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Introduction: High-grade gliomas are the most common primary brain tumors in adults, and they usually have a quick fatal course. Average survival is 18 months, mainly, because of tumor resistance to Stupp protocol. Objective: To determine high-grade glioma patient survival and the effect of persuasion variables on survival. Materials and methods: We conducted a longitudinal descriptive study in which 80 untreated recently diagnosed high-grade glioma patients participated. A survey was conducted regarding their exposure to some risk factors, degree of genetic instability in peripheral blood using micronucleus quantification on binuclear lymphocytes, micronuclei in reticulocytes and sister-chromatid exchanges in lymphocytes. In the statistical analysis, this study constructed life tables, used the Kaplan-Meier, and the log-rank test, and in the multivariate analysis, a Cox proportional hazards model was constructed. Results: Eighty patients' clinical, demographic and lifestyle characteristics were analyzed, as well as their survival rates and the average survival time is 784 days (interquartile range: 928). Factors like age, exposure at work to polycyclic hydrocarbons and the number of sister-chromatid exchanges in lymphocytes in the first sampling was significantly survivalrelated in the multivariate analysis. Conclusion: We determined that only three of the analyzed variables have an important effect on survival time when it comes to high-grade glioma patients.
Introducción. Los gliomas de alto grado son los tumores cerebrales primarios más comunes en adultos y, por lo general, tienen un curso mortal rápido. La supervivencia media es de 18 meses, principalmente, como consecuencia de la resistencia del tumor al protocolo Stupp. Objetivo. Determinar la supervivencia de los pacientes con glioma de alto grado y el efecto de las variables de persuasión en la supervivencia. Materiales y métodos. Se llevó a cabo un estudio descriptivo longitudinal en el que participaron 80 pacientes con diagnóstico reciente de glioma de alto grado no tratados. Se hizo una encuesta sobre su exposición a algunos factores de riesgo, grado de inestabilidad genética en sangre periférica mediante cuantificación de micronúcleos en linfocitos binucleares, micronúcleos en reticulocitos e intercambios de cromátidas hermanas en linfocitos. En el análisis estadístico, se construyeron tablas de vida, se utilizó Kaplan-Meier y la prueba de rangos logarítmicos, y en el análisis multivariado, se construyó un modelo de riesgos proporcionales de Cox. Resultados. Se analizaron las características clínicas, demográficas y de estilo de vida de 80 pacientes, así como sus tasas de supervivencia y el tiempo medio de supervivencia fue de 784 días (rango intercuartílico: 928). Factores como la edad, la exposición laboral a hidrocarburos policíclicos y el número de intercambios de cromátidas hermanas en linfocitos en el primer muestreo se relacionaron significativamente con la supervivencia en el análisis multivariante. Conclusión. Según los resultados, el estudio determinó que solo tres de las variables analizadas tienen un efecto importante en el tiempo de supervivencia cuando se trata de pacientes con glioma de alto grado.
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Neoplasias Encefálicas , Glioma , Humanos , Glioma/mortalidad , Glioma/patología , Glioma/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Longitudinales , Análisis de Supervivencia , Factores de Riesgo , Intercambio de Cromátides Hermanas , Exposición Profesional/efectos adversos , Anciano , Estimación de Kaplan-Meier , Clasificación del TumorRESUMEN
Recent studies in Diffuse Midline Gliomas (DMG) demonstrated a strong connection between epigenome dysregulation and metabolic rewiring. Here, we evaluated the value of targeting a glycolytic protein named Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase 3 (PFKFB3) in H3.3K27M DMG. We observed that the viability of H3.3K27M cells is dramatically reduced by PFK15, a potent inhibitor of PFKFB3. Furthermore, PFKFB3 inhibition induced apoptosis and G2/M arrest. Interestingly, CRISPR-Knockout of the K27M mutant allele has a synergistic effect on the observed phenotype. Altogether, we identified PFKFB3 as a new target for H3.3K27M DMG, making PFK15 a potential candidate for future animal studies and clinical trials.
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Glioma , Histonas , Fosfofructoquinasa-2 , Humanos , Glioma/metabolismo , Glioma/patología , Glioma/genética , Fosfofructoquinasa-2/metabolismo , Fosfofructoquinasa-2/genética , Histonas/metabolismo , Histonas/genética , Línea Celular Tumoral , Niño , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Apoptosis , Mutación , Glucólisis/efectos de los fármacosRESUMEN
BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood. RESULTS: miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models. CONCLUSIONS: These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma.
