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1.
Anticancer Res ; 39(11): 5983-5990, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704823

RESUMO

BACKGROUND/AIM: DJ-1, an oncogenic molecule, helps to maintain somatic stem cells by reducing the intracellular level of reactive oxygen species (ROS). This study investigated the role of DJ-1 in glioma stem cells (GSCs). MATERIALS AND METHODS: U87-MG (U87) and U251-MG (U251) glioblastoma cell lines that express wild-type and mutant p53, respectively, were used. These were cultured with DJ-1-targeting siRNA and subjected to a variety of in vitro experiments or intracranial transplantation into nude mice. RESULTS: Knockdown of DJ-1 reduced clonogenicity only in U87 cells, which was rescued by p53 depletion. ROS accumulated in DJ-1-depleted cells, although treatment with N-acetyl cysteine, which quenches ROS, did not affect exhaustion of CSCs among U87 cells by DJ-1 knockdown. In a serial transplantation study, DJ-1 knockdown prolonged the survival of mice in secondary transplantation. CONCLUSION: DJ-1 plays a pivotal role in maintenance of stem cell self-renewal in the U87 cell line.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Autorrenovação Celular , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Proteína Desglicase DJ-1/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Proteína Desglicase DJ-1/antagonistas & inibidores , Proteína Desglicase DJ-1/genética , RNA Interferente Pequeno/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 39(11): 6007-6014, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704826

RESUMO

BACKGROUND/AIM: The histone demethylase NO66 regulates gene and protein expression. Epidermal growth factor receptor (EGFR) is a key oncogenic factor for glioblastoma. This study aimed to examine the role of NO66 in glioblastoma. MATERIALS AND METHODS: The prognostic value of NO66 expression in 263 human glioma tissues and 510 glioblastoma tissues was examined by Kaplan and Meier survival analysis. Immunoblot analysis of EGFR expression, cell proliferation assays and cell cycle analysis were performed in glioblastoma cells after NO66 knockdown. RESULTS: In 263 human glioma tissues, high levels of NO66 expression correlated with advanced disease stage and poor patient prognosis. In 510 glioblastoma tissues, high levels of NO66 expression also predicted poor patient prognosis. NO66 knockdown reduced EGFR expression and cell proliferation in glioblastoma cells. CONCLUSION: High levels of NO66 in glioma and glioblastoma tissues predict poor patient prognosis, and NO66 is required for EGFR expression and glioblastoma cell proliferation.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células , Dioxigenases/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Histona Desmetilases/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Dioxigenases/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Seguimentos , Glioma/genética , Glioma/metabolismo , Histona Desmetilases/genética , Humanos , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
3.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 817-822, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750824

RESUMO

Objective To investigate the role of RAD51 in cell proliferation, migration and chemosensitivity to temozolomide (TMZ) using U251 glioma cell line, and to clarify the underlying molecular mechanism. Methods TCGA database was utilized to analyze the expression changes of RAD51 in gliomas. RAD51 was over-expressed or knocked down in U251 glioma cells via lentivirus infection, or its activity was inhibited by small molecule inhibitors. Cell proliferation and migration ability were examined by CCK-8 assay, colony formation assay, and scratch wound-healing assay; CCK-8 assay and flow cytometry were performed to assess the effect of RAD51 on the sensitivity of glioma cells upon the treatment of temozolomide. Western blotting was used to determine the alteration of P53. Results The expression of RAD51 significantly increased in glioma tissues. RAD51 enhanced the proliferation and migration ability of U251 glioma cells; knockdown of RAD51 enhanced the sensitivity of U251 glioma cells to temozolomide. Over-expression of RAD51 increased the expression of P53, whereas knockdown of RAD51 decreased the expression of P53. Conclusion RAD51 plays an oncogene function in glioma cells. RAD51 over-expression enhances the proliferation and migration of glioma cells. RAD51 knockdown increases the sensitivity of glioma cells to temozolomide.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular , Proliferação de Células , Glioblastoma/patologia , Rad51 Recombinase/metabolismo , Temozolomida/farmacologia , Apoptose , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos
4.
Medicine (Baltimore) ; 98(45): e17583, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702614

