Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 154
Filtrar
1.
Brain ; 145(2): 700-712, 2022 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-35288744

RESUMO

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.


Assuntos
Síndrome de Creutzfeldt-Jakob , Insônia Familiar Fatal , Doenças Priônicas , Príons , Biomarcadores/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Humanos , Insônia Familiar Fatal/genética , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Proteínas Priônicas/genética , Príons/genética , alfa-Sinucleína
2.
Cell Mol Neurobiol ; 42(4): 1005-1020, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33245508

RESUMO

The tumor resistance of glioblastoma cells in vivo is thought to be enhanced by their heterogeneity and plasticity, which are extremely difficult to curb in vitro. The external microenvironment shapes the molecular profile of tumor culture models, thus influencing potential therapy response. Our study examines the expression profile of selected lncRNAs involved in tumor resistance network in three different glioblastoma-derived models commonly utilized for testing drug response in vitro. Differential expression analysis revealed significant divergence in lncRNA profile between parental tumors and tumor-derived cell cultures in vitro, including the following particles: MALAT1, CASC2, H19, TUSC7, XIST, RP11-838N2.4, DLX6-AS1, GLIDR, MIR210HG, SOX2-OT. The examined lncRNAs influence the phenomenon of tumor resistance via their downstream target genes through a variety of processes: multi-drug resistance, epithelial-mesenchymal transition, autophagy, cell proliferation and viability, and DNA repair. A comparison of in vivo and in vitro expression identified differences in the levels of potential lncRNA targets, with the highest discrepancies detected for the MDR1, LRP1, BCRP and MRP1 genes. Co-expression analyses confirmed the following interrelations: MALAT1-TYMS, MALAT1-MRP5, H19-ZEB1, CASC2-VIM, CASC2-N-CAD; they additionally suggest the possibility of MALAT1-BCRP, MALAT1-mTOR and TUSC7-PTEN interconnections in glioblastoma. Although our results clearly demonstrate that the artificial ex vivo microenvironment changes the profile of lncRNAs related to tumor resistance, it is difficult to anticipate the final phenotypic effect, since this phenomenon is a complex one that involves a network of molecular interactions underlying a variety of cellular processes.


Assuntos
Glioblastoma , RNA Longo não Codificante , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Técnicas de Cultura de Células , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/uso terapêutico , RNA Longo não Codificante/genética , Microambiente Tumoral
3.
BMC Cancer ; 19(1): 544, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170943

RESUMO

BACKGROUND: The understanding of the molecular biology of pediatric neuronal and mixed neuronal-glial brain tumors is still insufficient due to low frequency and heterogeneity of those lesions which comprise several subtypes presenting neuronal and/or neuronal-glial differentiation. Important is that the most frequent ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNET) showed limited number of detectable molecular alterations. In such cases analyses of additional genomic mechanisms seem to be the most promising. The aim of the study was to evaluate microRNA (miRNA) profiles in GGs, DNETs and pilocytic asytrocytomas (PA) and test the hypothesis of plausible miRNA connection with histopathological subtypes of particular pediatric glial and mixed glioneronal tumors. METHODS: The study was designed as the two-stage analysis. Microarray testing was performed with the use of the miRCURY LNA microRNA Array technology in 51 cases. Validation set comprised 107 samples used during confirmation of the profiling results by qPCR bioinformatic analysis. RESULTS: Microarray data was compared between the groups using an analysis of variance with the Benjamini-Hochberg procedure used to estimate false discovery rates. After filtration 782 miRNAs were eligible for further analysis. Based on the results of 10 × 10-fold cross-validation J48 algorithm was identified as the most resilient to overfitting. Pairwise comparison showed the DNETs to be the most divergent with the largest number of miRNAs differing from either of the two comparative groups. Validation of array analysis was performed for miRNAs used in the classification model: miR-155-5p, miR-4754, miR-4530, miR-628-3p, let-7b-3p, miR-4758-3p, miRPlus-A1086 and miR-891a-5p. Model developed on their expression measured by qPCR showed weighted AUC of 0.97 (95% CI for all classes ranging from 0.91 to 1.00). A computational analysis was used to identify mRNA targets for final set of selected miRNAs using miRWalk database. Among genomic targets of selected molecules ZBTB20, LCOR, PFKFB2, SYNJ2BP and TPD52 genes were noted. CONCLUSIONS: Our data showed the existence of miRNAs which expression is specific for different histological types of tumors. miRNA expression analysis may be useful in in-depth molecular diagnostic process of the tumors and could elucidate their origins and molecular background.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Árvores de Decisões , Ganglioglioma/genética , MicroRNAs/genética , Transcriptoma , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Análise em Microsséries , Estudos Prospectivos , Curva ROC
4.
Am J Med Genet A ; 179(8): 1622-1627, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31173478