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Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , MicroARNs , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Glioma/genética , Glioma/metabolismo , Animales , Ratones , Xenoinjertos , Trasplante de Neoplasias , Neoplasias Encefálicas/genética , MicroARNs/metabolismoRESUMEN
The 2021 World Health Organization (WHO) classification has updated the definition of grade 2 gliomas and the presence of isocitrate dehydrogenase (IDH) mutation has been deemed the cornerstone of diagnosis. Though slow-growing and having a low proliferative index, grade 2 gliomas are incurable by surgery and complementary treatments are vital to improving prognosis. This guideline provides recommendations on the multidisciplinary treatment of grade 2 astrocytomas and oligodendrogliomas based on the best evidence available.
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Neoplasias Encefálicas , Glioma , Clasificación del Tumor , Humanos , Glioma/terapia , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Isocitrato Deshidrogenasa/genética , Astrocitoma/terapia , Astrocitoma/patología , Astrocitoma/genética , Oligodendroglioma/terapia , Oligodendroglioma/genética , Oligodendroglioma/patología , Sociedades MédicasRESUMEN
HJURP is overexpressed in several cancer types and strongly correlates with patient survival. However, the mechanistic basis underlying the association of HJURP with cancer aggressiveness is not well understood. HJURP promotes the loading of the histone H3 variant, CENP-A, at the centromeric chromatin, epigenetically defining the centromeres and supporting proper chromosome segregation. In addition, HJURP is associated with DNA repair but its function in this process is still scarcely explored. Here, we demonstrate that HJURP is recruited to DSBs through a mechanism requiring chromatin PARylation and promotes epigenetic alterations that favor the execution of DNA repair. Incorporation of HJURP at DSBs promotes turnover of H3K9me3 and HP1, facilitating DNA damage signaling and DSB repair. Moreover, HJURP overexpression in glioma cell lines also affected global structure of heterochromatin independently of DNA damage induction, promoting genome-wide reorganization and assisting DNA damage response. HJURP overexpression therefore extensively alters DNA damage signaling and DSB repair, and also increases radioresistance of glioma cells. Importantly, HJURP expression levels in tumors are also associated with poor response of patients to radiation. Thus, our results enlarge the understanding of HJURP involvement in DNA repair and highlight it as a promising target for the development of adjuvant therapies that sensitize tumor cells to irradiation.
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Cromatina , Glioma , Humanos , Centrómero/metabolismo , Proteína A Centromérica/genética , Proteína A Centromérica/metabolismo , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Glioma/genéticaRESUMEN
In recent decades, there have been significant advances in the diagnosis of diffuse gliomas, driven by the integration of novel technologies. These advancements have deepened our understanding of tumor oncogenesis, enabling a more refined stratification of the biological behavior of these neoplasms. This progress culminated in the fifth edition of the WHO classification of central nervous system (CNS) tumors in 2021. This comprehensive review article aims to elucidate these advances within a multidisciplinary framework, contextualized within the backdrop of the new classification. This article will explore morphologic pathology and molecular/genetics techniques (immunohistochemistry, genetic sequencing, and methylation profiling), which are pivotal in diagnosis, besides the correlation of structural neuroimaging radiophenotypes to pathology and genetics. It briefly reviews the usefulness of tractography and functional neuroimaging in surgical planning. Additionally, the article addresses the value of other functional imaging techniques such as perfusion MRI, spectroscopy, and nuclear medicine in distinguishing tumor progression from treatment-related changes. Furthermore, it discusses the advantages of evolving diagnostic techniques in classifying these tumors, as well as their limitations in terms of availability and utilization. Moreover, the expanding domains of data processing, artificial intelligence, radiomics, and radiogenomics hold great promise and may soon exert a substantial influence on glioma diagnosis. These innovative technologies have the potential to revolutionize our approach to these tumors. Ultimately, this review underscores the fundamental importance of multidisciplinary collaboration in employing recent diagnostic advancements, thereby hoping to translate them into improved quality of life and extended survival for glioma patients.