RESUMO

BACKGROUND: Long noncoding RNA paternally expressed 10 (lncRNA PEG10) is highly expressed in a variety of human cancers and related to the clinical prognosis of patients. However, to date there has been no previous study evaluating the prognostic significance of lncRNA PEG10 in gliomas. In the present study, we investigated the expression levels of lncRNA PEG10 to determine the prognostic value of this oncogene in human gliomas. METHODS: Expression levels of lncRNA PEG10 were detected by real-time polymerase chain reaction in a hospital-based study cohort of 147 glioma patients and 23 cases of patients with craniocerebral trauma tissues. Associations of lncRNA PEG10 expression with clinicopathological variables and clinical outcome of glioma patients were investigated. RESULTS: The results indicated that expression levels of lncRNA PEG10 were significantly increased in human gliomas compared to normal control brain tissues. In addition, lncRNA PEG10 expression was progressively increased from pathologic grade I to IV (P = .009) and correlated with the Karnofsky performance status (P = .018) in glioma patients. Furthermore, we also found that glioma patients with increased expression of lncRNA PEG10 had a higher risk to relapse and a statistically significant shorter overall survival (OS) than patients with reduced expression of lncRNA PEG10. In multivariate analysis, expression level of lncRNA PEG10 was found to be an independent prognostic factor for both progression-free survival and OS in glioma patients. CONCLUSIONS: LncRNA PEG10 served as an oncogene and played crucial roles in the progression of glioma. Molecular therapy targeted on lncRNA PEG10 might bring significant benefits to the clinical outcome of malignant glioma.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , RNA Longo não Codificante/genética , Regulação para Cima , Adulto , Idoso , Neoplasias Encefálicas/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Análise de Sobrevida , Adulto Jovem
5.
J Photochem Photobiol B ; 201: 111640, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734545

RESUMO

Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase and heme oxygenase-1 and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).


Assuntos
Corantes Fluorescentes/química , Microscopia Confocal , Protoporfirinas/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Ácido Aminolevulínico/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Corantes Fluorescentes/metabolismo , Genisteína/metabolismo , Genisteína/farmacologia , Glioblastoma/patologia , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/metabolismo , Humanos , Metaloporfirinas/química , Metaloporfirinas/metabolismo , Metaloporfirinas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Protoporfirinas/metabolismo , Protoporfirinas/farmacologia
6.
Anticancer Res ; 39(10): 5733-5739, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570475

RESUMO

BACKGROUND/AIM: To analyze patterns of care and overall survival for elderly patients with malignant brain tumors. MATERIALS AND METHODS: The database from the National Health Insurance Service was searched January 2008-December 2016. A total of 1,607 patients aged 65-year-old or more with malignant brain tumors who underwent surgery or biopsy were extracted. Treatment performed in 180 days after surgery was divided into no treatment (N=522), radiotherapy (RT) (N=351), chemotherapy (N=69), and chemotherapy plus RT (N=665). Survival was recorded at 3, 6, 9, 12, 18, and 24 months after surgery. RESULTS: Patients were divided into groups by age: 65-69, 70-74, 75-79, and ≥80 years. Chemotherapy plus RT was most commonly used in all age groups except those aged 80 years and more. Treatment modality after surgery or biopsy was significantly prognostic (p<0.001) in univariate analysis. CONCLUSION: Adjuvant treatment can be recommended for elderly patients with malignant brain tumors based on data from the National Health Insurance Service.


Assuntos
Neoplasias Encefálicas/terapia , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Quimioterapia Adjuvante/métodos , Bases de Dados Factuais , Feminino , Humanos , Masculino , Programas Nacionais de Saúde , Prognóstico , Radioterapia Adjuvante/métodos , República da Coreia
7.
Radiol Clin North Am ; 57(6): 1199-1216, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582045

RESUMO

Radiographic monitoring of posttreatment glioblastoma is important for clinical trials and determining next steps in management. Evaluation for tumor progression is confounded by the presence of treatment-related radiographic changes, making a definitive determination less straight-forward. The purpose of this article was to describe imaging tools available for assessing treatment response in glioblastoma, as well as to highlight the definitions, pathophysiology, and imaging features typical of true progression, pseudoprogression, pseudoresponse, and radiation necrosis.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Diagnóstico por Imagem/métodos , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Lesões por Radiação/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Progressão da Doença , Glioblastoma/patologia , Humanos , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Imagem Multimodal , Necrose , Tomografia por Emissão de Pósitrons , Lesões por Radiação/patologia
8.
Life Sci ; 236: 116917, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614149

