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1.
J Neurooncol ; 136(3): 445-452, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29150788

RESUMEN

Glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET) is a rare variant of glioblastoma, which was renamed as glioblastoma with a primitive neuronal component (GBM-PN) in new WHO classification of tumours of the central nervous system in 2016. There are few publications on the investigation of GBM-PN. In this study, PCR mRNA arrays on 6 cases of conventional GBM and 10 cases of GBM-PN showed high mRNA level of CDK4 in GBM-PN and low mRNA level of EGFR in GBM-PN. Immunohistochemical stains on tissue microarrays with 28 cases of conventional GBM and 13 cases of GBM-PN demonstrated that CDK4 was selectively expressed in the primitive neuronal component of all GBM-PN cases while EGFR was positive in conventional GBM and glial component of GBM-PN, but was negative in the primitive neuronal component of all GBM-PN cases. Immunohistochemical stains with antibodies against proteins that interact with CDK4 in cell cycle regulation, such as CDK6, cyclin D1 and p16(INK4a), were performed on these GBM-PN and GBM cases. CDK6 was patchily positive in rare cases of GBM-PN and cyclin D1 was negative in GBM-PN cases. p16(INK4a) is traditionally known as an inhibitor of CDK4 and CDK6. p16(INK4a) might not be the inhibitor of CDK4 in GBM-PN cases because seven GBM-PN cases were positive for both CDK4 and p16(INK4a). It indicates that CDK4 and p16(INK4a) might play a crucial role in GBM-PN pathogenesis. Since CDK4 and EGFR are highly expressed in the primitive neuronal component and in the glial component of GBM-PN respectively, the combination of CDK4/6 inhibitor and targeted therapy against EGFR might be potential effective therapeutic regimen for GBM-PN. CDK4 and EGFR immuohistochemical stain patterns make the diagnosis of GBM-PN much easier.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Tumores Neuroectodérmicos Primitivos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/patología , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroectodérmicos Primitivos/patología , ARN Mensajero/metabolismo
2.
Tumour Biol ; 37(8): 10577-86, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26857280

RESUMEN

Glioblastoma (GBM) is the highly malignant glioma and exhibits microvascular proliferation. PCR mRNA arrays and immunohistochemical stains on tissue microarray demonstrated that the expression level of PDGFRB in GBM microvascular proliferation was significantly higher than that in GBM tumor cells while the expression level of EGFR was lower in microvascular proliferation than in GBM tumor cells. PDGFRB protein was selectively expressed in pericytes in GBM microvascular proliferation. By analyzing The Cancer Genome Atlas (TCGA) datasets for GBM, it was found that genomic DNA alterations were the main reason for the high expression of EGFR in GBM tumor cells. Our miRNA microarray data showed that microRNAs (miRNAs) (miR-193b-3p, miR-518b, miR-520f-3p, and miR-506-5p) targeting PDGFRB were downregulated in microvascular proliferation, which might be the most likely reason for the high expression of PDGFRB in GBM microvascular proliferation. The increase of several miRNAs (miR-133b, miR-30b-3p, miR-145-5p, and miR-146a-5p) targeting EGFR in GBM microvascular proliferation was one of the reasons for the lack of expression of EGFR in GBM microvascular proliferation. These findings implicated that miRNAs, such as miR-506, miR-133b, miR-145, and miR-146a, that target PDGFRB or EGFR, might be potential therapeutic agents for GBM. A new generation of targeted therapeutic agents against both EGFR and PDGFRB might be developed in the future.


Asunto(s)
Neoplasias Encefálicas/irrigación sanguínea , Receptores ErbB/biosíntesis , Regulación Neoplásica de la Expresión Génica , Glioblastoma/irrigación sanguínea , Proteínas de Neoplasias/biosíntesis , Pericitos/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Femenino , Genes erbB-1 , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Análisis de Matrices Tisulares
3.
J Neurooncol ; 126(3): 405-13, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26526033

