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1.
Int J Nanomedicine ; 16: 1805-1817, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33692623

RESUMEN

Introduction: RNA interference is a promising therapy in glioma treatment. However, the application of RNA interference has been limited in glioma therapy by RNA instability and the lack of tumor targeting. Here, we report a novel DNA tetrahedron, which can effectively deliver small interfering RNA to glioma cells and induce apoptosis. Methods: siRNA, a small interfering RNA that can suppress the expression of survivin in glioma, was loaded into the DNA tetrahedron (TDN). To enhance the ability of active targeting of this nanoparticle, we modified one side of the DNA nanostructure with aptamer as1411 (As-TDN-R), which can selectively recognize the nucleolin in the cytomembrane of tumor cells. The modified nanoparticles were characterized by agarose gel electrophoresis, dynamic light scattering, and transmission electron microscopy. The serum stability was evaluated by agarose gel electrophoresis. Nucleolin was detected by Western blot and immunofluorescence, and targeted cellular uptake was examined by flow cytometry. The TUNEL assay, flow cytometry, and Western Blot were used to detect apoptosis in U87 cells. The gene silencing of survivin was examined by qPCR, Western Blot, and immunofluorescence. Results: As-TDN-R alone showed better stability towards siRNA, indicating that TDN was a good siRNA protector. Compared with TDN alone, there was increased intercellular uptake of As-TDN-R by U87 cells, evidenced by overexpressed nucleolin in glioma cell lines. TUNEL assay, flow cytometry, and Western Blot revealed increased apoptosis in the As-TDN-R group. The downregulation of survivin protein and mRNA expression levels indicated that As-TDN-R effectively silenced the target gene. Conclusion: The novel nanoparticle can serve as a good carrier for targeting siRNA delivery in glioma. Further exploration of the DNA nanostructure can greatly promote the application of DNA-based drug systems in glioma.


Asunto(s)
ADN/química , Técnicas de Transferencia de Gen , Glioma/terapia , Nanoestructuras/química , ARN Interferente Pequeño/administración & dosificación , Apoptosis/efectos de los fármacos , Aptámeros de Nucleótidos/química , Muerte Celular , Línea Celular Tumoral , Supervivencia Celular , Regulación hacia Abajo , Endocitosis , Silenciador del Gen , Glioma/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Nanoestructuras/ultraestructura , Oligodesoxirribonucleótidos/química , Fosfoproteínas/metabolismo , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/metabolismo , Survivin/metabolismo
2.
Medicine (Baltimore) ; 100(10): e24850, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725839

RESUMEN

ABSTRACT: Factors associated with the prognosis of low-grade glioma remain undefined. In this study, we examined whether the maximal tumor diameter in the preoperative tumor magnetic resonance imaging (MRI) T2 image is associated with the prognosis of grade II gliomas patients, aiming to provide insights into the clinical prediction of patient outcome.We retrospectively analyzed the clinical data of patients with Grade II glioma, who were hospitalized in Xiangya Hospital, Central South University, from 2011 to 2016. Kaplan-Meier and Cox proportional hazards analyses were performed to determine the association between maximal tumor diameter and prognosis.A total of 90 patients with grade II glioma were included in this study. Mean patient age was 37.7 ±â€Š13.0 years, and 58.9% of them were male. Kaplan-Meier survival analysis of overall survival (overall survival [OS], P = .009) and event-free survival (EFS, P = .002) revealed statistically significant differences between the patients with lesion diameter <7 cm and those with lesion diameter ≥7 cm. The maximal tumor diameter in the preoperative tumor MRI T2 image was identified as a prognostic factor of OS (P = .013), while constituting an independent risk factor for EFS (P = .002) alongside elevated histological grade after recurrence (P = .006).The maximal tumor diameter in the preoperative tumor MRI T2 image independently predicts OS and EFS in patients with grade II glioma.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Glioma/diagnóstico por imagen , Glioma/patología , Imagen por Resonancia Magnética , Adulto , Neoplasias Encefálicas/cirugía , Femenino , Glioma/cirugía , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Periodo Preoperatorio , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos
3.
J Transl Med ; 19(1): 99, 2021 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-33676540