RESUMO

AIMS: To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM. MAIN METHODS: A genome-wide hierarchical bi-clustering based on previously published microarray databases identified Nuclear Factor I A (NFIA) as one of the most significantly upregulated genes correlated to TMZ resistance in GBM. Then, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, Western blotting and in vivo xenograft models with artificially induced TMZ-resistant U87 cells. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of NFIA in glioma patients. Last, luciferase reporter assay was performed to study the transcriptional regulation of NFIA on the nuclear factor κb (NF-kB) pathway. KEY FINDINGS: NFIA was correlated with TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated with adverse outcomes of glioma patients, especially in GBM patients. Moreover, NFIA contributed to the acquired TMZ resistance of GBM cells, while suppression of NFIA via lentivirus reduced cell proliferation, tumorigenesis and resistance to TMZ of GBM. Additionally, NFIA promoted transcription activity that regulated the expression of NF-kB. Last, NFIA induced phosphorylation of NF-kB p65 at serine 536, thus inducing TMZ resistance in GBM cells. Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to acquired TMZ resistance in GBM. SIGNIFICANCE: Abnormally activated NFIA-NF-kB signaling was strongly correlated with acquired TMZ resistance and poor prognosis in GBM, and it could be a new therapeutic target for TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , NF-kappa B/metabolismo , Fatores de Transcrição NFI/metabolismo , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Nus , NF-kappa B/genética , Fatores de Transcrição NFI/genética , Prognóstico , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Nanomedicine ; 14: 5925-5942, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534331

RESUMO

Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood-brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.


Assuntos
Neoplasias Encefálicas/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Nanotecnologia/métodos , Regeneração Nervosa , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Humanos , Tropismo
10.
Adv Exp Med Biol ; 1167: 207-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31520357

RESUMO

Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Genomic amplifications, activating mutations, and overexpression of receptor tyrosine kinases (RTKs) such as EGFR, and genes in core RTK signaling transduction pathways such as PI3K are common in GBM. However, efforts to target these pathways have been largely unsuccessful in the clinic, and the median survival of GBM patients remains poor at 14-15 months. Therefore, to improve patient outcomes, there must be a concerted effort to elucidate the underlying biology involved in GBM tumorigenesis. Drosophila melanogaster has been a highly effective model for furthering our understanding of GBM tumorigenesis due to a number of experimental advantages it has over traditional mouse models. For example, there exists extensive cellular and genetic homology between humans and Drosophila, and 75% of genes associated with human disease have functional fly orthologs. To take advantage of these traits, we developed a Drosophila GBM model with constitutively active variants of EGFR and PI3K that effectively recapitulated key aspects of GBM disease. Researchers have utilized this model in forward genetic screens and have expanded on its functionality to make a number of important discoveries regarding requirements for key components in GBM tumorigenesis, including genes and pathways involved in extracellular matrix signaling, glycolytic metabolism, invasion/migration, stem cell fate and differentiation, and asymmetric cell division. Drosophila will continue to reveal novel biological pathways and mechanisms involved in gliomagenesis, and this knowledge may contribute to the development of effective treatment strategies to improve patient outcomes.


Assuntos
Neoplasias Encefálicas/patologia , Drosophila melanogaster , Glioblastoma/patologia , Adulto , Animais , Transformação Celular Neoplásica , Modelos Animais de Doenças , Humanos , Camundongos , Transdução de Sinais
11.
Cancer Radiother ; 23(6-7): 708-715, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31477442

RESUMO

Stereotactic radiation therapy of brain metastases is a treatment recognized as effective, well tolerated, applicable for therapeutic indications codified and validated by national and international guidelines. However, the effectiveness of this irradiation, the evolution of patient care and the technical improvements enabling its implementation make it possible to consider it in more complex situations: proximity of brain metastases to organs at risk; large, cystic, haemorrhagic or multiple brain metastases, combination with targeted therapies and immunotherapy, stereotactic radiotherapy in patients with a pacemaker. This article aims to put forward the arguments available to date in the literature and those resulting from clinical practice to provide decision support for the radiation oncologists.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Irradiação Craniana/métodos , Órgãos em Risco , Radiocirurgia/métodos , Neoplasias Encefálicas/patologia , Tronco Encefálico , Hemorragia Cerebral/complicações , Terapia Combinada/métodos , Contraindicações de Procedimentos , Humanos , Imunoterapia , Imagem por Ressonância Magnética/efeitos adversos , Terapia de Alvo Molecular , Nervo Óptico , Marca-Passo Artificial , Carga Tumoral
12.
Bratisl Lek Listy ; 120(9): 650-657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475548

RESUMO

In this contribution we present graph theoretical approach to image processing focus on biological data. We use the graph cut algorithms and extend them for obtaining segmentation of biological data. We deal with tumor brain cells and rats brain to show the existence and presence of inflammatory molecules. We introduce a completely new method for filtering of data (Tab. 3, Schema 4, Fig. 7, Ref. 13). Keywords: graph cuts, segmentation, tumore analyses of cells, computer morphometry.


