brain metastases (70 lesions) who were admitted to our oncology and Gamma Knife center from January 2020 to May 2022. All patients received intracranial SRT and had PTBE. Based on treatment with Bev, patients were categorized as SRT + Bev and SRT groups. Follow-up head magnetic resonance imaging was performed to calculate PTBE and tumor volume changes. The edema index (EI) was used to assess the severity of PTBE. Additionally, the extent of tumor reduction and intracranial progression-free survival (PFS) were compared between the two groups. RESULTS: The SRT + Bev group showed a statistically significant difference in EI values before and after radiotherapy (p = 0.0115), with lower values observed after treatment, but there was no difference in the SRT group (p = 0.4008). There was a difference in the distribution of EI grades in the SRT + Bev group (p = 0.0186), with an increased proportion of patients at grades 1-2 after radiotherapy, while there was no difference in the SRT group (p > 0.9999). Both groups demonstrated a significant reduction in tumor volume after radiotherapy (p < 0.05), but there was no difference in tumor volume changes between the two groups (p = 0.4089). There was no difference in intracranial PFS between the two groups (p = 0.1541). CONCLUSION: Bevacizumab significantly reduces the severity of PTBE after radiotherapy for lung cancer. However, its impact on tumor volume reduction and intracranial PFS does not reach statistical significance.
Assuntos
Edema Encefálico , Neoplasias Encefálicas , Neoplasias Pulmonares , Radiocirurgia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/etiologia , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Edema Encefálico/patologia , Estudos Retrospectivos , Radiocirurgia/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundárioRESUMO
Key Clinical Message: Temporal percutaneous transhepatic duodenum drainage (PTDD) seems to be effective in the treatment of postoperative afferent loop syndrome (ALS) following transverse loop colostomy for obstructive colorectal cancer. Abstract: Management of obstructive colorectal cancer still remains a challenge. There are various options with different risks of mortality and mobility for obstructive colorectal cancer. A rare unexpected postoperative ALS following a low anterior resection and transverse loop colostomy for obstructive colorectal cancer is presented in this report. A 64-year-old man had the acute ALS had been noted 10 days after transverse loop colostomy. An option was temporal PTDD treatment in the patient with history of Billroth's operation II for upper gastrointestinal bleeding 30 years ago. Acute ALS was treated by temporal PTDD. The drainage tube for PTDD was not removed until closure of the transverse colostomy 2 months later. The patient recovered uneventfully. Acute ALS after transverse loop colostomy for obstructive colorectal cancer is rare and has never been reported in the literature. The mechanism of acute ALS after construction of a loop colostomy and the treatment strategy of PTDD for acute ALS is presented.