Nas últimas décadas, houve avanços significativos no diagnóstico de gliomas difusos, impulsionados pela integração de novas tecnologias. Esses avanços aprofundaram nossa compreensão da oncogênese tumoral, permitindo uma estratificação mais refinada do comportamento biológico dessas neoplasias. Esse progresso culminou na quinta edição da classificação da OMS de tumores do sistema nervoso central (SNC) em 2021. Esta revisão abrangente tem como objetivo elucidar esses avanços de forma multidisciplinar, no contexto da nova classificação. Este artigo irá explorar a patologia morfológica e as técnicas moleculares/genéticas (imuno-histoquímica, sequenciamento genético e perfil de metilação), que são fundamentais no diagnóstico, além da correlação dos radiofenótipos da neuroimagem estrutural com a patologia e a genética. Aborda sucintamente a utilidade da tractografia e da neuroimagem funcional no planejamento cirúrgico. Destacaremos o valor de outras técnicas de imagem funcional, como ressonância magnética de perfusão, espectroscopia e medicina nuclear, na distinção entre a progressão do tumor e as alterações relacionadas ao tratamento. Discutiremos as vantagens das diferentes técnicas de diagnóstico na classificação desses tumores, bem como suas limitações em termos de disponibilidade e utilização. Além disso, os crescentes avanços no processamento de dados, inteligência artificial, radiômica e radiogenômica têm grande potencial e podem em breve exercer uma influência substancial no diagnóstico de gliomas. Essas tecnologias inovadoras têm o potencial de revolucionar nossa abordagem a esses tumores. Em última análise, esta revisão destaca a importância fundamental da colaboração multidisciplinar na utilização dos recentes avanços diagnósticos, com a esperança de traduzi-los em uma melhor qualidade de vida e uma maior sobrevida.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Glioma , Humanos , Inteligencia Artificial , Calidad de Vida , Glioma/diagnóstico por imagen , Glioma/genética , Imagen por Resonancia Magnética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias del Sistema Nervioso Central/diagnóstico por imagenRESUMEN
INTRODUCTION: Recently, the search for novel molecular markers in adult-type diffuse gliomas has grown substantially, yet with few novel breakthroughs. As the presence of a necrotic center is a differential diagnosis for more aggressive entities, we hypothesized that genes involved in necroptosis may play a role in tumor progression. AIM: Given that MLKL is the executioner of the necroptotic pathway, we evaluated whether this gene would help to predict prognosis of adult gliomas patients. METHODS: We analyzed a publicly available retrospective cohort (n = 530) with Kaplan Meier survival analysis (p<0.0001) and both uni- and multivariate Cox regression models. RESULTS: We determined that MLKL is an independent predictive prognostic marker for overall survival in these patients (HR: 2.56, p<0.001), even when controlled by the CNS5 gold-standard markers, namely IDH mutation and 1p/19q Codeletion (HR: 1.68, p = 0.013). These findings were confirmed in a validation cohort (n = 325), using the same cutoff value. Interestingly, higher expression of MLKL is associated with worse clinical outcome for adult-type diffuse glioma patients, which is opposite to what was found in other cell cancer types, suggesting that necroptosis undertakes an atypical detrimental role in glioma progression.
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Genes Reguladores , Glioma , Humanos , Adulto , Estudios Retrospectivos , Factores de Transcripción , Glioma/genética , Agresión , Proteínas QuinasasRESUMEN
High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO classification divides adult HGG into four subtypes: grade 3 oligodendroglioma (1p/19 codeleted, IDH-mutant); grade 3 IDH-mutant astrocytoma; grade 4 IDH-mutant astrocytoma, and grade 4 IDH wild-type glioblastoma (GB). Radiotherapy (RT) and chemotherapy (CTX) are the current standard of care for patients with newly diagnosed HGG. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent high-grade gliomas is not well defined and decision-making is usually based on prior strategies, as well as several clinical and radiological factors. Whereas the prognosis for GB is grim (5-year survival rate of 5-10%) outcomes for the other high-grade gliomas are typically better, depending on the molecular features of the tumor. The presence of neurological deficits and seizures can significantly impact quality of life.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Adulto , Humanos , Calidad de Vida , Recurrencia Local de Neoplasia , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , MutaciónRESUMEN
