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1.
World Neurosurg ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189916

RESUMO

OBJECTIVE: Traumatic brain injury (TBI) is a health problem worldwide, and therapeutic strategies to enhance brain tissue repair to lessen neurological sequels are imperative. We aimed to analyze the impact of the inflammatory process in TBI through CXCR4 and CXCR7 chemokine receptors and their ligands' CXCL11 and CXCL12 expression profile in search for potential new druggable targets. METHODS: Twelve pericontusional tissues from severe TBI patients submitted to surgical treatment and 20 control brain tissues from normal autopsy were analyzed for expression profile by RQ-PCR. CXCR7 and CXCR4 protein expressions were analyzed by immunohistochemistry. The findings were correlated with the clinical evolution. RESULTS: Increased gene expression of both receptors and their ligands was observed in TBI compared with controls, presenting high sensitivity and specificity to differentiate TBI from normal control (AUC ranging from 0.85 to 0.98, p < 0.001). In particular, CXCR7 expression highly correlated with CXCR4 and both ligands' expressions in TBI. Higher immunoreactions for CXCR7 and CXCR4 were identified in neurons and endothelial cells of TBI samples compared with controls. The patients presenting upregulated chemokine expression levels showed a trend toward favorable clinical evolution at up to 6 months of follow-up. CONCLUSION: The neuroprotective trend of CXCR4, CXCR7, CXCL11, and CXCL12 in TBI observed in this initial analysis warrants further studies with more patients, analyzing the involved signaling pathways for the development of new therapeutic strategies for TBI.

4.
Cancer Cell ; 35(3): 504-518.e7, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30827889

RESUMO

Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.


Assuntos
Neoplasias Encefálicas/terapia , Núcleo Celular/metabolismo , Glioma/terapia , PTEN Fosfo-Hidrolase/metabolismo , Pirimidinas/administração & dosagem , Tolerância a Radiação/efeitos dos fármacos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Reparo do DNA/efeitos dos fármacos , Feminino , Glioma/metabolismo , Humanos , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Pirimidinas/farmacologia , Rad51 Recombinase/metabolismo , Tirosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
World Neurosurg ; 122: e1536-e1541, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30471445

RESUMO

OBJECTIVE: To review the published data to create a more comprehensive natural history of multiple meningiomas (MM). METHODS: A review of MM published until now was carried out through a Medline search up to August 2018. The use of the "multiple meningiomas" keyword returned 278 articles, and the characteristics analyzed in our present cohort were searched on those publications. Articles without detailed description of clinical findings, neuroimaging confirmation of tumor multiplicity, follow-up at least of 5 years, and clear description of clinical findings were excluded. We added series to this review. RESULTS: 293 patients with MM were analyzed: 220 women and 73 men, with a total of 932 tumors (3.1 tumors per patient). The majority of tumors were located in the convexity (653% to 74.5%). The total number of tumors treated was 429 (43.9%): 338 (78.8%) by surgical resection and 91 (21.2%) by radiotherapy. Histopathologic description was available in 303 of 429 cases, being grade I in 272 (90.3%) cases, with a predominance of the meningothelial subtype (30.7%). Tumor recurrence was described in 32 (8.07%) among 397 and only 10 deaths (3.4%) of 281 reported cases, where this characteristic was evaluated. CONCLUSIONS: World Health Organization grade I predominance was observed among multiple meningiomas in similarity to single meningiomas. Only a fraction of MM patients (43.89%) needed treatment. A benign tumor behavior was corroborated by the observed low frequency of recurrence and mortality.


