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1.
Radiol Clin North Am ; 59(3): 305-322, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33926679

RESUMEN

Molecular features are now essential in distinguishing between glioma histologic subtypes. Currently, isocitrate dehydrogenase mutation, 1p19q codeletion, and MGMT methylation status play significant roles in optimizing medical and surgical treatment. Noninvasive pretreatment and post-treatment determination of glioma subtype is of great interest. Although imaging cannot replace the genetic panel at present, image findings have shown promising signs to identify and diagnose the types and subtypes of gliomas. This article details key imaging findings in the most common molecular glioma subtypes and highlights recent advances in imaging technologies to differentiate these lesions noninvasively.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética/métodos , Mutación/genética , Tomografía Computarizada por Rayos X/métodos , Proteínas Supresoras de Tumor/genética , Encéfalo/diagnóstico por imagen , Humanos , Metilación
2.
Radiol Clin North Am ; 59(3): 441-455, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33926688

RESUMEN

The 2016 World Health Organization brain tumor classification is based on genomic and molecular profile of tumor tissue. These characteristics have improved understanding of the brain tumor and played an important role in treatment planning and prognostication. There is an ongoing effort to develop noninvasive imaging techniques that provide insight into tissue characteristics at the cellular and molecular levels. This article focuses on the molecular characteristics of gliomas, transcriptomic subtypes, and radiogenomic studies using semantic and radiomic features. The limitations and future directions of radiogenomics as a standalone diagnostic tool also are discussed.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Diagnóstico por Imagen/métodos , Glioma/diagnóstico por imagen , Glioma/genética , /métodos , Encéfalo/diagnóstico por imagen , Humanos
3.
Mymensingh Med J ; 30(2): 315-322, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33830108

RESUMEN

Astrocytoma is the commonest primary brain tumor. These are feared due to their invasiveness in brain parenchyma so are less amenable to surgical removal and current chemotherapy regimens with a high mortality rate. Cell adhesion molecule (CAM) E-cadherin (CDH1) downregulation has been associated with tumors of different system and organs featuring invasion and metastasis. Therefore, the aim of the study was to find out the level of E-cadherin gene expression in low grade astrocytoma. In this cross-sectional study, 22 formalin fixed paraffin embedded tissue were taken as cases. Three non tumorous brain tissue and 1fresh post-mortem brain tissue were taken as control. Histological features were studied under light microscope with Haematoxylin and Eosin (H&E stain). Expression of CDH1 gene was analyzed by real time - polymerase chain reaction (RT-PCR) by comparative cyclic threshold (Ct) value method. The change in E-cadherin expression was measured by fold change in comparison with the control brain tissue. The data was tabulated and statistical analysis was performed. Among the 22 study cases 8(36.36%) were World Health Organization (WHO) Grade I and 14(63.63%) were WHO Grade II. All tumors showed downregulation of CDH1 gene in comparison with non-tumorous control tissue. The result is statistically significant (p=0.019). So, the study data revealed that downregulation of E-cadherin gene occurs in low grade astrocytoma and tumors of WHO Grade II showed more downregulation than Grade I tumors.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Antígenos CD/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Cadherinas/genética , Estudios Transversales , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa
4.
Adv Exp Med Biol ; 1280: 261-276, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33791988

RESUMEN

Metabolic reprogramming is an important characteristics of glioma, the most common form of malignant brain tumor. In this chapter, we aim to discuss some of the recently discovered metabolic alterations in glioma, including the dysregulated TCA cycle, amino acid, nucleotide, and lipid metabolism. We have also detailed some of the metabolomic applications in gliomas, particularly the analyses of body fluids and tissues of glioma patients. With new improvement of the technology, metabolomics will become a powerful tool to discover truly meaningful biomarkers for clinical applications in gliomas. Metabolomic studies of gliomas will also facilitate a better understanding of the molecular targets/pathways and the development of new therapeutic treatments for this devastating disease.