Assuntos
Algoritmos , Neoplasias Encefálicas/patologia , Processamento de Imagem Assistida por Computador , Modelos Teóricos , Animais , Encéfalo/citologia , Ratos
13.
J Cancer Res Clin Oncol ; 145(12): 3099-3104, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31549227

RESUMO

BACKGROUND: The American Society of Clinical Oncology and Friends of Cancer Research submitted recommendations to the FDA to reduce barriers in clinical trial participation. They proposed the removal of several specific exclusion criteria, including brain metastasis. Clinical trials involving small cell lung cancer (SCLC) have varying exclusion criteria regarding brain metastasis. METHODS: We completed an online search of clinicaltrials.gov for the query "SCLC, extensive stage." The trials were classified into a group of strict exclusion, allowed only if treated, allowed without treatment, or undefined. Relationships between status of brain metastasis in exclusion criteria and study characteristics (trial status, trial design, sponsor, location, and treatment groups) were investigated by Chi-squared test. The trends of exclusion status were investigated by a comparison against the variable time. RESULTS: Of the 204 eligible trials, 32 strictly excluded any form or history of CNS metastases, 129 allowed patients that are undergoing or have undergone CNS-specific therapy, 9 allowed patients without any CNS-specific therapy, and 34 did not mention any criteria involving CNS metastases. Studies conducted outside the United States and with single systemic therapy were associated with strict exclusion of brain metastasis (p = 0.026 and 0.039, respectively). The proportion of clinical trials with strict exclusion has remained around 15% for the past few decades. CONCLUSION: Non-US and single systemic therapy studies are more commonly associated with strict exclusion of brain metastasis in ES-SCLC trials. The strict exclusion of brain metastases in clinical trials has remained relatively constant for the past few decades.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Animais , Neoplasias Encefálicas/secundário , Ensaios Clínicos como Assunto , Humanos , Estados Unidos
14.
Cancer Sci ; 110(11): 3486-3496, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483918

RESUMO

Bone morphogenetic protein (BMP) signaling plays important roles in glioblastoma multiforme (GBM), a lethal form of brain tumor. BMP reduces GBM tumorigenicity through its differentiation- and apoptosis-inducing effects on glioma-initiating cells (GIC). However, some GIC do not respond to the tumor suppressive effects of BMP. Using a phosphoreceptor tyrosine kinase array, we found that EPHA6 (erythropoietin-producing hepatocellular carcinoma receptor A6) phosphorylation was regulated by BMP-2 signaling in some GIC. Analysis of The Cancer Genome Atlas showed that EPHA6 expression was lower in patients with GBM than in the normal brain, and that high EPHA6 expression was correlated with better prognosis. EPHA6 receptor increased the susceptibility of both sensitive and resistant GIC to BMP-2-induced apoptosis. The cooperative effect on apoptosis induction depended on the kinase activity of BMP type I receptor but was independent of EPHA6 kinase function. Overexpression of the EPHA6 receptor in GIC resulted in the formation of a protein complex of EPHA6 receptor and the BMP type I receptor ALK-2, which was associated with BMP-induced apoptosis in GIC. Intracranial injection of GIC into nude mice showed that gain-of-function of EPHA6 together with BMP-2 pretreatment slowed GBM tumor progression in the mouse brain and promoted mouse survival. In summary, EPHA6 together with BMP-2 signaling led to apoptotic cell death in GIC, and thus is a putative tumor suppressor in GBM.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Apoptose , Proteína Morfogenética Óssea 2/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Receptor EphA6/metabolismo , Animais , Proteína Morfogenética Óssea 2/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Prognóstico , Proteínas Supressoras de Tumor/metabolismo
15.
Br J Radiol ; 92(1103): 20190324, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31386559

