Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 17.537
Filtrar
1.
Anticancer Res ; 41(11): 5343-5353, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732404

RESUMO

Enhanced understanding of the molecular features of glioma has led to an expansion of murine glioma models and successful preclinical studies. However, clinical trials continue to have a high cost, extended production time, and low proportion of success. Studies in large-animal models of various cancer types have emerged to bridge the translational gap between in vitro and in vivo animal studies and human clinical trials. The anatomy and physiology of large animals are of more direct relevance to human disease, allowing for more rigorous testing of treatments such as surgical resection and adjuvant therapy in glioma. The recent generation of multiple porcine glioma models supports their use in high-throughput preclinical studies. The demonstration of spontaneous glioblastoma formation in canines further provides a unique avenue for the study of de novo glioma. The aim of this review was to outline the current status of large animal models of glioma and their value as a transitional step between rodent models and human clinical trials.


Assuntos
Neoplasias Encefálicas , Glioma , Pesquisa Médica Translacional , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Modelos Animais de Doenças , Cães , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Glioma/terapia , Haplorrinos , Humanos , Camundongos Transgênicos , Especificidade da Espécie , Sus scrofa
2.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638718

RESUMO

Despite the considerable advances in diagnostic methods in medicine, central nervous system (CNS) tumors, particularly the most common ones-gliomas-remain incurable, with similar incidence rates and mortality. A growing body of literature has revealed that degradation of the extracellular matrix by matrix metalloproteinases (MMPs) might be involved in the pathogenesis of CNS tumors. However, the subfamily of MMPs, known as disintegrin and metalloproteinase (ADAM) proteins are unique due to both adhesive and proteolytic activities. The objective of our review is to present the role of ADAMs in CNS tumors, particularly their involvement in the development of malignant gliomas. Moreover, we focus on the diagnostic and prognostic significance of selected ADAMs in patients with these neoplasms. It has been proven that ADAM12, ADAMTS4 and 5 are implicated in the proliferation and invasion of glioma cells. In addition, ADAM8 and ADAM19 are correlated with the invasive activity of glioma cells and unfavorable survival, while ADAM9, -10 and -17 are associated with tumor grade and histological type of gliomas and can be used as prognostic factors. In conclusion, several ADAMs might serve as potential diagnostic and prognostic biomarkers as well as therapeutic targets for malignant CNS tumors. However, future research on ADAMs biology should be performed to elucidate new strategies for tumor diagnosis and treatment of patients with these malignancies.


Assuntos
Proteínas ADAM/metabolismo , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Sistema Nervoso Central , Glioma , Proteínas de Neoplasias/metabolismo , Animais , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/enzimologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Glioma/diagnóstico , Glioma/enzimologia , Glioma/patologia , Glioma/terapia , Humanos , Gradação de Tumores , Invasividade Neoplásica
3.
Medicine (Baltimore) ; 100(39): e27248, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596120

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; therefore, lncRNAs are considered major components of the competitive endogenous RNA (ceRNA) network and have attracted growing attention. This study explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in the malignant differentiation of low-grade glioma (LGG) to glioblastoma (GBM) and their potential impact on the prognosis of patients with GBM. METHODS: LncRNA and messenger RNA (mRNA) data were extracted from the Cancer Genome Atlas (TCGA) database from 156 GBM samples and 529 LGG samples. Separately, the miRNA expression data were downloaded from the Gene Expression Omnibus database, with the GSE112009 dataset containing miRNA expression data from 10 GBM samples and 15 LGG samples. Weighted gene coexpression network analysis was performed to screen the glioma grade-related lncRNAs. Then, a ceRNA network was established. The database for annotation, visualization, and integrated discovery was adopted to conduct functional enrichment analysis based on 57 upregulated differentially expressed mRNAs in the ceRNA network. Finally, Kaplan-Meier curves were created for the survival analysis of 13 hub lncRNA by combining the clinical data of GBM patients in TCGA. RESULTS: A ceRNA network including 16 lncRNAs, 18 miRNAs, and 78 mRNAs specific to the malignant differentiation of LGG to GBM was established. The 57 upregulated differentially expressed mRNAs in the ceRNA network were significantly enriched in 35 gene ontology terms and 5 pathways. The survival analysis showed that 2 lncRNAs (LINC00261 and HOXA10-AS) were prognostic biomarkers for patients with GBM in TCGA. CONCLUSION: The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the malignant differentiation of LGG to GBM. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for GBM.