Asunto(s)
Neoplasias Encefálicas , Glioma , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Ciclo del Ácido Cítrico , Glioma/diagnóstico , Glioma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Metabolismo de los Lípidos , Metabolómica , Mutación
5.
Medicine (Baltimore) ; 100(16): e25603, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879726

RESUMEN

ABSTRACT: Gliomas have the highest incidence among primary brain tumors, and the extracellular matrix (ECM) plays a vital role in tumor progression. We constructed a risk signature using ECM-related genes to predict the prognosis of patients with gliomas.mRNA and clinical data from glioma patients were downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed ECM-related genes were screened, and a risk signature was built using least absolute shrinkage and selection operator (LASSO) Cox regression. Cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to assess immune infiltration in different risk groups. Gene set enrichment analysis (GSEA) was performed to explore the molecular mechanisms of the genes employed in the risk score.Differentially expressed ECM-related genes were identified, and their associated regulatory mechanisms were predicted via analysis of protein-protein interaction (PPI), transcription factor (TF) regulatory and TF coexpression networks. The established risk signature considered 17 ECM-related genes. The prognosis of the high-risk group was significantly worse than that of the low-risk group. We used the CGGA database to validate the signature. CIBERSORT indicated that the levels of naive B cells, activated memory CD4 T cells, regulatory T cells, gamma delta T cells, activated NK cells, monocytes, activated dendritic cells and activated mast cells were higher in the high-risk group. The levels of plasma cells, CD8 T cells, naive CD4 T cells, resting memory CD4 T cells, M0 macrophages, M1 macrophages, resting mast cells, and neutrophils were lower in the high-risk group. Ultimately, GSEA showed that the terms intestinal immune network for IgA production, primary immunodeficiency, and ECM receptor interaction were the top 3 terms enriched in the high-risk group. The terms Wnt signaling pathway, ErbB signaling pathway, mTOR signaling pathway, and calcium signaling pathway were enriched in the low-risk group.We built a risk signature to predict glioma prognosis using ECM-related genes. By evaluating immune infiltration and biofunctions, we gained a further understanding of this risk signature. This risk signature could be an effective tool for predicting glioma prognosis.This study did not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.


Asunto(s)
Neoplasias Encefálicas/genética , Matriz Extracelular/genética , Glioma/genética , Medición de Riesgo/normas , Adulto , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/mortalidad , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Glioma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Mapas de Interacción de Proteínas/genética , ARN Mensajero/genética , Reproducibilidad de los Resultados , Factores de Riesgo , Transducción de Señal/genética , Factores de Transcripción/genética
6.
Zhonghua Bing Li Xue Za Zhi ; 50(3): 229-235, 2021 Mar 08.
Artículo en Chino | MEDLINE | ID: mdl-33677887