Diffuse gliomas are tumors that arise from glial or glial progenitor cells. They are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or oligodendroglioma IDH-mutant, and 1p/19q-codeleted, both slower-growing tumors, or glioblastoma (GBM), a more aggressive tumor. Despite advances in the diagnosis and treatment of gliomas, the median survival time after diagnosis of GBM remains low, approximately 15 months, with a 5-year overall survival rate of only 6.8%. Therefore, new biomarkers that could support the earlier diagnosis and prognosis of these tumors would be of great value. MUC17, a membrane-bound mucin, has been identified as a potential biomarker for several tumors. However, the role of this mucin in adult gliomas has not yet been explored. Here, we show for the first time, in a retrospective study and by in silico analysis that MUC17 is one of the relevant mutant genes in adult gliomas. Moreover, that an increase in MUC17 methylation correlates with an increase in glioma malignancy grade. Patients with MUC17 mutations had a poorer prognosis than their wild-type counterparts in both GBM and non-GBM glioma cohorts. We also analyzed mutational profiles that correlated strongly with poor survival. Therefore, in this study, we present a new potential biomarker for further investigation, especially for the prognosis of adult diffuse gliomas.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Adulto , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Metilación , Estudios Retrospectivos , Glioma/diagnóstico , Glioma/genética , Glioma/patología , Mutación/genética , Pronóstico , Mucinas/genética , Isocitrato Deshidrogenasa/genéticaRESUMEN
Studies on the development of mRNA vaccines for central nervous system tumors have used gene expression profiles, clinical data and RNA sequencing from sources such as The Cancer Genome Atlas and Chinese Glioma Genome Atlas to identify effective antigens. These studies revealed several immune subtypes of glioma, each one linked to unique prognoses and genetic/immune-modulatory changes. Potential antigens include ARPC1B, BRCA2, COL6A1, ITGB3, IDH1, LILRB2, TP53 and KDR, among others. Patients with immune-active and immune-suppressive phenotypes were found to respond better to mRNA vaccines. While these findings indicate the potential of mRNA vaccines in cancer therapy, further research is required to optimize administration and adjuvant selection, and precisely identify target antigens.
Scientists study special vaccines for hard-to-treat brain tumors. They looked at things, such as information about patients and the small parts of cells that make up the tumor, to find ways to help. They found that brain tumors can make our body's defenses act differently. They also found some possible targets and unique defense patterns that are special to each patient when fighting these tumors. Patients with these special defenses and good targets might respond better to treatment with vaccines. This is exciting because it means that in the future, we might have treatments made for each person. But we still need to do more research to figure out how to get these vaccines to the tumor, so this research gives us hope that we can find better treatments and more choices for people with brain cancer. If we keep researching, we might find even better treatments in the future.
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Vacunas contra el Cáncer , Glioma , Humanos , ARN Mensajero/genética , Glioma/genética , Glioma/terapia , Pronóstico , Adyuvantes InmunológicosRESUMEN
OBJECTIVE: To investigate the value of a nomogram based on multiparametric and multiregional MR images to predict Isocitrate Dehydrogenase-1 (IDH1) gene mutations in glioma. DATA AND METHODS: The authors performed a retrospective analysis of 110 MR images of surgically confirmed pathological gliomas; 33 patients with IDH1 gene Mutation (IDH1-M) and 77 patients with Wild-type IDH1 (IDH1-W) were divided into training and validation sets in a 7:3 ratio. The clinical features were statistically analyzed using SPSS and R software. Three glioma regions (rCET, rE, rNEC) were outlined using ITK-SNAP software and projected to four conventional sequences (T1, T2, Flair, T1C) for feature extraction using AI-Kit software. The extracted features were screened using R software. A logistic regression model was established, and a nomogram was generated using the selected clinical features. Eight models were developed based on different sequences and ROIs, and Receiver Operating Characteristic (ROC) curves were used to evaluate the predictive efficacy. Decision curve analysis was performed to assess the clinical usefulness. RESULTS: Age was selected with Radscore to construct the nomogram. The Model 1 AUC values based on four sequences and three ROIs were the highest in these models, at 0.93 and 0.89, respectively. Decision curve analysis indicated that the net benefit of model 1 was higher than that of the other models for most Pt-values. CONCLUSION: A nomogram based on multiparametric and multiregional MR images can predict the mutation status of the IDH1 gene accurately.