Assuntos
Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Glioma/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Humanos
4.
Molecules ; 26(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34641360

RESUMO

Despite the significant relevance of photodynamic therapy (PDT) as an efficient strategy for primary and adjuvant anticancer treatment, several challenges compromise its efficiency. In order to develop an "ideal photosensitizer" and the requirements applied to photosensitizers for PDT, there is still a need for new photodynamic agents with improved photophysical and photobiological properties. In this study, we performed a detailed characterization of two tetracyanotetra(aryl)porphyrazine dyes with 4-biphenyl (pz II) and 4-diethylaminophenyl (pz IV) groups in the periphery of the porphyrazine macrocycle. Photophysical properties, namely, fluorescence quantum yield and lifetime of both photosensitizers, demonstrate extremely high dependence on the viscosity of the environment, which enables them to be used as viscosity sensors. PzII and pz IV easily enter cancer cells and efficiently induce cell death under light irradiation. Using fluorescence lifetime imaging microscopy, we demonstrated the possibility of assessing local intracellular viscosity and visualizing viscosity changes driven by PDT treatment with the compounds. Thus, pz II and pz IV combine the features of potent photodynamic agents and viscosity sensors. These data suggest that the unique properties of the compounds provide a tool for PDT dosimetry and tailoring the PDT treatment regimen to the individual characteristics of each patient.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Glioma/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Oxigênio Singlete/química , Animais , Carcinoma de Células Escamosas/patologia , Glioma/patologia , Humanos , Camundongos , Fármacos Fotossensibilizantes/química , Células Tumorais Cultivadas , Viscosidade
5.
Nat Genet ; 53(10): 1469-1479, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594037

RESUMO

Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling-integrating DNA methylation, transcriptome and genotype within the same cells-of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Plasticidade Celular/genética , Epigênese Genética , Glioma/genética , Glioma/patologia , Padrões de Herança/genética , Transcrição Genética , Linhagem Celular Tumoral , Ilhas de CpG/genética , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Humanos , Isocitrato Desidrogenase/genética , Filogenia , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas/genética , Análise de Célula Única , Transcriptoma/genética
6.
Biomed Res Int ; 2021: 5516819, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504897

RESUMO

Automated detection of brain tumor location is essential for both medical and analytical uses. In this paper, we clustered brain MRI images to detect tumor location. To obtain perfect results, we presented an unsupervised robust PCA algorithm to clustered images. The proposed method clusters brain MR image pixels to four leverages. The algorithm is implemented for five brain diseases such as glioma, Huntington, meningioma, Pick, and Alzheimer's. We used ten images of each disease to validate the optimal identification rate. According to the results obtained, 2% of the data in the bad leverage part of the image were determined, which acceptably discerned the tumor. Results show that this method has the potential to detect tumor location for brain disease with high sensitivity. Moreover, results show that the method for the Glioma images has approximately better results than others. However, according to the ROC curve for all selected diseases, the present method can find lesion location.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Análise de Componente Principal/métodos , Algoritmos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Análise por Conglomerados , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/patologia , Imageamento por Ressonância Magnética/métodos , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Meningioma/diagnóstico por imagem , Meningioma/patologia , Curva ROC
7.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502082

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying the molecular drivers of DIPG progression is of the utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not yet been elucidated in DIPG. Herein, we studied the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGGs). The expression and sub-cellular location of H19 lncRNA were validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs. normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in the up-regulation of oncogenic let-7 target (e.g., SULF2 and OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate for treating this incurable cancer.