RESUMEN

Objective: To investigate the clinicopathological and molecular characteristics of the epithelioid glioblastoma (eGBM) with BRAF V600E mutation. Methods: Sixteen cases of eGBM with BRAF V600E mutation diagnosed at the West China Hospital of Sichuan University, China from 2012 to 2019 were collected. Their clinicopathological and molecular characteristics were analyzed. Results: The range of patients' age was from 7 to 61 years (median 31.5 years). There were 4 males and 12 females, with a male to female ratio of 1∶3. Eleven cases were newly diagnosed eGBM and five cases had a previous history of astrocytomas. Most of the tumors were located in the cerebral hemisphere, often in the frontal lobe, with an average diameter of 4.6 cm (2.0-8.0 cm). The tumors were composed of relatively uniform, closely packed epithelioid cells, some showing discohesion, with distinct cell membrane, eosinophilic cytoplasm, eccentric nuclei, distinct nucleoli and mitotic activity. Palisaded/coagulative necrosis was seen in all cases. Glomerular microvascular proliferation was seen in most of the cases, while mono-or multi-nucleated tumor giant cells were seen in some cases. Focal sarcomatoid area was seen in 2 cases, and focal pleomorphic xanthoastrocytoma (PXA)-like area was seen in 3 cases. Immunohistochemistry showed variable positivity for GFAP, Olig2 and p53. The median Ki-67 index was 30% (10%-50%). Only one case lost ATRX protein expression. Sanger sequencing identified the BRAF V600E mutation in all sixteen patients. Five cases also had mutations in the TERT gene promoter. No IDH1 (R132) or IDH2 (R172) mutation was detected. Surgical resection of the tumors was performed for all patients, and 3 patients also received adjuvant radiotherapy and chemotherapy. Follow-up data were available for 15 patients, with a follow-up time of 1-89 months (median 10 months). Among the 15 patients, 7 patients died of disease and another 5 patients had recurrences. The overall survival time of the patients under 35 years of age was significantly longer than that of the patients aged 35 years or older (P=0.014), but their progression-free survival was not statistically different (P=0.232). Conclusions: eGBM with BRAF V600E mutation is more commonly detected in young women than other the populations (i.e. elderly or male). The epithelioid morphology should include rhabdoid meningioma, anaplastic PXA, atypical teratoid/rhabdoid tumor, metastatic tumors, and melanoma in its differential diagnosis. PXA-like area is observed in some eGBM cases, suggesting a relationship of these two types of tumor. eGBM is a high-grade malignant tumor and most of the cases show recurrences or deaths in a short-period time. The younger patients have a relatively better prognosis than the older ones.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Adolescente , Adulto , Anciano , Astrocitoma/genética , Neoplasias Encefálicas/genética , Niño , China , Femenino , Glioblastoma/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Adulto Joven
7.
BMC Cancer ; 21(1): 265, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33706745

RESUMEN

BACKGROUND: Gliosarcoma (GSM) is a distinct and aggressive variant of glioblastoma multiforme (GBM) with worse prognosis and few treatment options. It is often managed with the same treatment modalities with temozolomide (TMZ) as in GBM. However, the therapeutic benefits on GSM from such treatment regimen is largely unknown. Patient-derived xenograft (PDX) models have been used widely to model tumor progression, and subsequently to validate biomarkers and inform potential therapeutic regimens. Here, we report for the first time the successful development of a PDX model of secondary GSM. METHODS: Tissue obtained from a tumor resection revealed a secondary GSM arising from GBM. The clinical, radiological, and histopathological records of the patient were retrospectively reviewed. Samples obtained from surgery were cultured ex vivo and/or implanted subcutaneously in immunocompromised mice. Histopathological features between the primary GBM, secondary GSM, and GSM PDX are compared. RESULTS: In explant culture, the cells displayed a spindle-shaped morphology under phase contrast microscopy, consistent with the sarcomatous component. GSM samples were subcutaneously engrafted into immunocompromised mice after single-cell suspension. Xenografts of serial passages showed enhanced growth rate with increased in vivo passage. We did not observe any histopathological differences between the secondary GSM and its serial in vivo passages of PDX tumors. CONCLUSIONS: Our PDX model for GSM retained the histopathological characteristics of the engrafted tumor from the patient. It may provide valuable information to facilitate molecular and histopathological modelling of GSM and be of significant implication in future research to establish precise cancer medicine for this highly malignant tumor.


Asunto(s)
Neoplasias Encefálicas/terapia , Quimioradioterapia/efectos adversos , Glioblastoma/terapia , Gliosarcoma/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Animales , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/cirugía , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proteínas de Ciclo Celular/análisis , Proteínas de Ciclo Celular/genética , Quimioradioterapia/métodos , Craneotomía , Femenino , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/patología , Gliosarcoma/etiología , Gliosarcoma/genética , Gliosarcoma/patología , Humanos , Imagen por Resonancia Magnética , Ratones , Persona de Mediana Edad , Mutación , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Cultivo Primario de Células , Temozolomida/uso terapéutico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Nat Cell Biol ; 23(3): 278-291, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33664496

RESUMEN

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.