Assuntos
Neoplasias Meníngeas , Meningioma , Neoplasias Primárias Múltiplas , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Neoplasias Meníngeas/epidemiologia , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/cirurgia , Meningioma/epidemiologia , Meningioma/patologia , Meningioma/cirurgia , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia
6.
PLoS One ; 10(8): e0135831, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26313749

RESUMO

Gene set analysis aims to identify predefined sets of functionally related genes that are differentially expressed between two conditions. Although gene set analysis has been very successful, by incorporating biological knowledge about the gene sets and enhancing statistical power over gene-by-gene analyses, it does not take into account the correlation (association) structure among the genes. In this work, we present CoGA (Co-expression Graph Analyzer), an R package for the identification of groups of differentially associated genes between two phenotypes. The analysis is based on concepts of Information Theory applied to the spectral distributions of the gene co-expression graphs, such as the spectral entropy to measure the randomness of a graph structure and the Jensen-Shannon divergence to discriminate classes of graphs. The package also includes common measures to compare gene co-expression networks in terms of their structural properties, such as centrality, degree distribution, shortest path length, and clustering coefficient. Besides the structural analyses, CoGA also includes graphical interfaces for visual inspection of the networks, ranking of genes according to their "importance" in the network, and the standard differential expression analysis. We show by both simulation experiments and analyses of real data that the statistical tests performed by CoGA indeed control the rate of false positives and is able to identify differentially co-expressed genes that other methods failed.


Assuntos
Algoritmos , Neoplasias Encefálicas/genética , Biologia Computacional/métodos , Gráficos por Computador , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Biomarcadores Tumorais/genética , Regulação da Expressão Gênica , Humanos , Modelos Biológicos
7.
Pathol Oncol Res ; 21(2): 229-40, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24970694

RESUMO

The CXCR7, a new receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytomas tissues and to evaluate its interactions with CXCR4 and HIF1α expression and IDH1 mutation. CXCR7, CXCR4 and HIF1α mRNA expression were evaluated in 129 frozen samples of astrocytomas. IDH1 mutation status was analyzed with gene expressions, matched with clinicopathological parameters and overall survival time. Protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. There was significant difference in the expression levels of the genes studied between astrocytomas and non-neoplasic (NN) controls (p < 0.001). AGII showed no significant correlation between CXCR7/HIF1α (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). GBM showed significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1α (p = 0.008). HIF1α overexpression was associated with higher expressions of CXCR7 (p = 0.01) and CXCR4 (p < 0.0001), while IDH1 mutation was associated with lower CXCR7 (p = 0.009) and CXCR4 (p = 0.0005) mRNA expressions. Protein expression increased with malignancy and in U87MG cell line was mainly localized in the cellular membrane. CXCR7 was overexpressed in astrocytoma and correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1α in GBM. Overexpression HIF1α was related with higher expressions of CXCR7 and CXCR4, otherwise IDH1 mutation related with lower expression of both genes. No association between CXCR7 and CXCR4 expression and survival data was related.


Assuntos
Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isocitrato Desidrogenase/genética , Mutação/genética , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinogênese , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Isocitrato Desidrogenase/metabolismo , Estimativa de Kaplan-Meier , Gradação de Tumores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/genética , Receptores CXCR4/genética , Regulação para Cima
8.
Oncotarget ; 3(7): 709-22, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22869205

RESUMO

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.


Assuntos
Neoplasias Encefálicas/classificação , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Glioma/classificação , Isocitrato Desidrogenase/genética , Mutação , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Feminino , Inativação Gênica , Glioma/genética , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Prognóstico , Proteínas de Ligação a RNA , Telômero/genética , Proteína Nuclear Ligada ao X
9.
Rev. cuba. estomatol ; 48(4): 410-415, oct.-dic. 2011.
Artigo em Espanhol | LILACS | ID: lil-615141