Assuntos
Neoplasias do Tronco Encefálico/genética , Proliferação de Células , Glioma/genética , RNA Longo não Codificante/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Neoplasias do Tronco Encefálico/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Histonas/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mutação , RNA Longo não Codificante/genética
8.
Nat Commun ; 12(1): 5530, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545083

RESUMO

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Amplificação de Genes , Glioma/genética , Recidiva Local de Neoplasia/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Adolescente , Adulto , Criança , Deleção Cromossômica , Análise por Conglomerados , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico/genética , Genoma Humano , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Radiação , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Genética , Adulto Jovem
9.
Nat Commun ; 12(1): 5531, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545084

RESUMO

Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors, as potentially effective therapies.


Assuntos
Glioma/genética , Glioma/patologia , Radiação , Adolescente , Criança , Estudos de Coortes , Simulação por Computador , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Gradação de Tumores , Transcriptoma/genética , Adulto Jovem
10.
Front Immunol ; 12: 668391, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539622

RESUMO

The binding of platelet-derived growth factor D (PDGF-DD) to the NKp44 receptor activates a distinct transcriptional program in primary IL-2 expanded human natural killer (NK) cells. We were interested in knowing if the PDGF-DD-NKp44 pathway of NK cell activation might play a clinically relevant role in anti-tumor immunity. In order to address this question, we determined transcriptional signatures unique to resting, IL-2 expanded, and PDGF-DD activated, NK cells, in addition to different T cell subsets, and established the abundance of these immune cell phenotypes in The Cancer Genome Atlas (TCGA) low-grade glioma (LGG) dataset using CIBERSORT. Our results show that LGG patient tumors enriched for either the PDGF-DD activated NK cell or memory CD8+ T cell phenotypes are associated with a more favorable prognosis. Combined cell phenotype analyses revealed that patients with LGG tumors enriched for the PDGF-DD activated NK cell phenotype and the CD4+ T helper cell phenotype had a more favorable prognosis. High expression of transcripts encoding members of the killer cell lectin-like receptor (KLR) family, such as KLRK1 and KLRC2, KLRC3 and KLRC4 in LGG tumors were associated with more favorable prognosis, suggesting that these NK cell family receptors may play a prominent role in LGG anti-tumor immunity. Finally, many of the TCGA findings were reciprocated in LGG patients from the Chinese Glioma Genome Atlas (CGGA) dataset. Our results provide transcriptomic evidence that PDGF-DD activated NK cells and KLR family receptors may play an important clinical role in immune surveillance of LGG.


Assuntos
Neoplasias Encefálicas/metabolismo , Perfilação da Expressão Gênica , Glioma/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Linfócitos do Interstício Tumoral/metabolismo , Linfocinas/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcriptoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/imunologia , Glioma/patologia , Humanos , Interleucina-2/metabolismo , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfocinas/genética , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Gradação de Tumores , Fenótipo , Fator de Crescimento Derivado de Plaquetas/genética , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Transdução de Sinais , Microambiente Tumoral
11.
Int J Mol Sci ; 22(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34502484

RESUMO

Malignant gliomas derive from brain glial cells and represent >75% of primary brain tumors. This includes anaplastic astrocytoma (grade III; AS), the most common and fatal glioblastoma multiforme (grade IV; GBM), and oligodendroglioma (ODG). We have generated patient-derived AS, GBM, and ODG cell models to study disease mechanisms and test patient-centered therapeutic strategies. We have used an aptamer-based high-throughput SOMAscan® 1.3K assay to determine the proteomic profiles of 1307 different analytes. SOMAscan® proteomes of AS and GBM self-organized into closely adjacent proteomes which were clearly distinct from ODG proteomes. GBM self-organized into four proteomic clusters of which SOMAscan® cluster 4 proteome predicted a highly inter-connected proteomic network. Several up- and down-regulated proteins relevant to glioma were successfully validated in GBM cell isolates across different SOMAscan® clusters and in corresponding GBM tissues. Slow off-rate modified aptamer proteomics is an attractive analytical tool for rapid proteomic stratification of different malignant gliomas and identified cluster-specific SOMAscan® signatures and functionalities in patient GBM cells.


