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1.
Medicine (Baltimore) ; 100(36): e26750, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516487

RESUMO

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


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Antígeno Ki-67/sangue , Linfócitos/citologia , Neutrófilos/citologia , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade
3.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445547

RESUMO

Gangliosides serve as antitumor therapy targets and aberrations in their composition strongly correlate with tumor growth and invasiveness. Anaplastic ganglioglioma is a rare, poorly characterized, malignant neuronal-glial tumor type. We present the first comparative characterization of ganglioside composition in anaplastic ganglioglioma vs. peritumoral and healthy brain tissues by combining mass spectrometry and thin-layer chromatography. Anaplastic ganglioglioma ganglioside composition was highly distinguishable from both peritumoral and healthy tissue despite having five to six times lower total content. Ten out of twelve MS-identified ganglioside classes, defined by unique glycan residues, were represented by a large number and considerable abundance of individual species with different fatty acid residues (C16-C24) in ceramide portions. The major structurally identified class was tumor-associated GD3 (>50%) with 11 species; GD3 (d18:1/24:0) being the most abundant. The dominant sphingoid base residue in ganglioside ceramides was sphingosine (d18:1), followed by eicosasphingosine (d20:1). The peritumoral tissue ganglioside composition was estimated as normal. Specific ganglioside composition and large variability of ganglioside ceramide structures determined in anaplastic ganglioglioma demonstrate realistic ganglioside expression patterns and correspond to the profile of high-grade malignancy brain tumors.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Carcinoma/patologia , Cromatografia em Camada Delgada/métodos , Ganglioglioma/patologia , Gangliosídeos/metabolismo , Espectrometria de Massas/métodos , Idoso , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Carcinoma/metabolismo , Feminino , Ganglioglioma/metabolismo , Gangliosídeos/análise , Humanos , Pessoa de Meia-Idade
4.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445646

RESUMO

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


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Radiossensibilizantes/farmacologia , Radioterapia/métodos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Humanos
5.
Molecules ; 26(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34443374

RESUMO

The activation of NFAT (nuclear factor of activated T cells) transcription factors by calcium-dependent phosphatase calcineurin is a key step in controlling T cell activation and plays a vital role during carcinogenesis. NFATs are overexpressed in many cancers, including the most common primary brain tumor, gliomas. In the present study, we demonstrate the expression of NFATs and NFAT-driven transcription in several human glioma cells. We used a VIVIT peptide for interference in calcineurin binding to NFAT via a conserved PxIxIT motif. VIVIT was expressed as a fusion protein with a green fluorescent protein (VIVIT-GFP) or conjugated to cell-penetrating peptides (CPP), Sim-2 or 11R. We analyzed the NFAT expression, phosphorylation, subcellular localization and their transcriptional activity in cells treated with peptides. Overexpression of VIVIT-GFP decreased the NFAT-driven activity and inhibited the transcription of endogenous NFAT-target genes. These effects were not reproduced with synthetic peptides: Sim2-VIVIT did not show any activity, and 11R-VIVIT did not inhibit NFAT signaling in glioma cells. The presence of two calcineurin docking sites in NFATc3 might require dual-specificity blocking peptides. The cell-penetrating peptides Sim-2 or 11R linked to VIVIT did not improve its action making it unsuitable for evaluating NFAT dependent events in glioma cells with high expression of NFATc3.


Assuntos
Neoplasias Encefálicas/patologia , Calcineurina/metabolismo , Glioma/patologia , Fatores de Transcrição NFATC/metabolismo , Oligopeptídeos/farmacologia , Transdução de Sinais , Sequência de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , Glioma/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Fatores de Transcrição NFATC/química , Oligopeptídeos/química , Peptídeos/farmacologia , Transporte Proteico/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
6.
Molecules ; 26(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34443689