RESUMEN

Glioblastoma (GBM) is the most common primary malignant brain tumor. Microvascular proliferation is one of the characteristic pathologic features of GBM. Mitochondrial dysfunction plays an important role in the pathogenesis of GBM. In this study, microvascular proliferation from GBM and normal brain blood vessels were laser microdissected and total RNA was isolated from these microvasculatures. The difference of mRNA expression profiles among GBM microvasculature, normal brain blood vessels and GBM tumor cells was evaluated by mitochondria and metabolism PCR gene arrays. It was found that the mRNA levels of ATP5A1 and ATP5B in GBM tumor cells as well as microvascular proliferation were significantly higher compared with normal brain blood vessels. Immunohistochemical stains with anti-ATP5A1 antibody or anti-ATP5B antibody were performed on tissue microarray, which demonstrated strongly positive expression of ATP5A1 and ATP5B in GBM tumor cells and GBM microvascular proliferation while normal blood vessels were negative. By analyzing The Cancer Genome Atlas data sets for GBM and other cancers, genomic DNA alterations (mutation, amplification or deletion) were less likely the reason for the high expression of ATP5A1 and ATP5B in GBM. Our miRNA microarray data showed that miRNAs that target ATP5A1 or ATP5B were down-regulated, which might be the most likely reason for the high expression of ATP5A1 and ATP5B in GBM tumor cells and microvascular proliferation. These findings help us better understand the pathogenesis of GBM, and agents against ATP5A1 and/or ATP5B might effectively kill both tumor cells and microvascular proliferation in GBM. MiRNAs, such as Let-7f, miR-16, miR-23, miR-100 and miR-101, that target ATP5A1 or ATP5B, might be potential therapeutic agents for GBM.


Asunto(s)
Neoplasias Encefálicas/genética , Endotelio Vascular/metabolismo , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Microvasos/metabolismo , ATPasas de Translocación de Protón Mitocondriales/genética , Factores de Acoplamiento de la Fosforilación Oxidativa/genética , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Endotelio Vascular/citología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Técnicas para Inmunoenzimas , MicroARNs/genética , Microvasos/citología , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Factores de Acoplamiento de la Fosforilación Oxidativa/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares , Células Tumorales Cultivadas
4.
Int J Hyperthermia ; 26(6): 556-64, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20707650

RESUMEN

PURPOSE: The cytotoxic effect of the combination treatment of TNF-alpha and hyperthermia on L929 and TNF-alpha-resistant L929 (rL929) cells was investigated. MATERIALS AND METHODS: L929 cells were treated with TNF-alpha (5 ng/mL), heating at 43 degrees C or the combination of TNF-alpha and heating. The cells were harvested at different time within the 24-hour period. The viability and the type of cell death of the harvested cells were examined. RESULTS: When L929 cells were treated with a combination of TNF-alpha and heating the cells died quickly and apoptosis increased to an overwhelming extent, especially in the group pre-treated with TNF-alpha for 1 h prior to heating. Although rL929 cells were resistant to TNF-alpha alone, the cells became sensitive to TNF-alpha treatment when combined with heating. Similar to the L929 cell, the cells also died rapidly and exhibited apoptosis to a higher extent. Using an Annexin-V-FITC kit and flow cytometer, we found that both necrosis and apoptosis occurred. Agarose gel electrophoresis of DNA extracted from treated cells showed that the DNA fragments were multiples of approximately 200 bp. Furthermore, by studying the kinetics of cell death and apoptosis, we found that the loss of cell membrane integrity preceded the DNA fragmentation in both L929 and rL929 cells. CONCLUSION: The results suggested that hyperthermia may enhance the necrotic and apoptotic effects of TNF-alpha on some tumour cells and overcome the resistance of some tumour cells to TNF-alpha.


Asunto(s)
Apoptosis/efectos de los fármacos , Resistencia a Medicamentos/fisiología , Fiebre/fisiopatología , Fibrosarcoma/patología , Factor de Necrosis Tumoral alfa/farmacología , Animales , Apoptosis/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Modelos Animales de Enfermedad , Fibrosarcoma/fisiopatología , Ratones , Necrosis
5.
Brain Tumor Pathol ; 36(3): 129-134, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30715630

RESUMEN

Glioblastoma with a primitive neuronal component (GBM-PN) was renamed from glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET) in the new WHO classification of tumors of the central nervous system in 2016. GBM-PN is a rare variant of glioblastoma. There were not so many publications on the investigation of GBM-PN. We did whole exome sequencing for 11 GBM-PN cases and found that the percentage of TP53, PIK3CA, PIK3R1, or PTEN mutation in our GBM-PN cases (72.7%, 27.3%, 27.3%, and 27.3% respectively) was much higher than that in cases in TCGA GBM 2008, TCGA GBM 2013, and TCGA lower-grade glioma databases. The findings indicate that GBM-PN is a distinct variant of glioblastoma. The next-generation sequencing can play a role in the diagnosis of GBM-PN especially for small biopsy cases. Eight out of 11 cases showed mutations in PTEN-PI3K pathway, which indicates that targeted therapeutic agents (PI3K inhibitors, mTORC1 inhibitors or dual PI3K/mTOR inhibitors) may be used for the treatment of GBM-PN in the future.