Assuntos
Aptâmeros de Nucleotídeos/química , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteoma/metabolismo , Proteômica , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Células Tumorais Cultivadas
12.
Front Immunol ; 12: 685213, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539626

RESUMO

Background: Glioma is the most common type of primary brain tumor in adults. Patients with the most malignant form have an overall survival time of <16 months. Although considerable progress has been made in defining the adapted therapeutic strategies, measures to counteract tumor escape have not kept pace, due to the developed resistance of malignant glioma. In fact, identifying the nature and role of distinct tumor-infiltrating immune cells in glioma patients would decipher potential mechanisms behind therapy failure. Methods: We integrated into our study glioma transcriptomic datasets from the Cancer Genome Atlas (TCGA) cohort (154 GBM and 516 LGG patients). LM22 immune signature was built using CIBERSORT. Hierarchical clustering and UMAP dimensional reduction algorithms were applied to identify clusters among glioma patients either in an unsupervised or supervised way. Furthermore, differential gene expression (DGE) has been performed to unravel the top expressed genes among the identified clusters. Besides, we used the least absolute shrinkage and selection operator (LASSO) and Cox regression algorithm to set up the most valuable prognostic factor. Results: Our study revealed, following gene enrichment analysis, the presence of two distinct groups of patients. The first group, defined as cluster 1, was characterized by the presence of immune cells known to exert efficient antitumoral immune response and was associated with better patient survival, whereas the second group, cluster 2, which exhibited a poor survival, was enriched with cells and molecules, known to set an immunosuppressive pro-tumoral microenvironment. Interestingly, we revealed that gene expression signatures were also consistent with each immune cluster function. A strong presence of activated NK cells was revealed in cluster 1. In contrast, potent immunosuppressive components such as regulatory T cells, neutrophils, and M0/M1/M2 macrophages were detected in cluster 2, where, in addition, inhibitory immune checkpoints, such as PD-1, CTLA-4, and TIM-3, were also significantly upregulated. Finally, Cox regression analysis further corroborated that tumor-infiltrating cells from cluster 2 exerted a significant impact on patient prognosis. Conclusion: Our work brings to light the tight implication of immune components on glioma patient prognosis. This would contribute to potentially developing better immune-based therapeutic approaches.


Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Linfócitos do Interstício Tumoral/imunologia , Biomarcadores Tumorais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Glioma/mortalidade , Glioma/patologia , Humanos , Linfócitos do Interstício Tumoral/patologia , Análise Multivariada , Prognóstico , Análise de Sobrevida , Microambiente Tumoral
13.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576059

RESUMO

In recent decades, endogenous nanocarrier-exosomes have received considerable scientific interest as drug delivery systems. The unique proteo-lipid architecture allows the crossing of various natural barriers and protects exosomes cargo from degradation in the bloodstream. However, the presence of this bilayer membrane as well as their endogenous content make loading of exogenous molecules challenging. In the present work, we will investigate how to promote the manipulation of vesicles curvature by a high-pressure microfluidic system as a ground-breaking method for exosomes encapsulation. Exosomes isolated from Uppsala 87 Malignant Glioma (U87-MG) cell culture media were characterized before and after the treatment with high-pressure homogenization. Once their structural and biological stability were validated, we applied this novel method for the encapsulation in the lipidic exosomal bilayer of the chemotherapeutic Irinotecan HCl Trihydrate-CPT 11. Finally, we performed in vitro preliminary test to validate the nanobiointeraction of exosomes, uptake mechanisms, and cytotoxic effect in cell culture model.