RESUMO

Effective intracerebral delivery is key for glioma treatment. However, the drug delivery system within the brain is largely limited by its own adverse physical and chemical properties, low targeting efficiency, the blood-brain barrier and the blood-brain tumor barrier. Herein, we developed a simple, safe and efficient biomimetic nanosuspension. The C6 cell membrane (CCM) was utilized to camouflaged the 10-hydroxycamptothecin nanosuspension (HCPT-NS) in order to obtain HCPT-NS/CCM. Through the use of immune escape and homotypic binding of the cancer cell membrane, HCPT-NS/CCM was able to penetrate the blood-brain barrier and target tumors. The HCPT-NS is only comprised of drugs, as well as a small amount of stabilizers that are characterized by a simple preparation method and high drug loading. Similarly, the HCPT-NS/CCM is able to achieve targeted treatment of glioma without any ligand modification, which leads it to be stable and efficient. Cellular uptake and in vivo imaging experiments demonstrated that HCPT-NS/CCM is able to effectively cross the blood-brain barrier and was concentrated at the glioma site due to the natural homing pathway. Our results reveal that the glioma cancer cell membrane is able to promote drug transport into the brain and enter the tumor via a homologous targeting mechanism.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Membrana Celular/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Nanopartículas/química , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Ratos , Suspensões , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento
7.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361013

RESUMO

Glioblastoma (GBM) is the most aggressive and common primary tumor of the central nervous system. It is characterized by having an infiltrating growth and by the presence of an excessive and aberrant vasculature. Some of the mechanisms that promote this neovascularization are angiogenesis and the transdifferentiation of tumor cells into endothelial cells or pericytes. In all these processes, the release of extracellular microvesicles by tumor cells plays an important role. Tumor cell-derived extracellular microvesicles contain pro-angiogenic molecules such as VEGF, which promote the formation of blood vessels and the recruitment of pericytes that reinforce these structures. The present study summarizes and discusses recent data from different investigations suggesting that Netrin-1, a highly versatile protein recently postulated as a non-canonical angiogenic ligand, could participate in the promotion of neovascularization processes in GBM. The relevance of determining the angiogenic signaling pathways associated with the interaction of Netrin-1 with its receptors is posed. Furthermore, we speculate that this molecule could form part of the microvesicles that favor abnormal tumor vasculature. Based on the studies presented, this review proposes Netrin-1 as a novel biomarker for GBM progression and vascularization.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Neovascularização Patológica/genética , Netrina-1/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Neovascularização Patológica/metabolismo , Receptores de Netrina/genética , Receptores de Netrina/metabolismo , Netrina-1/genética , Transdução de Sinais
8.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361090

RESUMO

Glioblastoma (GBM) is a highly lethal cancer that is universally refractory to the standard multimodal therapies of surgical resection, radiation, and chemotherapy treatment. Temozolomide (TMZ) is currently the best chemotherapy agent for GBM, but the durability of response is epigenetically dependent and often short-lived secondary to tumor resistance. Therapies that can provide synergy to chemoradiation are desperately needed in GBM. There is accumulating evidence that adaptive resistance evolution in GBM is facilitated through treatment-induced epigenetic modifications. Epigenetic alterations of DNA methylation, histone modifications, and chromatin remodeling have all been implicated as mechanisms that enhance accessibility for transcriptional activation of genes that play critical roles in GBM resistance and lethality. Hence, understanding and targeting epigenetic modifications associated with GBM resistance is of utmost priority. In this review, we summarize the latest updates on the impact of epigenetic modifications on adaptive resistance evolution in GBM to therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Glioblastoma/tratamento farmacológico , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Evolução Molecular , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos
9.
Biomed Res Int ; 2021: 5554436, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368351

RESUMO

Background: Although the prognosis of low-grade glioma is better than that of glioblastoma, there are still some groups with poor prognosis. The integrated stress response contributes to the malignant progress of tumors. As there had limited research focused on the integrated stress status in LGG, it is urgent to profile and reclassify LGG based on the integrated stress response. Methods: Information of glioma patients was obtained from the Chinese Glioma Genome Atlas, The Cancer Genome Atlas, and the GSE16011 cohorts. Statistical analyses were conducted using GraphPad Prism 8 and R language. Results: We summarized and quantified four types of integrated stress responses. Relationships between these four types of stress states and the clinical characteristics were analyzed in low-grade glioma. We then reclassified the patients based on these four scores and found that cluster 2 had the worst prognosis, while cluster 1 had the best prognosis. We also established an accurate integrated stress response risk signature for predicting cluster 2. We found that immune response and suppressive immune cell components were more enriched in the high-risk group. We also profiled the genomic differences between the low- and high-risk groups, including the nonmissense mutation of driver genes and the copy number variations. Conclusion: Low-grade glioma patients were divided into three clusters based on the integrated stress status, with cluster 2 exhibiting malignant transformation trends. The signature adequately reflected the traits of cluster 2, while a high risk score indicated a worse prognosis and an enriched inhibitory immune microenvironment.