RESUMEN

BACKGROUND: Glioma, the most common primary brain tumor, account Preparing figures for 30 to 40% of all intracranial tumors. Herein, we aimed to study the effects of M2 macrophage-derived exosomal microRNAs (miRNAs) on glioma cells. METHODS: First, we identified seven differentially expressed miRNAs in infiltrating macrophages and detected the expression of these seven miRNAs in M2 macrophages. We then selected hsa-miR-15a-5p (miR-15a) and hsa-miR-92a-3p (miR-92a) for follow-up studies, and confirmed that miR-15a and miR-92a were under-expressed in M2 macrophage exosomes. Subsequently, we demonstrated that M2 macrophage-derived exosomes promoted migration and invasion of glioma cells, while exosomal miR-15a and miR-92a had the opposite effects on glioma cells. Next, we performed the target gene prediction in four databases and conducted target gene validation by qRT-PCR, western blot and dual luciferase reporter gene assays. RESULTS: The results revealed that miR-15a and miR-92a were bound to CCND1 and RAP1B, respectively. Western blot assays demonstrated that interference with the expression of CCND1 or RAP1B reduced the phosphorylation level of AKT and mTOR, indicating that both CCND1 and RAP1B can activate the PI3K/AKT/mTOR signaling pathway. CONCLUSION: Collectively, these findings indicate that M2 macrophage-derived exosomal miR-15a and miR-92a inhibit cell migration and invasion of glioma cells through PI3K/AKT/mTOR signaling pathway.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Exosomas/metabolismo , Glioma/metabolismo , Macrófagos/metabolismo , MicroARNs/metabolismo , Transducción de Señal , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Biología Computacional , Ciclina D1/metabolismo , Glioma/patología , Humanos , Microscopía Electrónica de Transmisión , Nanopartículas/química , Invasividad Neoplásica , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Células THP-1 , Serina-Treonina Quinasas TOR/metabolismo , Proteínas de Unión al GTP rap/metabolismo
4.
J Cancer Res Clin Oncol ; 147(4): 1007-1017, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33547950

RESUMEN

The TERT promoter (pTERT) mutations, C228T and C250T, play a significant role in malignant transformation by telomerase activation, oncogenesis and immortalisation of cells. C228T and C250T are emerging as important biomarkers in many cancers including glioblastoma multiforme (GBM), where the prevalence of these mutations is as high as 80%. Additionally, the rs2853669 single nucleotide polymorphism (SNP) may cooperate with these pTERT mutations in modulating progression and overall survival in GBM. Using liquid biopsies, pTERT mutations, C228T and C250T, and other clinically relevant biomarkers can be easily detected with high precision and sensitivity, facilitating longitudinal analysis throughout therapy and aid in cancer patient management.In this review, we explore the potential for pTERT mutation analysis, via liquid biopsy, for its potential use in personalised cancer therapy. We evaluate the relationship between pTERT mutations and other biomarkers as well as their potential clinical utility in early detection, prognostication, monitoring of cancer progress, with the main focus being on brain cancer.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Glioma/patología , Mutación , Telomerasa/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Humanos , Pronóstico
5.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33537802