Asunto(s)
Antígenos CD/metabolismo , Neoplasias Encefálicas/enzimología , Cadherinas/metabolismo , Glioblastoma/enzimología , ARN Circular/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Antígenos CD/genética , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones Desnudos , Invasividad Neoplásica , ARN Circular/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771989

RESUMEN

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglía/metabolismo , Selectina-P/genética , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Selectina-P/antagonistas & inhibidores , Selectina-P/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética
10.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669859

RESUMEN

Titanium dioxide and zinc oxide are two of the most widely used nanomaterials. We assessed the effects of noncytotoxic doses of both nanomaterials on T98G human glioblastoma cells by omic approaches. Surprisingly, no effects on the transcriptome of T98G cells was detected after exposure to 5 µg/mL of zinc oxide nanoparticles during 72 h. Conversely, the transcriptome of the cells exposed to 20 µg/mL of titanium dioxide nanoparticles during 72 h revealed alterations in lots of biological processes and molecular pathways. Alterations to the transcriptome suggests that exposure to titanium dioxide nanoparticles might, potentially, compromise the integrity of the blood brain barrier integrity and cause neuroinflammation. The latter issue was further confirmed phenotypically with a proteomic analysis and by recording the release of interleukin 8. Titanium dioxide also caused autophagy, which was demonstrated through the increase in the expression of the autophagy-related 3 and microtubule associated protein 1 light chain 3 alpha genes. The proteomic analysis revealed that titanium dioxide nanoparticles might have anticancerigen properties by downregulating genes involved in the detoxication of anthracyclines. A risk assessment resulting from titanium dioxide exposure, focusing on the central nervous system as a potential target of toxicity, is necessary.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Nanopartículas/toxicidad , Titanio/toxicidad , Transcriptoma/genética , Óxido de Zinc/toxicidad , Autofagia/efectos de los fármacos , Autofagia/genética , Neoplasias Encefálicas/ultraestructura , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Glioblastoma/ultraestructura , Humanos , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Proteómica , Transcriptoma/efectos de los fármacos , Agua/química
11.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673213

RESUMEN

Glioblastoma multiforme (GBM) is amongst the deadliest of human cancers, with a median survival rate of just over one year following diagnosis. Characterized by rapid proliferation and diffuse infiltration into the brain, GBM is notoriously difficult to treat, with tumor cells showing limited response to existing therapies and eventually developing resistance to these interventions. As such, there is intense interest in better understanding the molecular alterations in GBM to guide the development of more efficient targeted therapies. GBM tumors can be classified into several molecular subtypes which have distinct genetic signatures, and they show aberrant activation of numerous signal transduction pathways, particularly those connected to receptor tyrosine kinases (RTKs) which control glioma cell growth, survival, migration, invasion, and angiogenesis. There are also non-canonical modes of RTK signaling found in GBM, which involve G-protein-coupled receptors and calcium channels. This review uses The Cancer Genome Atlas (TCGA) GBM dataset in combination with a data-mining approach to summarize disease characteristics, with a focus on select molecular pathways that drive GBM pathogenesis. We also present a unique genomic survey of RTKs that are frequently altered in GBM subtypes, as well as catalog the GBM disease association scores for all RTKs. Lastly, we discuss current RTK targeted therapies and highlight emerging directions in GBM research.


Asunto(s)
Neoplasias Encefálicas/enzimología , Proliferación Celular , Glioblastoma/enzimología , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioblastoma/genética , Glioblastoma/patología , Humanos , Proteínas de Neoplasias/genética , Fosforilación/genética , Proteínas Tirosina Quinasas Receptoras/genética
12.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33649841