Assuntos
Neoplasias Encefálicas/patologia , Genômica , Glioma/patologia , Estresse Fisiológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Análise por Conglomerados , Variações do Número de Cópias de DNA/genética , Glioma/genética , Glioma/imunologia , Humanos , Mutação/genética , Gradação de Tumores , Fenótipo , Fatores de Risco , Microambiente Tumoral/imunologia
10.
J Enzyme Inhib Med Chem ; 36(1): 1541-1552, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238111

RESUMO

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Quinases da Família src/metabolismo
11.
Nat Commun ; 12(1): 4228, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244484

RESUMO

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/patologia , Desoxiadenosinas/metabolismo , Glioblastoma/genética , Purina-Núcleosídeo Fosforilase/deficiência , Tionucleosídeos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/metabolismo , Desoxiadenosinas/análise , Feminino , Secções Congeladas , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Homozigoto , Humanos , Metabolômica , Metionina Adenosiltransferase/metabolismo , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Proteína-Arginina N-Metiltransferases/metabolismo , Purina-Núcleosídeo Fosforilase/genética , Deleção de Sequência , Tionucleosídeos/análise , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Aging (Albany NY) ; 13(13): 17673-17689, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34252882

RESUMO

BACKGROUND: In this study, we determine the potential roles and uncover the regulatory mechanisms of circCCDC66 in regulating cell growth and cell metastasis of glioma. METHODS: qRT-PCR was used to detect the expressions of circCCDC66 in gliomas and tissues. The biological function of circCCDC66 in glioma cell lines was elucidated by functional experiments. Cell counting kit-8 and transwell were used to detect the effect of circCCDC66 on the proliferation, migration and invasion of glioma cells. Bioinformatics analysis was applied to reveal the targets of circCCDC66. RESULTS: The results showed circCCDC66 was overexpressed in glioma and acted as an oncogene. CircCCDC66 knockdown suppressed the proliferation, migration, and invasion of glioma cells. We constructed a circCCDC66 regulating miRNA network and revealed miR-320a was a potential target of circCCDC66, which was down-regulated in high-grade gliomas compared to low-grade gliomas. Bioinformatics analysis showed circCCDC66-miR-320a/b axis was involved in regulating multiple cancer-related pathways. Furthermore, we identified FOXM1 as a key target of circCCDC66, which was involved in regulating DNA damage response pathways. In mechanism study, circCCDC66 could sponge miR-320a, thereby increasing the expression of FOXM1. CONCLUSIONS: CircCCDC66 could facilitate glioma cells proliferation, invasion and migration by down-regulating miR-320a and up-regulating FOXM1.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas do Olho/genética , Proteína Forkhead Box M1/genética , Glioma/genética , Glioma/patologia , MicroRNAs/genética , RNA Circular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Invasividade Neoplásica , Regulação para Cima
13.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206482

RESUMO

Gliomas and glioblastomas are very aggressive forms of brain tumors, prone to the development of a multitude of resistance mechanisms to therapeutic treatments, including cytoprotective autophagy. In this work, we investigated the role and mechanism of action of the combination of a ruthenacarborane derivative with 8-hydroxyquinoline (8-HQ), linked via an ester bond (complex 2), in rat astrocytoma C6 and human glioma U251 cells, in comparison with the two compounds alone, i.e., the free carboxylic acid (complex 1) and 8-HQ, and their non-covalent combination ([1 + 8-HQ], in 1:1 molar ratio). We found that only complex 2 was able to significantly affect cellular viability in glioma U251 cells (IC50 11.4 µM) via inhibition of the autophagic machinery, most likely acting at the early stages of the autophagic cascade. Contrary to 8-HQ alone, complex 2 was also able to impair cellular viability under conditions of glucose deprivation. We thus suggest different mechanisms of action of ruthenacarborane complex 2 than purely organic quinoline-based drugs, making complex 2 a very attractive candidate for evading the known resistances of brain tumors to chloroquine-based therapies.


Assuntos
Antineoplásicos , Astrocitoma , Neoplasias Encefálicas , Complexos de Coordenação , Quinolinas , Rutênio , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Astrocitoma/tratamento farmacológico , Astrocitoma/metabolismo , Astrocitoma/patologia , Morte Celular Autofágica , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Quinolinas/química , Quinolinas/farmacologia , Ratos , Rutênio/química , Rutênio/farmacologia
14.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203727

RESUMO

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB).