RESUMEN

Paris saponin H (PSH) is a type of steroid saponin derived from Rhizoma Paridis (RP; the rhizome of Paris). In our previous studies, saponins from RP exerted antiglioma activity in vitro. However, the effects of PSH on glioma have not been elucidated. The aim of the present study was to evaluate the effects of PSH on U251 glioblastoma cells and elucidate the possible underlying mechanism. The cells were treated with PSH at various concentrations for 48 h, and the cell viability, invasion, apoptosis and cycle progression were assessed using specific assay kits. The activation of Akt, 44/42­mitogen­activated protein kinase (MAPK) and the expression levels of A1 adenosine receptor (ARA1) and ARA3 were assessed by western blotting. The results demonstrated that PSH inhibited cell viability, migration and invasion, and induced apoptosis. Treatment of U251 cells with PSH induced the upregulation of p21 and p27, and the downregulation cyclin D1 and S­phase kinase associated protein 2 protein expression levels, which induced cell cycle arrest at the G1 phase. The results also demonstrated that PSH inhibited the expression of ARA1, and the agonist of ARA1, 2­chloro­N6­cyclopentyladenosine, reversed the effects of PSH. Hypoxia induced increases in the ARA3, hypoxia­inducible factor­1α (HIF­1α) and vascular endothelial growth factor (VEGF) protein expression levels, which were associated with the activation of the Akt and P44/42 MAPK pathways. Compared with the hypoxia group, PSH inhibited the expression levels of ARA3, HIF­1α and VEGF, as well as the phosphorylation levels of Akt and 44/42 MAPK, and repressed HIF­1α transcriptional activity. Furthermore, the results demonstrated that PSH inhibited the expression of HIF­1α by inhibiting the phosphorylation of Akt and 44/42 MAPK mediated by ARA3. Taken together, these results suggested that PSH reduced U251 cell viability via the inhibition of ARA1 and ARA3 expression, and further inhibited Akt and 44/42 MAPK phosphorylation, induced apoptosis and cell cycle arrest.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A3/metabolismo , Saponinas/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fase G1/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
6.
Nat Commun ; 12(1): 1014, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33579922

RESUMEN

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy-independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.


Asunto(s)
Plasticidad de la Célula/fisiología , Glioma/metabolismo , Microambiente Tumoral/fisiología , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patología , Glioma/patología , Humanos , Ratones , Células Madre Neoplásicas , Pericitos/metabolismo , Receptor Notch1/genética
7.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33435537

RESUMEN

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood-brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.


Asunto(s)
Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioma/genética , Transducción de Señal/genética , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Terapia Combinada , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Glioblastoma/terapia , Glioma/metabolismo , Glioma/patología , Glioma/terapia , Humanos , Transducción de Señal/efectos de los fármacos , Temozolomida/uso terapéutico
8.
Cell Prolif ; 54(3): e12988, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33442944

RESUMEN

OBJECTIVES: Circadian rhythm controls complicated physiological activities in organisms. Circadian clock genes have been related to tumour progression, but its role in glioma is unknown. Therefore, we explored the relationship between dysregulated circadian clock genes and glioma progression. MATERIALS AND METHODS: Samples were divided into different groups based on circadian clock gene expression in training dataset (n = 672) and we verified the results in other four validating datasets (n = 1570). The GO and GSEA enrichment analysis were conducted to explore potential mechanism of how circadian clock genes affected glioma progression. The single-cell RNA-Seq analysis was conducted to verified previous results. The immune landscape was evaluated by the ssGSEA and CIBERSORT algorithm. Cell proliferation and viability were confirmed by the CCK8 assay, colony-forming assay and flow cytometry. RESULTS: The cluster and risk model based on circadian clock gene expression can predict survival outcome. Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome. Samples in high-risk group manifested higher activation of immune pathway and cell cycle. Tumour immune landscape suggested high-risk tumour infiltrated more immunocytes and more sensitivity to immunotherapy. Interfering TIMELESS expression affected circadian clock gene expression, inhibited tumour cell proliferation and arrested cell cycle at the G0/G1 phase. CONCLUSIONS: Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle. The risk model can predict glioma survival outcome, and this model can also be applied to pan-cancer.


Asunto(s)
Proliferación Celular/fisiología , Relojes Circadianos/genética , Ritmo Circadiano/fisiología , Glioma/patología , Ciclo Celular/fisiología , Progresión de la Enfermedad , Glioma/mortalidad , Humanos
9.
Nat Commun ; 12(1): 92, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397920

RESUMEN

Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique 1H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-13C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-13C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.