RESUMEN

Recent studies have reported that gene amplified in squamous cell carcinoma 1 (GASC1) is involved in the progression of several types of cancer. However, whether GASC1 promotes glioma progression remains unknown. Therefore, the present study aimed to investigate the effect of GASC1 exposure on glioma tumorigenesis. The western blot demonstrated that grade III and IV glioma tissues exhibited a higher mRNA and protein expression of GASC1. Moreover, CD133+ U87 or U251 cells from magnetic cell separation exhibited a higher GASC1 expression. Invasion Transwell assay, clonogenic assay and wound healing assay have shown that GASC1 inhibition using a pharmacological inhibitor and specific short hairpin (sh)RNA suppressed the invasive, migratory and tumorsphere forming abilities of primary culture human glioma cells. Furthermore, GASC1­knockdown decreased notch receptor (Notch) responsive protein hes family bHLH transcription factor 1 (Hes1) signaling. GASC1 inhibition reduced notch receptor 1 (NOTCH1) expression, and a NOTCH1 inhibitor enhanced the effects of GASC1 inhibition on the CD133+ U87 or U251 cell tumorsphere forming ability, while NOTCH1 overexpression abrogated these effects. In addition, the GASC1 inhibitor caffeic acid and/or the NOTCH1 inhibitor DAPT (a γ­Secretase Inhibitor), efficiently suppressed the human glioma xenograft tumors. Thus, the present results demonstrated the importance of GASC1 in the progression of glioma and identified that GASC1 promotes glioma progression, at least in part, by enhancing NOTCH signaling, suggesting that GASC1/NOTCH1 signaling may be a potential therapeutic target for glioma treatment.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Receptor Notch1/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Ácidos Cafeicos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Diaminas/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/genética , Masculino , Ratones Desnudos , Interferencia de ARN , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/genética , Transducción de Señal/genética , Tiazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
13.
BMC Cancer ; 21(1): 251, 2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750353

RESUMEN

BACKGROUND: To accurately predict the prognosis of glioma patients. METHODS: A total of 541 samples from the TCGA cohort, 181 observations from the CGGA database and 91 samples from our cohort were included in our study. Long non-coding RNAs (LncRNAs) associated with glioma WHO grade were evaluated by weighted gene co-expression network analysis (WGCNA). Five lncRNA features were selected out to construct prognostic signatures based on the Cox regression model. RESULTS: By weighted gene co-expression network analysis (WGCNA), 14 lncRNAs related to glioma grade were identified. Using univariate and multivariate Cox analysis, five lncRNAs (CYTOR, MIR155HG, LINC00641, AC120036.4 and PWAR6) were selected to develop the prognostic signature. The Kaplan-Meier curve depicted that the patients in high risk group had poor prognosis in all cohorts. The areas under the receiver operating characteristic curve of the signature in predicting the survival of glioma patients at 1, 3, and 5 years were 0.84, 0.92, 0.90 in the CGGA cohort; 0.8, 0.85 and 0.77 in the TCGA set and 0.72, 0.90 and 0.86 in our own cohort. Multivariate Cox analysis demonstrated that the five-lncRNA signature was an independent prognostic indicator in the three sets (CGGA set: HR = 2.002, p < 0.001; TCGA set: HR = 1.243, p = 0.007; Our cohort: HR = 4.457, p = 0.008, respectively). A nomogram including the lncRNAs signature and clinical covariates was constructed and demonstrated high predictive accuracy in predicting 1-, 3- and 5-year survival probability of glioma patients. CONCLUSION: We established a five-lncRNA signature as a potentially reliable tool for survival prediction of glioma patients.


Asunto(s)
Neoplasias Encefálicas/mortalidad , Biología Computacional/métodos , Glioma/mortalidad , ARN Largo no Codificante/análisis , Neoplasias Encefálicas/genética , Redes Reguladoras de Genes , Glioma/genética , Humanos , Nomogramas , Pronóstico , Modelos de Riesgos Proporcionales
14.
Medicine (Baltimore) ; 100(13): e25346, 2021 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-33787635