RESUMO

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder, with only about 100 cases reported worldwide. It is characterized by congenital lesions of the eye, skin, and central nervous system. Only recently, potential causative FGFR1 point mutations have been identified in brain tumors and cultured skin biopsies from patients with this condition. Here, we analyzed the molecular status of a patient with ECCL and a coexisting pilocytic astrocytoma with detected FGFR1 N546K mutation. The presence of the alteration in both affected and unaffected tissues has been evaluated using Sanger sequencing and droplet digital polymerase chain reaction (ddPCR) technique. The ddPCR analysis showed differential distribution of the alteration in all specimens, including unaffected and untreated samples. Therefore, we confirm that FGFR1 N546K is a plausible causative mutation of ECCL patients and could be associated with a risk of brain tumor development. We also show the usefulness of sensitive ddPCR method for detection of low levels of autosomal mosaic mutation in blood or swabs. We suggest that utilization of this method may improve the diagnostic process, especially when targeted therapies are considered.


Assuntos
Astrocitoma/diagnóstico , Astrocitoma/genética , Oftalmopatias/diagnóstico , Oftalmopatias/genética , Lipomatose/diagnóstico , Lipomatose/genética , Mosaicismo , Mutação , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Fácies , Perfilação da Expressão Gênica , Humanos , Imageamento por Ressonância Magnética , Fenótipo
5.
Nature ; 501(7465): 102-6, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23903654

RESUMO

Prion infections cause lethal neurodegeneration. This process requires the cellular prion protein (PrP(C); ref. 1), which contains a globular domain hinged to a long amino-proximal flexible tail. Here we describe rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the α1 and α3 helices of the PrP(C) globular domain. Ligands included seven distinct monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of globular domain ligands required neuronal PrP(C), was exacerbated by PrP(C) overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. We also found that neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. We conclude that PrP(C) consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrP(C) mutant, PrP(Δ94-134), indicating that the flexible tail mediates toxicity in two distinct PrP(C)-related conditions. Flexible tail-mediated toxicity may conceivably play a role in further prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides.


Assuntos
Anticorpos/imunologia , Anticorpos/toxicidade , Maleabilidade , Príons/química , Príons/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/toxicidade , Sítios de Ligação de Anticorpos , Calpaína/metabolismo , Cerebelo , Síndrome de Creutzfeldt-Jakob/metabolismo , Reagentes de Ligações Cruzadas , Mapeamento de Epitopos , Feminino , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/toxicidade , Técnicas In Vitro , Ligantes , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Dados de Sequência Molecular , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Proteínas PrPC/química , Proteínas PrPC/genética , Proteínas PrPC/imunologia , Príons/genética , Espécies Reativas de Oxigênio/metabolismo , Deleção de Sequência/genética , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/toxicidade
6.
Nature ; 482(7384): 226-31, 2012 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-22286061

RESUMO

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Cromatina/genética , Glioblastoma/genética , Histonas/genética , Mutação/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Bases , Criança , Cromatina/metabolismo , Proteínas Correpressoras , DNA Helicases/genética , Análise Mutacional de DNA , Exoma/genética , Perfilação da Expressão Gênica , Histonas/metabolismo , Humanos , Chaperonas Moleculares , Dados de Sequência Molecular , Proteínas Nucleares/genética , Telômero/genética , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X
7.
Alzheimers Dement ; 14(6): 751-763, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29391125

RESUMO

INTRODUCTION: Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown. METHODS: Cerebrospinal fluid NFL levels were quantified in nonprimarily neurodegenerative neurological and psychiatric diseases (n = 122), mild cognitive impairment (n = 48), Alzheimer's disease (n = 108), dementia with Lewy bodies/Parkinson's disease dementia (n = 53), vascular dementia (n = 46), frontotemporal dementia (n = 41), sporadic Creutzfeldt-Jakob disease (sCJD, n = 132), and genetic prion diseases (n = 182). RESULTS: The highest NFL levels were detected in sCJD, followed by vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease dementia, Alzheimer's disease, and mild cognitive impairment. In sCJD, NFL levels correlated with cerebrospinal fluid tau and disease duration. NFL levels were able to differentiate sCJD from nonprimarily neurodegenerative neurological and psychiatric diseases (area under the curve = 0.99, 95% confidence interval: 0.99-1) and from the other diagnostic groups showing cognitive impairment/dementia of a non-CJD etiology (area under the curve = 0.90, 95% confidence interval: 0.87-0.92). Compared to nonprimarily neurodegenerative neurological and psychiatric diseases, NFL was also elevated in genetic prion diseases associated with the E200K, V210I, P102L, and D178N prion protein gene mutations. DISCUSSION: Increased NFL levels are a common feature in neurodegenerative dementias.