Asunto(s)
Neoplasias Encefálicas/genética , Homeostasis del Telómero , Telómero/metabolismo , Alanina/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Isótopos de Carbono/metabolismo , Línea Celular Tumoral , Ingeniería Genética , Glioma/genética , Glioma/metabolismo , Glioma/patología , Ácido Láctico/metabolismo , Masculino , Metaboloma , Modelos Biológicos , Clasificación del Tumor , Proteínas de Neoplasias/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Ácido Pirúvico/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Desnudas , Telomerasa/genética , Telomerasa/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Gene ; 776: 145445, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33484758

RESUMEN

Glioblastom Multiforme (GBM) is the most invasive and malignant member of the IV grade of the subclass Astrocytoma according to the last assessment of the 2016 WHO report. Due to the resistance to treatment and weak response, as well as the topographical structure of the blood brain barrier, the treatment is also difficult due to the severe clinical manifestation, and new treatment methods and new therapeutic agents are needed. Temozolomide (TMZ) is widely used in the treatment of glioblastoma and is considered as the primary treatment modality. TMZ, a member of the class of cognitive agents, is currently considered the most effective drug because it can easily pass through the blood brain barrier. Glucose metabolism is a complex energy producing machine that, a glucose molecule produces 38 molecules of ATP after full glycolytic catabolism. According to Otto Warburg's numerous studies cancer cells perform the first glycolytic step without entering the mitochondrial step. These cells produce lactic acid and make the micro-media more acidic even in aerobic conditions. This phenomenon is attributed to the Warburg hypothesis and either as aerobic glycolysis. Although glycolysis enzymes are the primary actors of this phenotypic expression, some genetic and epigenetic factors are no exception. We experimentally used KC7F2 active ingredient to target cancer metabolism. In our study, we evaluated cancer metabolism in combination with the effect of TMZ chemotherapeutic agent, examining the effect of two different agents separately and in combination to observe the effects of cancer cell proliferation, survival, apoptosis and expression of metabolism genes on expression. We observed that the combined effect of reduced the effective dose of the TMZ alkylating agent and that the effect was increased and the effect of the combined teraphy is assessed from a metabolic point of view and that it suppresses aerobic glycolysis.


Asunto(s)
Disulfuros/farmacología , Glioma/tratamiento farmacológico , Sulfonamidas/farmacología , Temozolomida/farmacología , Antineoplásicos/farmacología , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Disulfuros/metabolismo , Resistencia a Antineoplásicos/genética , Glioblastoma/patología , Glioma/patología , Glucosa/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Sulfonamidas/metabolismo , Temozolomida/metabolismo
11.
Anticancer Res ; 41(2): 619-633, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517266

RESUMEN

BACKGROUND/AIM: The outlook for patients with high grade glioma (HGG) remains dismal. Hence, attention has focused on numerous innovative treatments. Our group has proposed a strategy on the use of a combination of polyphenols, as anti-invasive agents for the management of these neoplasms. MATERIALS AND METHODS: The aim of this study was to evaluate the in vitro effects of citrus flavonoids (tangeretin, nobiletin, naringin and limonin) and berry extracts (chokeberry, elderberry and bilberry) on selected mediators of invasion in 2 HGG cell cultures. RESULTS: The IC50 values could only be determined for tangeretin and chokeberry extract. The rest were non-functional in this context. Immunocytochemistry and flow cytometry results showed that chokeberry extract was most effective in down-regulating the expression of CD44. Similarly, RT-PCR data supported its ability to reduce gene expression of MMP-14 and EGFR. 2D invasion assays confirmed that inhibition is greater with chokeberry extract. CONCLUSION: Both polyphenols have anti-invasive potential but chokeberry extract is a stronger agent for glioma management.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Frutas , Glioma/tratamiento farmacológico , Extractos Vegetales/farmacología , Polifenoles/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Citrus , Receptores ErbB/genética , Receptores ErbB/metabolismo , Frutas/química , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Invasividad Neoplásica , Extractos Vegetales/aislamiento & purificación , Polifenoles/aislamiento & purificación , Prunus , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Vaccinium myrtillus
12.
J Comput Assist Tomogr ; 45(1): 110-120, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33475317