Assuntos
Antineoplásicos/química , Sistemas de Liberação de Medicamentos , Exossomos/química , Glioma/tratamento farmacológico , Antineoplásicos/farmacologia , Meios de Cultura/química , Glioma/patologia , Ensaios de Triagem em Larga Escala , Humanos , Microfluídica , Medicina de Precisão
14.
Medicine (Baltimore) ; 100(36): e26750, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516487

RESUMO

ABSTRACT: To investigate the correlation between preoperative inflammatory markers, Ki-67 expression and the pathological grade of glioma, and to provide a reference for clinical prediction of glioma prognosis.A total of 45 glioma patients who underwent surgery with complete clinical and pathological data were in our hospital from January 2012 to December 2018 were enrolled. Glioma was divided into WHO grade I to IV. Forty-five healthy health examiners with matched clinical characteristics were included to the control group. Blood routine tests were recorded at admission in both the glioma and control group. The ratio of neutrophil to lymphocyte cytometry (NLR), derived neutrophil to lymphocyte ratio (dNLR) (white blood cell count - neutrophil count to neutrophil count), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI, serum albumin content + 5 × lymphocyte count) were calculated. The expression of Ki-67 in glioma was detected by immunohistochemistry. The relationship between the above markers, Ki-67 expression and pathological grade of glioma was evaluated with receiver operating characteristics curve analysis and Spearman correlation test. The correlation between the markers and Ki-67 were also determined.NLR, dNLR, PLR were increased in the glioma group (P < .001, <.001, .002), whereas red blood cell distribution width (RDW) was decreased (P = .009). All the glioma samples expressed Ki-67 with varying degree. Receiver operating characteristics curve analysis reveals NLR, dNLR, PLR, and RDW have significant discriminating ability in differentiating the glioma and control sample. NLR, PLR, PNI, and Ki-67 were significantly correlated with glioma pathology grade (P = .023, .006, .019, <.05), while dNLR and RDW were not associated with glioma grade. Finally, NLR and PLR were related to Ki-67 expression in glioma patients (P = .002, .022), while dNLR and RDW were not related to Ki-67 expression.Preoperative inflammatory markers NLR, PLR, PNI, and postoperative Ki-67 expression are associated with pathological grade of glioma. Detection of these markers may aid in better prediction of glioma prognosis.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Antígeno Ki-67/sangue , Linfócitos/citologia , Neutrófilos/citologia , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade
15.
Exp Cell Res ; 407(2): 112808, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34508744

RESUMO

Regulatory T (Treg) cells are thought to contribute to tumor pathogenesis by suppressing tumor immunosurveillance and antitumor immunity. T follicular regulatory (Tfr) cells are a recently characterized Treg subset that expresses both the Treg transcription factor (TF) Foxp3 and the T follicular helper (Tfh) TF Bcl-6. The role of Tfr cells in glioma patients remains unclear. In this study, we found that the level of Tfr cells, identified as Foxp3+Bcl-6+ CD4 T cells, was significantly elevated in tumor-infiltrating CD4 T cells from resected glioma tumors. Both Tfr cells and Treg cells significantly suppressed the proliferation and the cytotoxic capacity of CD8 T cells toward glioma tumor cells, and the suppression was positively associated with the proportion of Tfr cells and Treg cells, respectively. Tfr and Treg cells from glioma tumor samples demonstrated higher suppression potency than those from healthy blood samples and glioma blood samples. Interestingly, canonical CXCR5- Treg cells could suppress both CXCR5+ and CXCR5- CD8 T cells, albeit with stronger potency toward CXCR5- CD8 T cells. However, Tfr cells presented much higher suppression potency toward CXCR5+ CD8 T cells, whereas CXCR5+ CD8 T cells are a potent CD8 T cell subset previously described to have antiviral and antitumor roles. Overall, these data indicate that Tfr cells are enriched in glioma tumors and have suppressive capacity toward CD8 T cell-mediated effector functions.


Assuntos
Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Glioma/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas , Adulto Jovem
16.
Sci Rep ; 11(1): 18541, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535705