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Glioma , Nomogramas , Humanos , Estudios Retrospectivos , Glioma/diagnóstico por imagen , Glioma/genética , Curva ROC , Mutación/genética , Imagen por Resonancia Magnética/métodos , Isocitrato Deshidrogenasa/genéticaRESUMEN
Extracellular matrix protein 2 (ECM2), which regulates cell proliferation and differentiation, has recently been reported as a prognostic indicator for multiple cancers, but its value in lower grade glioma (LGG) remains unknown. In this study, LGG transcriptomic data of 503 cases in The Cancer Genome Atlas (TCGA) database and 403 cases in The Chinese Glioma Genome Atlas (CGGA) database were collected to analyze ECM2 expression patterns and the relationship with clinical characteristics, prognosis, enriched signaling pathways, and immune-related markers. In addition, a total of 12 laboratory samples were used for experimental validation. Wilcoxon or Kruskal-Wallis tests demonstrated highly expressed ECM2 in LGG was positively associated with malignant histological features and molecular features such as recurrent LGG and isocitrate dehydrogenase (IDH) wild-type. Also, Kaplan-Meier (KM) curves proved high ECM2 expression could predict shorter overall survival in LGG patients, as multivariate analysis and meta-analysis claimed ECM2 was a deleterious factor for LGG prognosis. In addition, the enrichment of immune-related pathways for ECM2, for instance JAK-STAT pathway, was obtained by Gene Set Enrichment Analysis (GSEA) analysis. Furthermore, positive relationships between ECM2 expression with immune cells infiltration and cancer-associated fibroblasts (CAFs), iconic markers (CD163), and immune checkpoints (CD274, encoding PD-L1) were proved by Pearson correlation analysis. Finally, laboratory experiments of RT-qPCR and immunohistochemistry showed high expression of ECM2, as well as CD163 and PD-L1 in LGG samples. This study identifies ECM2, for the first time, as a subtype marker and prognostic indicator for LGG. ECM2 could also provide a reliable guarantee for further personalized therapy, synergizing with tumor immunity, to break through the current limitations and thus reinvigorating immunotherapy for LGG. AVAILABILITY OF DATA AND MATERIALS: Raw data from all public databases involved in this study are stored in the online repository (chengMD2022/ECM2 (github.com)).
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Neoplasias Encefálicas , Glioma , Humanos , Antígeno B7-H1 , Quinasas Janus , Pronóstico , Factores de Transcripción STAT , Transducción de Señal , Glioma/genética , Glioma/terapia , Inmunoterapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapiaRESUMEN
Medulloblastoma, neuroblastoma, and pediatric glioma account for almost 30% of all cases of pediatric cancers. Recent evidence indicates that pediatric nervous system tumors originate from stem or progenitor cells and present a subpopulation of cells with highly tumorigenic and stem cell-like features. These cancer stem cells play a role in initiation, progression, and resistance to treatment of pediatric nervous system tumors. Histone modification, DNA methylation, chromatin remodeling, and microRNA regulation display a range of regulatory activities involved in cancer origin and progression, and cellular identity, especially those associated with stem cell features, such as self-renewal and pluripotent differentiation potential. Here, we review the contribution of different epigenetic mechanisms in pediatric nervous system tumor cancer stem cells. The choice between a differentiated and undifferentiated state can be modulated by alterations in the epigenome through the regulation of stemness genes such as CD133, SOX2, and BMI1 and the activation neuronal of differentiation markers, RBFOX3, GFAP, and S100B. Additionally, we highlighted the stage of development of epigenetic drugs and the clinical benefits and efficacy of epigenetic modulators in pediatric nervous system tumors.
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Neoplasias Encefálicas , Glioma , Neoplasias del Sistema Nervioso , Humanos , Niño , Epigenoma , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/patología , Células Madre Neoplásicas/patología , Neoplasias del Sistema Nervioso/genética , Neoplasias del Sistema Nervioso/patologíaRESUMEN
OBJECTIVE: Cancer stem cells or cancer stemness has been confirmed to a major obstacle for glioma progression and it has also been reported that circRNAs play an important part in cancer progression. This study mainly focuses on revealing the role of circRPPH1 and the underlying mechanisms in glioma cell stemness. METHODS: In vitro experiment including RT-qPCR, Western blot, sphere-formation analysis, and ALDH1 activity, and in vivo tumorigenesis experiments were performed to evaluate the effects of circRPPH1 on glioma cell stemness. Luciferase reporter, ChIP, and DNA pull-down analysis were used to reveal the underlying mechanisms. RESULTS: It was found that circRPPH1 level was upregulated in glioma cell spheres and facilitated the stemness of glioma cells; C-FOS transcriptionally activated circRPPH1 expression via directly binding to circRPPH1 promoter in glioma cells. Moreover, circRPPH1 promoted the stemness of glioma cells dependent on c-FOS-mediated transcriptional activation. CONCLUSIONS: This study indicates that c-Fos-activated circRPPH1 contributes to glioma stemness and provides a potential target for glioma progression based on the c-FOS/circRPPH1 regulatory axis.