RESUMEN

OBJECTIVE: To investigate the value of radiomics analyses based on different magnetic resonance (MR) sequences in the noninvasive evaluation of glioma characteristics for the differentiation of low-grade glioma versus high-grade glioma, isocitrate dehydrogenase (IDH)1 mutation versus IDH1 wild-type, and mutation status and 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (+) versus MGMT promoter methylation (-) glioma. METHODS: Fifty-nine patients with untreated glioma who underwent a standard 3T-MR tumor protocol were included in the study. A total of 396 radiomics features were extracted from the MR images, with the manually delineated tumor as the volume of interest. Clinical imaging diagnostic features (tumor location, necrosis/cyst change, crossing midline, and the degree of enhancement or peritumoral edema) were analyzed by univariate logistic regression to select independent clinical factors. Radiomics and combined clinical-radiomics models were established for grading and molecular genomic typing of glioma by multiple logistic regression and cross-validation. The performance of the models based on different sequences was evaluated by using receiver operating characteristic curves, nomograms, and decision curves. RESULTS: The radiomics model based on T1-CE performed better than models based on other sequences in predicting the tumor grade and the IDH1 status of the glioma. The radiomics model based on T2 performed better than models based on other sequences in predicting the MGMT methylation status of glioma. Only the T1 combined clinical-radiomics model showed improved prediction performance in predicting tumor grade and the IDH1 status. CONCLUSIONS: The results demonstrate that state-of-the-art radiomics analysis methods based on multiparametric MR image data and radiomics features can significantly contribute to pretreatment glioma grading and molecular subtype classification.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioma/diagnóstico por imagen , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética/métodos , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Niño , Metilación de ADN , Femenino , Glioma/genética , Glioma/patología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Regiones Promotoras Genéticas , Adulto Joven
13.
Int J Mol Sci ; 22(2)2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33430434

RESUMEN

Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.


Asunto(s)
Proliferación Celular/genética , Cromatina/genética , Epigénesis Genética , Glioma/genética , Diferenciación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Glioma/patología , Proteínas Hedgehog/genética , Histonas/genética , Humanos , Regiones Promotoras Genéticas/genética
14.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33498463

RESUMEN

DNA methylation is an epigenetic change to the genome that impacts gene activities without modification to the DNA sequence. Alteration in the methylation pattern is a naturally occurring event throughout the human life cycle which may result in the development of diseases such as cancer. In this study, we analyzed methylation data from The Cancer Genome Atlas, under the Lower-Grade Glioma (LGG) and Glioblastoma Multiforme (GBM) projects, to identify methylation markers that exhibit unique changes in DNA methylation pattern along with tumor grade progression, to predict patient survival. We found ten glioma grade-associated Cytosine-phosphate-Guanine (CpG) sites that targeted four genes (SMOC1, KCNA4, SLC25A21, and UPP1) and the methylation pattern is strongly associated with glioma specific molecular alterations, primarily isocitrate dehydrogenase (IDH) mutation and chromosome 1p/19q codeletion. The ten CpG sites collectively distinguished a cohort of diffuse glioma patients with remarkably poor survival probability. Our study highlights genes (KCNA4 and SLC25A21) that were not previously associated with gliomas to have contributed to the poorer patient outcome. These CpG sites can aid glioma tumor progression monitoring and serve as prognostic markers to identify patients diagnosed with less aggressive and malignant gliomas that exhibit similar survival probability to GBM patients.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Metilación de ADN , Glioma/genética , Neoplasias Encefálicas/patología , Transportadores de Ácidos Dicarboxílicos/genética , Glioma/patología , Humanos , Canal de Potasio Kv1.4/genética , Persona de Mediana Edad , Proteínas de Transporte de Membrana Mitocondrial/genética , Osteonectina/genética , Pronóstico , Uridina Fosforilasa/genética
15.
J Comput Assist Tomogr ; 45(2): 300-307, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33512852