RESUMO

OBJECTIVE: This study was to investigate the relationship of diffusion features with molecule information, and then predict grade and survival in lower-grade gliomas. METHODS: 65 patients with primary lower-grade gliomas (WHO Grade II & III) who underwent conventional MRI and diffusion tensor imaging were retrospectively studied. The tumor region was automatically segmented into contrast-enhancing tumor, non-enhancing tumor, edematous and necrotic volumes. Diffusion features, including fractional anisotropy (FA), axial diffusivity, radial diffusivity and apparent diffusion coefficient (ADC), were extracted from each volume using histogram analysis. To estimate molecule biomarkers and predict clinical characteristics of grade and survival, support vector machine, generalized linear model, logistic regression and Cox regression were performed on the related features. RESULTS: The diffusion features in non-enhancing tumor volume showed differences between isocitrate dehydrogenase mutant and wild-type gliomas. And the mean accuracy of support vector machine classifiers was 0.79. Ki-67 labeling index was correlated with these features, which were combined to significantly estimate Ki-67 expression level (r = 0.657, p < 0.001). These features also showed differences between Grade II and III gliomas. A combination of them for grade classification resulted in an area under the curve of 0.914 (0.857-0.971). Mean FA and fifth percentile of ADC were independently associated with overall survival, with lower FA and higher ADC showing better survival outcome. CONCLUSION: In lower-grade gliomas, multiparametric and multiregional diffusion features could help predict molecule information, histological grade and survival. ADVANCES IN KNOWLEDGE: The multi parametric diffusion features in non-enhancing tumor were associated with molecule information, grade and survival in lower-grade gliomas.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Oligodendroglioma/patologia , Adulto , Idoso , Anisotropia , Astrocitoma/mortalidade , Neoplasias Encefálicas/mortalidade , Imagem de Tensor de Difusão/métodos , Estudos de Viabilidade , Feminino , Humanos , Antígeno Ki-67/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/mortalidade , Estudos Retrospectivos , Carga Tumoral , Adulto Jovem
16.
Anticancer Res ; 39(8): 4273-4277, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366517

RESUMO

BACKGROUND/AIM: For treatment of brain metastases, a patient's survival prognosis should be considered. Existing survival scores appear complex and require complete tumor staging. For many patients, a faster and simpler tool would be helpful. PATIENTS AND METHODS: This retrospective study investigated the prognostic value of the number of pre-treatment symptoms plus eight other factors on survival of patients irradiated for brain metastases. Other factors included whole-brain radiotherapy (WBRT) regimen, age, gender, performance score, primary tumor type, number of brain metastases, extracranial metastases, and interval between cancer diagnosis and WBRT. RESULTS: The number of symptoms (p=0.002) and all other factors were significantly associated with survival on univariate analyses. On multivariate analysis, all factors but the number of symptoms (p=0.47) and primary tumor type (p=0.48) were significant. CONCLUSION: Since the number of symptoms was not an independent predictor of survival, it cannot replace existing scoring tools and may only serve for orientation.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias/radioterapia , Prognóstico , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Irradiação Craniana/efeitos adversos , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/classificação , Neoplasias/patologia
17.
Anticancer Res ; 39(8): 4265-4271, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366516

RESUMO

BACKGROUND/AIM: Brain metastases are an additional challenge in patients with non-small-cell lung cancer (NSCLC) because most chemotherapy agents cannot cross the blood-brain barrier. Nivolumab has demonstrated efficacy in patients with advanced squamous NSCLC, but because patients with central nervous system (CNS) metastases are typically excluded from registration trials, 'field-practice' data are needed. PATIENTS AND METHODS: Patients in the Italian cohort of the Expanded Access Program (EAP) who had CNS metastases at baseline were analyzed. RESULTS: Thirty-seven patients with CNS metastases received a median of six doses of nivolumab. Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months. CONCLUSION: The safety and efficacy of nivolumab in patients with CNS metastases appear to be similar to those seen in the overall EAP cohort in Italy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/secundário , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
18.
Curr Top Med Chem ; 19(17): 1521-1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31362676