RESUMO

La distrofia muscular de Steinert tipo 1 afecta frecuentemente a los músculos de la masticación y puede causar debilidad muscular y alteraciones bucofaciales. Esta enfermedad se caracteriza por presentar el fenómeno de anticipación, en el cual la descendencia de una persona afectada desarrolla la enfermedad de manera más precoz. El objetivo de este trabajo fue reportar 2 casos de una madre y su hija con diagnóstico de distrofia muscular de Steinert. Se realizó un análisis de las características clínicas bucales y los efectos del fenómeno de anticipación de esta enfermedad mediante el examen odontológico, la medición de la fuerza masticatoria y la resonancia magnética nuclear de la articulación temporomandibular. La expresión clínica de la enfermedad fue más precoz en la hija que en la madre, lo que se relacionó con un mayor número de estructuras dentarias perdidas y de cambios degenerativos en la articulación temporomandibular, asociados a una menor fuerza masticatoria(AU)


ABSTRACT The Steinert's muscular dystrophy type 1 involves frequently the masticatory muscle causing muscular weakness and orofacial alterations; this entity is characterized by to present the anticipatory phenomenon where la offspring of a involved person develops the disease in an early way. The aim of present paper is to report 2 cases in mother and daughter diagnosed with the DM1 and to analyze the oral clinical features and the effects of anticipatory phenomenon of disease by stomatologic examination, measurement of masticatory strength and magnetic nuclear resonance of temporomandibular joint. The clinical expression of this disease was earlier in the daughter than in the mother, which was related to a greater number of lost teeth and of degenerative changes en la TMJ associated with a lesser masticatory strength(AU)


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Articulação Temporomandibular/diagnóstico por imagem , Força de Mordida , Distrofia Miotônica/diagnóstico
10.
Am J Trop Med Hyg ; 83(2): 271-3, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20682866

RESUMO

Severe rhabdomyolysis (creatine phosphokinase = 29,400 U/L) developed in a 16-year-old boy from Manaus, Brazil, after he started treatment with chloroquine for infection with Plasmodium vivax. Treatment led to myoglobinuria and acute renal failure. After hemodialysis, the patient improved and a muscle biopsy specimen showed no myophosphorylase or deaminase deficiency. This case of rhabdomyolysis associated with P. vivax infection showed no comorbidities. The pathogenesis is still unclear. Although rhabdomyolysis is generally reported as a complication of Plasmodium falciparum malaria, leading to metabolic and renal complications,1 it has been reported in a patient with P. vivax infection with myoadenylate deaminase deficiency.2 We report a case in a patient without typical muscle enzyme deficiencies in which severe rhabdomyolysis developed while the patients was being treated with chloroquine for a confirmed P. vivax infection.


Assuntos
Malária Vivax/complicações , Plasmodium vivax , Rabdomiólise/parasitologia , Adolescente , Animais , Brasil , Humanos , Malária Vivax/tratamento farmacológico , Masculino , Rabdomiólise/complicações
11.
Biochim Biophys Acta ; 1769(7-8): 437-42, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17588684

RESUMO

Comparative analysis of cancer stem cells with their neoplastic and non-neoplastic counterparts should help better understand the underlying molecular events leading to transformation and tumor dissemination. Here, we report a molecular signature comprised by genes with exclusive aberrant expression in CD133(+) cells, a reported subpopulation of tumorigenic stem-like cells, isolated from human glioblastomas. Microarrays covering 55,000 transcripts were used to compare gene expression profiles in purified subpopulations of CD133(+) and CD133(-) GBM cells. Sixteen genes, many of which not previously associated with astrocytomas, were found aberrantly expressed in CD133(+) cells, but not in CD133(-), when compared with corresponding non-neoplastic controls. Up-regulation of two of such genes, E2F2 and HOXC9, was detected in a set of 54 astrocytomas of different grades and significantly associated with malignancy. Due to their distinctive expression in CD133(+) cells, the use of E2F2 and HOXC9 as therapeutic targets for tumor eradication is suggested.