RESUMEN

OBJECTIVES: The Cancer Genome Atlas Research Network identified 4 novel protein expression-defined subgroups in patients with lower-grade gliomas (LGGs). The RPPA3 subtype had high levels of Epidermal Growth Factor Receptor and Human epidermal growth factor receptor-2, further increasing the chances for targeted therapy. In this study, we aimed to explore the relationships between magnetic resonance features and reverse phase protein array (RPPA) subtypes (R1-R4). METHODS: Survival estimates for the Cancer Genome Atlas cohort were generated using the Kaplan-Meier method and time-dependent receiver operating characteristic curves. A total of 153 patients with LGG with brain magnetic resonance imaging from The Cancer Imaging Archive were retrospectively analyzed. Least absolute shrinkage and selection operator algorithm was used to reduce the feature dimensions of the RPPA3 subtype. RESULTS: A total of 51 (33.3%) RPPA1 subtype, 42 (27.4) RPPA2 subtype, 19 (12.4%) RPPA3 subtype, and 38 (24.8%) RPPA4 subtype were identified. On multivariate logistic regression analysis, subventricular zone involvement [odds ratio (OR), 0.370; P = 0.006; 95% confidence interval (CI), 0.181-0.757) was associated with RPPA1 subtype [area under the curve (AUC), 0.598]. Volume of 60 cm3 or greater (OR, 5.174; P < 0.001; 95% CI, 2.182-12.267) was associated with RPPA2 subtype (AUC, 0.684). Proportion contrast-enhanced tumor greater than 5% (OR, 4.722; P = 0.010; 95% CI, 1.456-15.317), extranodular growth (OR, 5.524; P = 0.010; 95% CI, 1.509-20.215), and L/CS ratio equal to or greater than median (OR, 0.132; P = 0.003; 95% CI, 0.035-0.500) were associated with RPPA3 subtype (AUC, 0.825). Proportion contrast-enhanced tumor greater than 5% (OR, 0.206; P = 0.005; 95% CI, 0.068-0.625) was associated with RPPA4 subtype (AUC, 0.638). For the prediction of RPPA3 subtype, the nomogram showed good discrimination, with an AUC of 0.825 (95% CI, 0.711-0.939) and was well calibrated. The RPPA3 subtype was associated with shortest mean overall survival (RPPA3 subtype vs other: 613 vs 873 days; P < 0.05). The time-dependent receiver operating characteristic curves for the RPPA3 subtype was 0.72 (95% CI, 0.60-0.84) for survival at 1 year. Decision curve analysis indicated that prediction for the RPPA3 model was clinically useful. CONCLUSIONS: The RPPA3 subtype is an unfavorable prognostic biomarker for overall survival in patients with LGG. Radiogenomics analysis of magnetic resonance features can predict the RPPA subtype preoperatively and may be of clinical value in tailoring the management strategies in patients with LGG.


Asunto(s)
Neoplasias Encefálicas , Glioma , Imagen por Resonancia Magnética , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Femenino , Glioma/clasificación , Glioma/diagnóstico por imagen , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos
16.
Br J Radiol ; 94(1119): 20200699, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33332981