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Animais , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Evasão da Resposta Imune
15.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208139

RESUMO

Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein (PML) in primary Glioblastoma samples. PML is implicated in various ways in cancer biology. In the brain, PML participates in the physiological migration of the neural progenitor cells, which have been hypothesized to serve as the cell of origin of Glioblastoma. The role of PML in Glioblastoma progression has recently gained attention due to its controversial effects in overall Glioblastoma evolution. In this work, we studied the role of PML in Glioblastoma pathophysiology using the U87MG cell line. We genetically modified the cells to conditionally overexpress the PML isoform IV and we focused on its dual role in tumor growth and invasive capacity. Furthermore, we targeted a PML action mediator, the Enhancer of Zeste Homolog 2 (EZH2), via the inhibitory drug DZNeP. We present a combined in vitro-in silico approach, that utilizes both 2D and 3D cultures and cancer-predictive computational algorithms, in order to differentiate and interpret the observed biological results. Our overall findings indicate that PML regulates growth and invasion through distinct cellular mechanisms. In particular, PML overexpression suppresses cell proliferation, while it maintains the invasive capacity of the U87MG Glioblastoma cells and, upon inhibition of the PML-EZH2 pathway, the invasion is drastically eliminated. Our in silico simulations suggest that the underlying mechanism of PML-driven Glioblastoma physiology regulates invasion by differential modulation of the cell-to-cell adhesive and diffusive capacity of the cells. Elucidating further the role of PML in Glioblastoma biology could set PML as a potential molecular biomarker of the tumor progression and its mediated pathway as a therapeutic target, aiming at inhibiting cell growth and potentially clonal evolution regarding their proliferative and/or invasive phenotype within the heterogeneous tumor mass.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteína da Leucemia Promielocítica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Humanos , Modelos Biológicos , Invasividade Neoplásica , Esferoides Celulares/patologia
16.
J Clin Neurosci ; 90: 82-88, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275586

RESUMO

OBJECTIVES: Recurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma. PATIENTS AND METHODS: Eighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500 mg/day) and TMZ (50 mg/m2/day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions. RESULTS: From the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%). CONCLUSION: Apatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piridinas/uso terapêutico , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimioterapia Combinada , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Qualidade de Vida , Taxa de Sobrevida , Resultado do Tratamento
17.
J Comput Assist Tomogr ; 45(3): 463-471, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34297516

RESUMO

OBJECTIVE: To improve the understanding and the diagnosis of intracranial ependymal tumors. METHODS: The clinical, radiological and prognostic features of 48 supratentorial extraventricular ependymomas and 74 intraventricular ependymomas were summarized and compared. RESULTS: Supratentorial extraventricular ependymomas, most often located in the frontal lobe (33.3%) and classified as grade III (75.0%), had relatively large eccentric cysts (3.07 ± 2.03 cm), significant enhancement (84.8%), low apparent diffusion coefficient (ADC) values, and associated with higher mortality (41.3%). The majority of intraventricular lesions occurred in the fourth ventricle (86.5%) and classified as grade II (78.4%), had relatively small and multiple cystic changes (1.04 ± 0.87 cm), slight or moderate enhancement (76.9%), high ADC values and associated with lower mortality (20.7%). There were few significant differences between grade II and grade III tumors in these 2 groups, respectively. Young age, high grade and low ADC values are worse prognostic indicators for patients with supratentorial extraventricular ependymomas, but not for those with intraventricular ependymomas. CONCLUSIONS: Conventional radiological features, combined with clinical manifestations and quantitative information provided by diffusion-weighted imaging, may not only enhance the diagnosis and assist in determining prognosis but also provide a better pathophysiological understanding of intracranial ependymal tumors.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Ependimoma/diagnóstico por imagem , Neoplasias Supratentoriais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Fatores Etários , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Ependimoma/mortalidade , Ependimoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Gradação de Tumores , Prognóstico , Neoplasias Supratentoriais/mortalidade , Neoplasias Supratentoriais/patologia , Adulto Jovem
18.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209535

RESUMO

Epilepsy can be both a primary pathology and a secondary effect of many neurological conditions. Many papers show that neuroinflammation is a product of epilepsy, and that in pathological conditions characterized by neuroinflammation, there is a higher probability to develop epilepsy. However, the bidirectional mechanism of the reciprocal interaction between epilepsy and neuroinflammation remains to be fully understood. Here, we attempt to explore and discuss the relationship between epilepsy and inflammation in some paradigmatic neurological and systemic disorders associated with epilepsy. In particular, we have chosen one representative form of epilepsy for each one of its actual known etiologies. A better understanding of the mechanistic link between neuroinflammation and epilepsy would be important to improve subject-based therapies, both for prophylaxis and for the treatment of epilepsy.