RESUMO

Glioblastomas are the most common type of adult primary brain neoplasms. Clinically, it is helpful to identify biomarkers to predict the survival of patients with gliomas due to its poor outcome. Shugoshin 2 (SGO2) is critical in cell division and cell cycle progression in eukaryotes. However, the association of SGO2 with pathological grading and survival in patients with gliomas remains unclear. We analyzed the association between SGO2 expression and clinical outcomes from Gene Expression Omnibus (GEO) dataset profiles, The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA). SGO2 mRNA and protein expression in normal brain tissue and glioma cell lines were investigated via quantitative RT-PCR, Western blot, and IHC staining. The roles of SGO2 in proliferation, migration, and apoptosis of GBM cells were studied with wound-healing assay, BrdU assay, cell cycle analysis, and JC-1 assay. The protein-protein interaction (PPI) was analyzed via Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). SGO2 mRNA expression predicted higher grade gliomas than non-tumor brain tissues. Kaplan-Meier survival analysis showed that patients with high-grade gliomas with a higher SGO2 expression had worse survival outcomes. SGO2 mRNA and protein expression were upper regulated in gliomas than in normal brain tissue. Inhibition of SGO2 suppressed cell proliferation and migration. Also, PPI result showed SGO2 to be a potential hub protein, which was related to the expression of AURKB and FOXM1. SGO2 expression positively correlates with WHO pathological grading and patient survival, suggesting that SGO2 is a biomarker that is predictive of disease progression in patients with gliomas.


Assuntos
Neoplasias Encefálicas/patologia , Proteínas de Ciclo Celular/análise , Glioma/patologia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioma/diagnóstico , Glioma/genética , Humanos , Gradação de Tumores , Prognóstico
17.
Cancer Invest ; 39(10): 854-870, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34569407

RESUMO

The novel anti-neoplastic glycopeptide T11TS retards glioma both in in-vitro clinical samples and in-vivo models. This study investigates the correlation between altering the glioma microenvironment with glioma arrest and death. Flow cytometry, immunoblotting, ELISA, and co-immunoprecipitation were employed to investigate glioma cell arrest and death. Results include a decline in phosphorylation of Akt and attenuation of p21 phosphorylation (Thr145,Ser146) and disassociation of p-Akt-Mdm2 and p-Akt-BAD facilitating death by Akt>BAD. T11TS influence phosphorylation patterns in two focal axes Akt>p21 and Akt>Mdm2>p53. The current article provides crucial insight in deciphering the mechanism of T11TS induced glioma cell arrest and death.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Antígenos CD58/farmacologia , Glioma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Antígenos CD58/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Glioma/metabolismo , Glioma/patologia , Masculino , PTEN Fosfo-Hidrolase/análise , Fosforilação , Proteínas Proto-Oncogênicas c-mdm2/análise , Ratos , Ratos Wistar , Microambiente Tumoral , Proteína Supressora de Tumor p53/análise , Proteína de Morte Celular Associada a bcl/metabolismo
18.
BMC Cancer ; 21(1): 1025, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525976

RESUMO

BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.


Assuntos
Neoplasias Encefálicas/genética , Genes ras/genética , Glioma/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Análise Mutacional de DNA/métodos , Enzimas Reparadoras do DNA/metabolismo , Éxons/genética , Feminino , Glioblastoma/genética , Glioma/patologia , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/genética , Fenótipo , Regiões Promotoras Genéticas , Telomerase/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
19.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445646

RESUMO

Albeit the effort to develop targeted therapies for patients with high-grade gliomas (WHO grades III and IV) is evidenced by hundreds of current clinical trials, radiation remains one of the few effective therapeutic options for them. This review article analyzes the updates on the topic "radiotherapy of high-grade gliomas" during the period 1 January 2021-30 June 2021. The high number of articles retrieved in PubMed using the search terms ("gliom* and radio*") and manually selected for relevance indicates the feverish research currently ongoing on the subject. During the last semester, significant advances were provided in both the preclinical and clinical settings concerning the diagnosis and prognosis of high-grade gliomas, their radioresistance, and the inevitable side effects of their treatment with radiation. The novel information concerning tumor radiosensitization was of special interest in terms of therapeutic perspective and was discussed in detail.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Radiossensibilizantes/farmacologia , Radioterapia/métodos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Humanos
20.
Cell Mol Life Sci ; 78(17-18): 6161-6200, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34333711

RESUMO

Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , NF-kappa B/metabolismo , 2-Metoxiestradiol/química , 2-Metoxiestradiol/metabolismo , 2-Metoxiestradiol/uso terapêutico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Glioma/metabolismo , Glioma/patologia , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...