RESUMEN

OBJECTIVE: To evaluate the effect of artery input function (AIF) derived from different arteries for pharmacokinetic modeling on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters in the grading of gliomas. METHODS: 49 patients with pathologically confirmed gliomas were recruited and underwent DCE-MRI. A modified Tofts model with different AIFs derived from anterior cerebral artery (ACA), ipsilateral and contralateral middle cerebral artery (MCA) and posterior cerebral artery (PCA) was used to estimate quantitative parameters such as Ktrans (volume transfer constant) and Ve (fractional extracellular-extravascular space volume) for distinguishing the low grade glioma from high grade glioma. The Ktrans and Ve were compared between different arteries using Two Related Samples Tests (TRST) (i.e. Wilcoxon Signed Ranks Test). In addition, these parameters were compared between the low and high grades as well as between the grade II and III using the Mann-Whitney U-test. A p-value of less than 0.05 was regarded as statistically significant. RESULTS: All the patients completed the DCE-MRI successfully. Sharp wash-in and wash-out phases were observed in all AIFs derived from the different arteries. The quantitative parameters (Ktrans and Ve) calculated from PCA were significant higher than those from ACA and MCA for low and high grades, respectively (p < 0.05). Despite the differences of quantitative parameters derived from ACA, MCA and PCA, the Ktrans and Ve from any AIFs could distinguish between low and high grade, however, only Ktrans from any AIFs could distinguish grades II and III. There was no significant correlation between parameters and the distance from the artery, which the AIF was extracted, to the tumor. CONCLUSION: Both quantitative parameters Ktrans and Ve calculated using any AIF of ACA, MCA, and PCA can be used for distinguishing the low- from high-grade gliomas, however, only Ktrans can distinguish grades II and III. ADVANCES IN KNOWLEDGE: We sought to assess the effect of AIF on DCE-MRI for determining grades of gliomas. Both quantitative parameters Ktrans and Ve calculated using any AIF of ACA, MCA, and PCA can be used for distinguishing the low- from high-grade gliomas.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Medios de Contraste/farmacocinética , Glioma/diagnóstico por imagen , Glioma/patología , Aumento de la Imagen/métodos , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Arterias/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Reproducibilidad de los Resultados , Adulto Joven
17.
J Clin Neurosci ; 83: 56-63, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33334663

RESUMEN

In order to assess combined application of MRS and DWI for prediction cell proliferation and grade diagnosis of glioma, We prospectively collected the Cho/Cr, Cho/NAA, Cr/NAA of MRS and tumor parenchyma ADC (ADCT), contralateral mirror brain tissue ADC (ADCH), rADC (rADC = ADCT/ADCH). According to postoperative pathology, the patients were divided into two groups: LGG group and HGG group, compared differences of age, gender, Ki67, MRS, DWI between two groups. Next, we analyzed the correlation between MRS, DWI and Ki67. On this basis, the sensitivity and specificity of MRS, DWI and MRS combined with DWI (MRS + DWI) in diagnosis of glioma grade were evaluated. The differences of Ki67, Cho/Cr, Cho/NAA, Cr/NAA, ADCT, rADC between LGG group and HGG group were statistically significant (p = 0.000, 0.000, 0.000, 0.008, 0.000, and 0.000 respectively). From ROC curve, area under the curve (AUC), sensitivity and specificity of Cho/Cr, Cho/NAA, Cr/NAA, ADCT, rADC, PRE (MRS + DWI) were (0.901, 86.7%, 85.7%), (0.876, 80.0%, 82.1%), (0.704, 63.3%, 71.4%), (0.862, 82.1%, 83.3%), (0.820, 75.0%, 76.7%), (0.920, 86.7%, 89.3%), respectively. Fisher's linear discriminant functions results suggest: Y1 = -20.447 + 3.46•X1 + 17.141•X2 (LGG), Y2 = -19.415 + 4.828•X1 + 14.543•X2 (HGG). Our study suggested that MRS and DWI can effectively predict cell proliferation preoperative. MRS combined with DWI can further improve sensitivity and specificity in assessing the grade of glioma.


Asunto(s)
Neoplasias Encefálicas/diagnóstico , Proliferación Celular , Glioma/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Encéfalo/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Femenino , Glioma/diagnóstico por imagen , Glioma/patología , Humanos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Sensibilidad y Especificidad , Adulto Joven
18.
Neurology ; 96(7): e1063-e1069, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33361259