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Glioma , Células Madre Neoplásicas , Proteínas Proto-Oncogénicas c-fos , ARN Circular , Humanos , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Glioma/genética , Glioma/metabolismo , Células Madre Neoplásicas/metabolismo , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Circular/genética , ARN Circular/metabolismoRESUMEN
PURPOSE: Patients diagnosed with cancer often suffer from emotional stressors, such as anxiety, depression, and fear of death. However, whether fear stress could influence the glioma progression is still unclear. METHODS: Xenograft glioma animal models were established in nude mice. Tumor-bearing mice were subjected to fear stress by living closely with cats and then their depressive behaviors were measured using an open field test. Hematoxylin and eosin staining, the TUNEL staining and immunochemical staining were used to detect the histopathological changes of tumor tissues. Gene expression profiling was used to screen the aberrant gene expression. Methylated RNA immunoprecipitation was used to identify the RNA m6A level. Gene expression was measured by western blot and real-time PCR, respectively. RESULTS: We found that fear stress promoted glioma tumor progression in mice. Fear stress-induced upregulation of METTL3 and FSP1, increased m6A level of glioma tumor tissues, and inhibited ferroptosis in glioma progression, which were reversed by knockdown of METTL3 and FSP1 in vivo. In addition, we found that when iFSP1 (a ferroptosis inducer by targeting inhibition of FSP1) was introduced to glioma cells, the cells viability of glioma significantly was decreased and ferroptosis was enhanced in glioma cells. CONCLUSIONS: Fear stress-induced upregulation of METTL3 stabilized FSP1 mRNA by m6A modification, leading to tumor progression through inhibition of ferroptosis. Our study provides a new understanding of psychological effects on glioma development, and new insights for glioma therapy.
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Miedo , Ferroptosis , Glioma , Estrés Psicológico , Animales , Humanos , Ratones , Línea Celular Tumoral , Depresión/etiología , Depresión/genética , Depresión/psicología , Modelos Animales de Enfermedad , Miedo/fisiología , Miedo/psicología , Ferroptosis/genética , Ferroptosis/fisiología , Expresión Génica , Glioma/genética , Glioma/psicología , Metiltransferasas/genética , Ratones Desnudos , ARN Mensajero , Estrés Psicológico/etiología , Estrés Psicológico/genética , Estrés Psicológico/psicología , Regulación hacia Arriba/genéticaRESUMEN
Retinoblastoma-binding protein 8 (RBBP8) affects the prognosis of patients with malignancies through various mechanisms. However, its function in gliomas is unknown. Our study explored the effects of RBBP8 on the prognosis of glioma patients, as well as its regulatory role in the glioma immune microenvironment. We used various bioinformatics methods to analyze the transcriptional profiles and methylation data of RBBP8 in gliomas from multiple databases. Our results showed that the mRNA and protein expression of RBBP8 in gliomas was higher than that in normal tissues and positively correlated with malignant clinical features such as age and WHO grade. A Kaplan-Meier analysis showed that patients with high RBBP8 expression had a poor prognosis. Cox regression demonstrated that RBBP8 was an independent risk indicator and had good diagnostic value for the poor prognosis of glioma. Importantly, RBBP8 was positively correlated with many well-known immune checkpoints (e.g., CTLA4 and PDL-1). Finally, a gene set enrichment analysis revealed that RBBP8 was remarkably enriched in cancer-related pathways such as cell cycle, DNA replication and so on. In conclusion, this study is the first to elaborate on the value of RBBP8 in the pathological process of glioma for anti-tumor immunotherapy. In addition, the expression of RBBP8 and its methylation site, cg05513509, may provide potential targets for glioma therapy.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Metilación , Pronóstico , Glioma/diagnóstico , Glioma/genética , Glioma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Microambiente Tumoral , Endodesoxirribonucleasas/metabolismoRESUMEN
Although the literature about the functions of hyaluronan and the CD44 receptor in the brain and brain tumours is extensive, the role of the receptor for hyaluronan-mediated motility (RHAMM) in neural stem cells and gliomas remain poorly explored. RHAMM is considered a multifunctional receptor which performs various biological functions in several normal tissues and plays a significant role in cancer development and progression. RHAMM was first identified for its ability to bind to hyaluronate, the extracellular matrix component associated with cell motility control. Nevertheless, additional functions of this protein imply the interaction with different partners or cell structures to regulate other biological processes, such as mitotic-spindle assembly, gene expression regulation, cell-cycle control and proliferation. In this review, we summarise the role of RHAMM in normal brain development and the adult brain, focusing on the neural stem and progenitor cells, and discuss the current knowledge on RHAMM involvement in glioblastoma progression, the most aggressive glioma of the central nervous system. Understanding the implications of RHAMM in the brain could be useful to design new therapeutic approaches to improve the prognosis and quality of life of glioblastoma patients.