RESUMEN

RATIONALE: Glioblastoma is the most lethal and common malignant brain tumor but rare in patients with neurofibromatosis type 1. The clinical findings and pathological findings with gene signatures in female patients have not been well clarified. PATIENT CONCERNS: A 51-year-old female patient complained of headache and left limb weakness lasting for 20 days. The patient underwent a cesarean section 20 years ago and hysterectomy 1 year ago because of uterine leiomyomas. Multiple café-au-lait spots and neurofibromas were found over patient's chest, neck, back, and arms. The myodynamia of left distant and proximate epipodite were grade 0 and grade 1 respectively. The myodynamia of lower left limb was grade 3. DIAGNOSES: Magnetic resonance imaging revealed a malignant lesion which was most likely a glioblastoma in the right temporo-parietal lobe, approximately 5.6 × 5.9 × 6.9 cm in size with a rounded boundary. INTERVENTIONS: A right temporo-parietal craniotomy was performed to resect the space-occupying lesion for gross total removal. Then, the patient received concurrent chemoradiotherapy. Histological examination confirmed a glioblastoma without v-RAF murine sarcoma viral oncogene homolog B1 gene, isocitrate dehydrogenase 1 gene, and telomerase reverse transcriptase gene promoter mutations. OUTCOMES: After surgery, the headache was relieved and the muscular strength of left limbs did improve. After receiving the standard treatment regimen, the patient was alive at 13 months follow-up. LESSONS: This is the first reported glioblastoma in female neurofibromatosis type 1 patient without v-RAF murine sarcoma viral oncogene homolog B1 gene, isocitrate dehydrogenase 1 gene, and telomerase reverse transcriptase gene promoter mutations. Tumors in adult patients with these signatures were less aggressive with well-circumscribed border and had long-term survivals which strengthened the evidence that these patients may comprise a unique subset in glioblastoma.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Neurofibromatosis 1/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Craneotomía , Femenino , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética , Persona de Mediana Edad , Mutación , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/genética , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/patología , Lóbulo Parietal/cirugía , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Telomerasa/genética , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patología , Lóbulo Temporal/cirugía , Transcriptoma/genética
15.
Nat Commun ; 12(1): 1503, 2021 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-33686071

RESUMEN

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.


Asunto(s)
Neoplasias Encefálicas/inmunología , Líquido Cefalorraquídeo/inmunología , Leucocitos , Microambiente Tumoral/inmunología , Adenocarcinoma del Pulmón , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Linfocitos T CD8-positivos/inmunología , Humanos , Neoplasias Pulmonares , Pronóstico
16.
Magy Onkol ; 65(1): 59-70, 2021 Mar 17.
Artículo en Húngaro | MEDLINE | ID: mdl-33730118

RESUMEN

Our knowledge on low grade gliomas has grown extensively recently. Both molecular alterations and clinical trials unraveling their clinical significance are difficult to get familiar with. Thus, efforts made to reach any consensus are of upmost importance, so that multidisciplinary teams involved in patient management can make up-to-date, individually-tailored therapeutic plans. Our aims were to synthesize all the molecular and clinical investigations, recommendations and guidelines related to low grade gliomas in Hungarian language, and to define low and high risk prognostic groups with different therapeutic strategies. The roles of 21 molecular pathological markers and their significance levels in low grade gliomas are summarized in this paper. Data from relevant literature, as well as recommendations of neuro-oncological organizations were included. This summary could help to integrate diverse therapeutic plans of the past decades in low grade gliomas. Moreover, this paper may serve as a source for future revisions when updating low and high risk groups in low grade gliomas.


Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Humanos , Clasificación del Tumor , Pronóstico
17.
Sensors (Basel) ; 21(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668578

RESUMEN

Application of micro-Raman spectroscopy for the monitoring of quality of nanowire sensor chips fabrication has been demonstrated. Nanowire chips have been fabricated on the basis of «silicon-on-insulator¼ (SOI) structures (SOI-NW chips). The fabrication of SOI-NW chips was performed by optical litography with gas-phase etching. The so-fabricated SOI-NW chips are intended for highly sensitive detection of brain cancer biomarkers in humans. In our present study, two series of experiments have been conducted. In the first experimental series, detection of a synthetic DNA oligonucleotide (oDNA) analogue of brain cancer-associated microRNA miRNA-363 in purified buffer solution has been performed in order to demonstrate the high detection sensitivity. The second experimental series has been performed in order to reveal miRNA-363 itself in real human plasma samples. To provide detection biospecificity, the SOI-NW chip surface was modified by covalent immobilization of probe oligonucleotides (oDNA probes) complementary to the target biomolecules. Using the SOI-NW sensor chips proposed herein, the concentration detection limit of the target biomolecules at the level of 3.3 × 10-17 M has been demonstrated. Thus, the approach employing the SOI-NW chips proposed herein represents an attractive tool in biomedical practice, aimed at the early revelation of oncological diseases in humans.