RESUMEN

OBJECTIVE: To determine the incidence of venous thromboembolism (VTE) in lower-grade gliomas (LGGs, WHO grades II-III) and to stratify the risk of VTE by molecular subtype in gliomas grade II-IV, we performed a retrospective review of a large cohort of patients with glioma. METHODS: We performed a retrospective analysis of a cohort of 635 adult patients with glioma with molecular testing seen at the University of Virginia with a diagnosis of diffuse glioma established from January 2005 to August 2017. Estimates of cumulative incidence of VTE were calculated with death as competing risk; significance was determined using the Fine and Gray model. RESULTS: Of 256 patients with LGG, 81 were isocitrate dehydrogenase (IDH) wild-type; 113 IDH mutant, 1p/19q codeleted; and 62 IDH mutant, 1p/19q intact. With a median follow-up of 17.9 months, the overall cumulative incidence of VTE was 8.2% for grade II (147 patients), 9.2% for grade III (109 patients), and 30.5% for grade IV (334 patients). In grade II-IV patients, absence of an IDH mutation was associated with a threefold increase in VTE risk when compared to IDH-mutant patients (hazard ratio 3.06, 95% confidence interval 2.03-4.64). In patients with glioblastoma, there was no difference in VTE incidence according to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. CONCLUSION: Patients with LGG have a higher VTE risk compared to the general population, which is decreased, but not eliminated, in the presence of an IDH mutation. MGMT promoter methylation in glioblastoma does not affect the incidence of VTE.


Asunto(s)
Neoplasias Encefálicas/complicaciones , Glioma/complicaciones , Isocitrato Deshidrogenasa/genética , Tromboembolia Venosa/epidemiología , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Femenino , Glioma/genética , Glioma/patología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Regiones Promotoras Genéticas , Estudios Retrospectivos , Riesgo , Tromboembolia Venosa/etiología , Tromboembolia Venosa/genética
19.
Biomed Pharmacother ; 133: 111058, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378970

RESUMEN

Glioblastoma Multiforme (GBM) tumors contain a small population of glioma stem-like cells (GSCs) among the various differentiated GBM cells (d-GCs). GSCs drive tumor recurrence, and resistance to Temozolomide (TMZ), the standard of care (SoC) for GBM chemotherapy. In order to investigate a potential link between GSC specific mitochondria function and SoC resistance, two patient-derived GSC lines were evaluated for differences in their mitochondrial metabolism. In both the lines, GSCs had significantly lower mitochondrial -content, and -function compared to d-GCs. In vitro, the standard mitochondrial-specific inhibitors oligomycin A, antimycin A, and rotenone selectively inhibited GSC proliferation to a greater extent than d-GCs and human primary astrocytes. These findings indicate that mitochondrial inhibition can be a potential GSC-targeted therapeutic strategy in GBM with minimal off-target toxicity. Mechanistically the standard mitochondrial inhibitors elicit their GSC-selective cytotoxic effects through the induction of apoptosis or autophagy pathways. We tested for GSC proliferation in the presence of 3 safe FDA-approved drugs--trifluoperazine, mitoxantrone, and pyrvinium pamoate, all of which are also known mitochondrial-targeting agents. The SoC GBM therapeutic TMZ did not trigger cytotoxicity in glioma stem cells, even at 100 µM concentration. By contrast, trifluoperazine, mitoxantrone, and pyrvinium pamoate exerted antiproliferative effects in GSCs about 30-50 fold more effectively than temozolomide. Thus, we hereby demonstrate that FDA-approved mitochondrial inhibitors induce GSC-selective cytotoxicity, and targeting mitochondrial function could present a potential therapeutic option for GBM treatment.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Reposicionamiento de Medicamentos , Glioma/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal , Células Tumorales Cultivadas
20.
Int J Mol Sci ; 22(1)2020 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-33375505

RESUMEN

For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Microglía/citología , Microglía/metabolismo , Animales , Neoplasias Encefálicas/patología , Progresión de la Enfermedad , Glioblastoma/inmunología , Glioblastoma/patología , Glioma/inmunología , Glioma/metabolismo , Glioma/patología , Humanos , Antígenos Comunes de Leucocito/metabolismo , Células Mieloides/citología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Microambiente Tumoral
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