Asunto(s)
Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Ácido Hialurónico , Calidad de Vida , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Glioma/genética , Encéfalo/metabolismo , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismoRESUMEN
Gliomas are the deadliest of all primary brain tumors, and they constitute a serious global health problem. MicroRNAs (miRNAs) are gene expression regulators associated with glioma pathogenesis. Thus, miRNAs represent potential therapeutic agents for treating gliomas. However, miRNAs have not been established as part of the regular clinical armamentarium. This systemic review evaluates current molecular and pre-clinical studies with the aim of defining the most appealing supramolecular platform for administering therapeutic miRNA to patients with gliomas. An integrated analysis suggested that cationic lipid nanoparticles, functionalized with octa-arginine peptides, represent a potentially specific, practical, non-invasive intervention for treating gliomas. This supramolecular platform allows loading both hydrophilic (miRNA) and hydrophobic (anti-tumor drugs, like temozolomide) molecules. This systemic review is the first to describe miRNA delivery systems targeted to gliomas that integrate several types of molecules as active ingredients. Further experimental validation is warranted to confirm the practical value of miRNA delivery systems.
Asunto(s)
Neoplasias Encefálicas , Glioma , MicroARNs , Arginina , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Liposomas , MicroARNs/genética , MicroARNs/metabolismo , Nanopartículas , Péptidos , TemozolomidaRESUMEN
Gliomas represent 80% of all primary malignant brain tumors in adults. In view of this public health problem, the early detection through sensitive and specific molecular tumor markers analysis can help to improve gliomas diagnosis and prognosis as well as their staging, assessment of therapeutic response and detection of recurrence. Therefore, this review focuses in current gliomas tumor markers, IDH-1/2, 1p/19q, MGMT, ATRX, TERT, H3, EGFR, BRAF and Ki67 used in clinic worldwide and their importance to early detection, glioma histological and molecular classification as well as in predicting patient's therapeutic response. In addition, we present what are the steps in the requesting process for this type of examination in the Brazilian Public Health System (SUS) scope, which attends most of the Brazilian population. Thereby, this article is useful in demonstrating which markers are used in the clinical practice for glioma patients and can be performed in the SUS through partnerships/agreements between specialized health centers and clinical analysis laboratories. It is hoped that this work clarifies, the necessary subsidies to carry out the research of tumor markers in all institutions that serve SUS users, providing a service with equal conditions.
Asunto(s)
Neoplasias Encefálicas , Glioma , Adulto , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Brasil , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , PronósticoRESUMEN
BACKGROUND: Pilocytic astrocytoma is the most frequent pediatric glioma. Despite its overall good prognosis, complete surgical resection is sometimes unfeasible, especially for patients with deep-seated tumors. For these patients, the identification of targetable genetic alterations such as NTRK fusions, raised as a new hope for therapy. The presence of gene fusions involving NTRK2 has been rarely reported in pilocytic astrocytoma. The aim of the present study was to investigate the frequency of NTRK2 alterations in a series of Brazilian pilocytic astrocytomas. METHODS: Sixty-nine pilocytic astrocytomas, previously characterized for BRAF and FGFR1 alterations were evaluated. The analysis of NTRK2 alterations was performed using a dual color break apart fluorescence in situ hybridization (FISH) assay. RESULTS: NTRK2 fusions were successfully evaluated by FISH in 62 of the 69 cases. Neither evidence of NTRK2 gene rearrangements nor NTRK2 copy number alterations were found. CONCLUSIONS: NTRK2 alterations are uncommon genetic events in pilocytic astrocytomas, regardless of patients' clinicopathological and molecular features.