RESUMO

Cells metabolism alteration is the new hallmark of cancer, as well as an important method for carcinogenesis investigation. It is well known that the malignant cells switch to aerobic glycolysis pathway occurring also in healthy proliferating cells. Recently, it was shown that in malignant cells de novo synthesis of the intracellular fatty acid replaces dietary fatty acids which change the lipid composition of cancer cells noticeably. These alterations in energy metabolism and structural lipid production explain the high proliferation rate of malignant tissues. However, metabolic reprogramming affects not only lipid metabolism but many of the metabolic pathways in the cell. 2-hydroxyglutarate was considered as cancer cell biomarker and its presence is associated with oxidative stress influencing the mitochondria functions. Among the variety of metabolite detection methods, mass spectrometry stands out as the most effective method for simultaneous identification and quantification of the metabolites. As the metabolic reprogramming is tightly connected with epigenetics and signaling modifications, the evaluation of metabolite alterations in cells is a promising approach to investigate the carcinogenesis which is necessary for improving current diagnostic capabilities and therapeutic capabilities. In this paper, we overview recent studies on metabolic alteration and oncometabolites, especially concerning brain cancer and mass spectrometry approaches which are now in use for the investigation of the metabolic pathway.


Assuntos
Neoplasias Encefálicas/metabolismo , Espectrometria de Massas , Neoplasias Encefálicas/patologia , Humanos
19.
J Clin Neurosci ; 68: 39-44, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31399318

RESUMO

The standard medical care of glioblastoma (GBM) patients with good performance status is based on focal brain radiotherapy (40-60 Gy) with concurrent temozolomide (TMZ) followed by adjuvant TMZ. Newly diagnosed multifocal and/or multicentric GBM (M/M GBM) cases are usually treated with TMZ alone: whole brain chemoradiotherapy (CRT) is avoided for safety reasons. To our knowledge, no study has investigated the safety and efficacy of whole-brain radiotherapy (WBRT) with concurrent TMZ in M/M GBM patients. This retrospective study sought to assess the role of WBRT associated with concurrent TMZ followed by TMZ alone in this population. Eleven patients with pathologically proven M/M GBM (≥3 lobes) were treated with WBRT between April 2009 and September 2017. The median age was 50 years [34-74]. The median dose of radiotherapy was 45 Gy at 1.8 Gy per fraction over 37 days [29-41], with concurrent daily TMZ at the dose of 75 mg/m2. This treatment was followed by adjuvant monthly TMZ (150 mg/m2-D1-D5). All pathology slides and radiology images were reviewed. The median overall and progression-free survival times for all patients were 10 months [4-25] and 5 months [3-21], respectively. There was no grade 3-4 toxicity due to radiotherapy. One patient stopped the TMZ during the radiochemotherapy period and 9 patients received adjuvant TMZ with a median number of 5 cycles [2-8]. Our study supports the safety and the efficacy of WBRT with TMZ in newly diagnosed M/M GBM. Larger prospective studies are needed to support our results.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Irradiação Craniana/métodos , Glioblastoma/terapia , Temozolomida/administração & dosagem , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/patologia , Quimiorradioterapia/efeitos adversos , Irradiação Craniana/efeitos adversos , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Temozolomida/efeitos adversos
20.
BMC Neurol ; 19(1): 200, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426757

RESUMO

BACKGROUND: Primary central nervous system (CNS) small lymphocytic lymphoma (SLL), as a type of low-grade lymphoma, is extremely rare. The diagnosis of CNS SLL is challenging due to its variable clinical and radiological features, which may overlap with those of diffuse large B-cell lymphoma (DLBCL). Primary CNS SLL differs from DLBCL in that it has an indolent clinical course and a good prognosis. Thus, it is important to distinguish SLL from DLBCL. By reviewing the literature, only two cases of low-grade SLL, primarily located in the CNS and involving the brain parenchyma and dura, have been reported. To our knowledge, primary CNS SLL in the bilateral ventricles has never been reported. Interestingly, the two cases in our report are identical in terms of the clinical presentations, magnetic resonance imaging (MRI) features, pathological results and prognoses. CASE PRESENTATION: Both patients presented with headaches. MRI suggested solid lesions located in the bilateral ventricles that were isointense on T1-weighted images and hypointense on T2-weighted images. After the injection of contrast agent (gadolinium, Gd), the intraventricular lesions were homogeneously enhanced and hyperperfused. CSF cytology revealed malignant cells. Brain biopsy revealed diffuse proliferation of small lymphocytes with positive labelling of B-cell immunomarkers. The primary origin in the CNS was confirmed with no evidence of systemic lymphoma. Two patients were given high doses of methotrexate-based chemotherapy and were free from symptoms and progression for more than 1-year of follow-up. CONCLUSIONS: The presence of homogeneously enhanced intraventricular MRI lesions should raise the suspicion of primary CNS SLL.


Assuntos
Neoplasias Encefálicas/patologia , Ventrículos Cerebrais/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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