Assuntos
Suscetibilidade a Doenças , Epilepsia/etiologia , Inflamação/complicações , Animais , Biomarcadores , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Terapia Combinada , Gerenciamento Clínico , Epilepsia/diagnóstico , Epilepsia/metabolismo , Epilepsia/terapia , Predisposição Genética para Doença , Humanos , Inflamação/etiologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Avaliação de Sintomas , Resultado do Tratamento
19.
J Clin Neurosci ; 90: 1-7, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275531

RESUMO

Pineal germinoma is rare with high cure rates following craniospinal radiotherapy. Efforts to reduce the radiotherapy dose and field via combination with chemotherapy suggest comparable disease control and reduced neurocognitive impairments, while the efficacy of immunotherapy in pineal germinoma remains undetermined. This report aimed to review clinical outcomes in patients treated for pineal germinoma in Queensland, Australia, and assess for Programmed Death-Ligand1 (PD-L1) expression. Patients who commenced radiation and/or chemotherapy for pineal germinoma from 2005 to 2017 were retrospectively identified using Queensland Oncology Online database. Demographic, diagnostic, treatment, and outcome data was obtained from electronic medical records. PD-L1 immuno-histochemistry was performed on available specimens. Eighteen patients with long-term follow-up data were identified. Median age at diagnosis was 16.8 years (range 9-46 years). Diagnosis was made histologically in fifteen patients, and radiologically in three. All patients underwent radiotherapy (median 36 Gy (range 21-54 Gy)) with lower median dose delivered with whole ventricle irradiation (12/18patients) than craniospinal irradiation (5/18patients). Sixteen patients received chemotherapy preceding radiotherapy. All patients are alive at median 7.25 years from primary treatment completion (range 2.03-13.1 years). Relapse occurred in three patients (16.67%) following treatment response, all of whom achieved remission following high-dose chemotherapy with stem-cell support and craniospinal radiotherapy. Post-treatment functional outcomes were similarly excellent. PD-L1 expression was low (1-49% cells) or negative in 87% of tumours tested but results were confounded by specimen quality and availability. Reduced-dose radiotherapy with chemotherapy does not compromise outcome and is standard of care at this institution. Immunotherapy is unlikely to become standard treatment in the near future.


Assuntos
Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Germinoma/terapia , Glândula Pineal/patologia , Adolescente , Adulto , Austrália , Neoplasias Encefálicas/patologia , Criança , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Germinoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Queensland , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
20.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210107

RESUMO

Brain tumors are the most common malignant primary intracranial tumors of the central nervous system. They are often recognized too late for successful therapy. Minimally invasive methods are needed to establish a diagnosis or monitor the response to treatment of CNS tumors. Brain tumors release molecular information into the circulation. Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a substitute for tumor tissue. Tumor-derived biomarkers include nucleic acids, proteins, and tumor-derived extracellular vesicles that accumulate in blood or cerebrospinal fluid. In recent years, circulating tumor cells have also been identified in the blood of glioblastoma patients. In this review of the literature, the authors highlight the significance, regulation, and prevalence of molecular biomarkers such as O6-methylguanine-DNA methyltransferase, epidermal growth factor receptor, and isocitrate dehydrogenase. Herein, we critically review the available literature on plasma circulating tumor cells (CTCs), cell-free tumors (ctDNAs), circulating cell-free microRNAs (cfmiRNAs), and circulating extracellular vesicles (EVs) for the diagnosis and monitoring of brain tumor. Currently available markers have significant limitations. While much research has been conductedon these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Células Neoplásicas Circulantes/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Detecção Precoce de Câncer , Vesículas Extracelulares/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Biópsia Líquida , Células Neoplásicas Circulantes/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/genética , Prognóstico
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