Asunto(s)
Glioblastoma/genética , Tumores Neuroectodérmicos Primitivos/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase Ia , Femenino , Glioma/patología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neuronas/patología , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Proteína p53 Supresora de Tumor/genética , Secuenciación del Exoma/métodos
6.
Nanomaterials (Basel) ; 8(12)2018 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-30501038

RESUMEN

InxGa1-xN nanowires (NWs) have drawn great attentions for their applications in optoelectronic and energy conversion devices. Compared to conventional substrates, metal substrates can offer InxGa1-xN NW devices with better thermal conductivity, electric conductivity, and mechanic flexibility. In this article, InxGa1-xN NWs were successfully grown on the surface of a tantalum (Ta) substrate via vapor-liquid-solid chemical vapor deposition (VLS-CVD), as characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), scanning and transmission electron microscope (STEM), and photoluminescence spectroscopy (PL). It was found that the surface pretreatment of Ta and the composition of metallic catalysts played important roles in the formation of NWs. A dimpled nitrided Ta surface combined with a catalyst of nickle is suitable for VLS-CVD growth of the NWs. The obtained InxGa1-xN NWs grew along the [1100] direction with the presence of basal stacking faults and an enriched indium composition of ~3 at.%. The successful VLS-CVD preparation of InxGa1-xN nanowires on Ta substrates could pave the way for the large-scale manufacture of optoelectronic devices in a more cost-effective way.

7.
J Biol Chem ; 279(44): 45594-602, 2004 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-15322120

RESUMEN

Alanine substitutions were made for 15 amino acids in the cytoplasmic loop between transmembrane helices 6 and 7 (L6/7) of the human alpha(1)-subunit of Na,K-ATPase. Most mutations reduced Na,K-ATPase activity by less than 50%; however, the mutations R834A, R837A, and R848A reduced Na,K-ATPase activity by 75, 89, and 66%, respectively. Steady-state phosphoenzyme formation from ATP was reduced in mutants R834A, R837A, and R848A, and R837A also had a faster E(2)P --> E(2) dephosphorylation rate compared with the wild-type enzyme. Effects of L6/7 mutations on the phosphorylation domain of the protein were also demonstrated by (18)O exchange, which showed that intrinsic rate constants for P(i) binding and/or reaction with the protein were altered. Although most L6/7 mutations had no effect on the interaction of Na(+) or K(+) with Na,K-ATPase, the E825A, E828A, R834A, and R837A mutations reduced the apparent affinity of the enzyme for both Na(+) and K(+) by 1.5-3-fold. 1-Bromo-2,4,6-tris(methylisothiouronium)benzene (Br-TITU(3+)), a competitive antagonist of Rb(+) and Na(+) occlusion, was used to test whether charged residues in L6/7 are involved in binding monovalent cations and cation antagonists. Br-TITU(3+) inhibited ouabain binding to wild type Na,K-ATPase with an IC(50) of 30 microM. Ouabain binding to the E825A, E828A, R834A, or R837A mutants was still inhibited by Br-TITU(3+), indicating that Br-TITU(3+) does not bind to charged residues in L6/7. This observation makes it unlikely that L6/7 functions as a cytoplasmic cation binding site in Na,K-ATPase, and together with the effects of L6/7 mutations on phosphate interactions with the enzyme suggests that L6/7 is important in stabilizing the phosphorylation domain and its relationship to the ion binding sites of the protein.


Asunto(s)
Pliegue de Proteína , ATPasa Intercambiadora de Sodio-Potasio/química , Secuencia de Aminoácidos , Humanos , Elementos de la Serie de los Lantanoides/farmacología , Datos de Secuencia Molecular , Ouabaína/metabolismo , Fosforilación , Potasio/metabolismo , Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/fisiología , Relación Estructura-Actividad
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