Assuntos
Astrócitos/patologia , Astrocitoma/metabolismo , Transformação Celular Neoplásica/patologia , Fator de Transcrição E2F2/biossíntese , Proteínas de Homeodomínio/biossíntese , Perfilação da Expressão Gênica , Humanos , Células Tumorais Cultivadas , Regulação para Cima
12.
Cancer Lett ; 224(2): 321-7, 2005 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-15914282

RESUMO

Alteration in TP53 is the most common genetic event reported for many tumors, including astrocytomas. The majority of studies, on analyzing TP53 mutations, have not included all splice junctions. Consequently, splice site mutations are thought to be relatively infrequent. TP53 were examined for mutations by polymerase chain reaction, single strand conformation polymorphism and direct sequencing in cases of diffuse astrocytomas. We found TP53 mutations in 17.8% (8 out of 45) of the tumors tested: 3 splicing, 3 missense and 2 silent mutations. We have shown that splice site mutations of TP53 are more frequent than previously reported. These findings emphasize the importance of thorough screening of TP53 mutations in gliomas.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Genes p53 , Sítios de Splice de RNA , Análise Mutacional de DNA , Humanos , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase
13.
Epilepsy Behav ; 4(2): 133-41, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12697137

RESUMO

We investigated a series of patients with epileptic psychosis in Brazil and compared our findings with those of other authors. We evaluated 38 outpatients with epileptic psychosis with a semistructured clinical interview, Annett inventory for hand dominance, international classifications for seizures and syndromes, and DSM-IV for psychosis diagnoses. We studied course and outcome for epilepsy and psychosis. Gender distribution was approximately even. Epilepsy and psychiatric disorders among relatives and early CNS insults in personal histories were frequent findings. Mean age of epilepsy onset was 9.3 years. Epilepsy started before psychosis in all cases, and evolved to clinical refractoriness. There was a predominance of temporal lobe epilepsy. Mean age of psychosis onset was 27.4 years, after a mean duration of epilepsy of 18.1 years, with predominance of schizophrenic presentations with interictal onset, frequent psychiatric admissions, suicide attempts, and postpsychosis functional decline. Tumors or lesions of an embryologic nature were uncommon, but mesial temporal sclerosis was frequent.


Assuntos
Epilepsia/epidemiologia , Transtornos Psicóticos/epidemiologia , Adulto , Idoso , Brasil/epidemiologia , Comorbidade , Manual Diagnóstico e Estatístico de Transtornos Mentais , Emprego/estatística & dados numéricos , Epilepsia/diagnóstico , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/genética , Índice de Gravidade de Doença , Fatores de Tempo
14.
Arq. neuropsiquiatr ; 58(4): 1002-8, Dec. 2000.
Artigo em Inglês | LILACS | ID: lil-273838

RESUMO

This is a retrospective study of 21 surgically treated patients with temporal lobe tumors and epilepsy. Evaluation included clinical data, EEG findings, structural scans, pathological diagnosis and post-surgical follow-up. There were 9 cases of ganglioglioma, 5 pilocytic astrocytoma, 3 ganglioneuroma, 2 dysembryoplastic neuroepithelial tumor, 1 pleomorphic xantoastrocytoma, and 1 meningioangiomatosis. Mean follow-up time was 22 months and outcome was evaluated according to Engel's classification; 76.2 percent were classified in class I and 23.8 percent in II and III. All patients classes II and III had been submitted to mesial and neocortical resections. There were no differences related to clinical characteristics, pathological diagnosis or duration of follow-up in patients seizure-free or not. All patients had abnormal MRI and ten of these had normal CT; the MRI characteristics were compared to pathological diagnosis and specific histological characteristics of the tumors were not discernible by MRI. We concluded that MRI was essential for the diagnosis and precise location of TL tumors. Ganglioglioma was the most frequent tumor and lesionectomy associated to mesial resection doesn't guarantee a better prognosis


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Neoplasias Encefálicas/cirurgia , Epilepsia do Lobo Temporal/cirurgia , Lobo Temporal/cirurgia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/etiologia , Seguimentos , Imageamento por Ressonância Magnética , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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