Asunto(s)
Técnicas Biosensibles , Neoplasias Encefálicas , MicroARNs , Nanocables , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Humanos , MicroARNs/genética , Plasma , Control de Calidad , Silicio , Espectrometría Raman
18.
J Med Chem ; 64(3): 1570-1583, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33523674

RESUMEN

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Receptores Androgénicos/efectos de los fármacos , Antagonistas de Andrógenos/toxicidad , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Humanos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Receptores Androgénicos/genética , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Nat Commun ; 12(1): 937, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568653

RESUMEN

The global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised. Here, using whole-genome and RNA sequencing from 854 tumors of more than 30 different types from the Children's Brain Tumor Tissue Consortium, we report the altered expression of hundreds of genes in association with the presence of nearby SSV breakpoints. SSV-mediated expression changes involve gene fusions, altered cis-regulation, or gene disruption. SSVs considerably extend the numbers of patients with tumors somatically altered for critical pathways, including receptor tyrosine kinases (KRAS, MET, EGFR, NF1), Rb pathway (CDK4), TERT, MYC family (MYC, MYCN, MYB), and HIPPO (NF2). Compared to initial tumors, progressive or recurrent tumors involve a distinct set of SSV-gene associations. High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes. Compared to adult cancers, pediatric brain tumors would involve a different set of genes with SSV-altered cis-regulation. Our comprehensive and pan-histology genomic analyses reveal SSVs to play a major role in shaping the transcriptome of pediatric brain tumors.


Asunto(s)
Neoplasias Encefálicas/genética , Reordenamiento Génico , Estudios de Cohortes , Regulación Neoplásica de la Expresión Génica , Genómica , Humanos , Mutación , Pediatría/estadística & datos numéricos , Análisis de Secuencia de ARN , Secuenciación del Exoma Completo
20.
Medicine (Baltimore) ; 100(6): e24458, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578538

RESUMEN

RATIONALE: The rare BRAF L597Q (c.T1790A) point mutation has been previously reported in childhood acute lymphoblastic leukemia. We present the first rare case of occult papillary thyroid carcinoma with BRAF L597Q mutation in a Tibetan patient. PATIENT CONCERNS: A 57-year-old male patient presented with a protruding mass on the left forehead for 2 years and numbness in the right limb for 3 weeks. DIAGNOSES: The patient had a double mutation of BRAF L597Q and V600E in 2 separate lesions at thyroid and brain, the immunohistochemical staining showed that the cytokeratin (CK), thyroglobulin (Tg) and thyroid transforming factor-1 (TTF-1) were immunoreactive. All the findings supported the diagnosis of solitary brain metastasis of occult papillary thyroid carcinoma. INTERVENTIONS: The patient underwent left frontal lobe metastasis (thyroid cancer) resection that involved craniectomy and artificial skull repair. OUTCOMES: During the 24-month follow-up, no postoperative complications or recurrence and metastasis were found. LESSONS: This is the first case of solitary brain metastasis of occult papillary thyroid carcinoma with double mutation of BRAF L597Q and V600E in 2 separate lesions reported in the literature. Our study extends the disease spectrum of occult papillary thyroid carcinoma and suggests that the BRAF L597Q mutation might play a specific role in inducing the solitary brain metastasis of occult papillary thyroid carcinoma in a Chinese Tibetan patient, but the detailed molecular mechanism remains to be confirmed by a large number of functional experiments and clinical research.


Asunto(s)
Neoplasias Encefálicas/secundario , Mutación Puntual/genética , Proteínas Proto-Oncogénicas B-raf/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Tomografía Computarizada por Rayos X
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