Assuntos
Demência/líquido cefalorraquidiano , Doenças Priônicas/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Demência/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Priônicas/diagnóstico
8.
Dement Geriatr Cogn Disord ; 43(1-2): 71-80, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28056460

RESUMO

BACKGROUND: Several biomarkers have been proposed to discriminate sporadic Creutzfeldt-Jakob disease (sCJD) from other dementias and control cases. However, their clinical accuracy depends on the PRNP codon 129 genotype, leaving it unclear how well established markers behave in untested conditions. METHODS: We analyzed 14-3-3, tau, p-tau levels, and the p-tau/tau ratio in a population sample collected from Polish hospitals including nondementia, dementia, and definite sCJD cases and validated their parameters according to previously established cutoffs. Additionally, the correlation between biomarkers and disease duration as well as the influence of the PRNP129 polymorphism are reported. RESULTS: The tau levels and p-tau/tau ratios differed considerably between sCJD and clinically characterized non-CJD cases (p < 0.001). p-tau was only elevated in sCJD when compared to cases without dementia (p < 0.05). Tau and the p-tau/tau ratio showed a sensitivity of 95 and 100%, respectively, in detecting sCJD cases. A negative correlation between tau levels and disease duration, but not the timing of lumbar puncture was observed. CONCLUSION: The present findings confirmed the value of the p-tau/tau ratio as a robust sCJD biomarker and suggest a role for tau as prognostic marker.


Assuntos
Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Proteínas 14-3-3/líquido cefalorraquidiano , Idoso , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Demência/líquido cefalorraquidiano , Demência/diagnóstico , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Polônia , Polimorfismo Genético/genética , Proteínas Priônicas/líquido cefalorraquidiano , Proteínas Priônicas/genética , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Punção Espinal , Proteínas tau/líquido cefalorraquidiano
9.
Alzheimers Dement ; 13(6): 710-719, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27870938

RESUMO

INTRODUCTION: Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context. METHODS: We established the clinical parameters for prion disease diagnosis for the quantification of CSF α-synuclein in patients with sporadic (n = 234) and genetic (n = 56) prion diseases, in cases with cognitive impairment/dementia or neurodegenerative disease (n = 278), and in the neurologic control group (n = 111). RESULTS: An optimal cutoff value of 680 pg/mL α-synuclein results in 94% sensitivity and 96% specificity when diagnosing sporadic Creutzfeldt-Jakob disease (CJD). Genetic CJD cases showed increased CSF α-synuclein values. No increased α-synuclein levels were detected in non-CJD cases with rapid progression course. DISCUSSION: Detection of α-synuclein in the CSF of patients with suspected CJD is a valuable diagnostic test reaching almost full discrimination from non-prion disease cases. These data highlight the utility of CSF α-synuclein quantification in front of classical CSF biomarkers in clinical routine.


Assuntos
Doenças Priônicas/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Idoso , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Humanos , Pessoa de Meia-Idade , Sensibilidade e Especificidade
10.
Acta Neuropathol ; 131(6): 847-63, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26920151

RESUMO

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.


Assuntos
Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA/genética , Glioma/genética , Mutação/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Adulto , Feminino , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteínas Proto-Oncogênicas B-raf/genética , Adulto Jovem
11.
Neurol Neurochir Pol ; 50(4): 288-93, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375146

RESUMO

Meningiomas (MGs) are the most frequent primary tumours of the central nervous system (CNS) and exhibit a large spectrum of histological types and clinical phenotypes. The WHO classification of CNS tumours established strict diagnostic criteria of the benign (Grade 1), atypical (Grade 2) and anaplastic (Grade 3) subtypes. Combined with the resection rate, WHO grading has the most crucial role as the prognostic factor. Additionally, such biomarkers as Ki-67/MIB-1, progesterone receptors and phosphor-histone H3 were correlated with MG progression. Recently, it was suggested that the aggressive behaviour of some MGs is attributed to molecular alterations, regardless of their histopathology. The analysis of loss of heterozygosity (LOH) at chromosomes 1, 9, 10, 14 and 22 was performed. The presented case of WHO Grade 2 MG initially exhibited LOH at chromosomes 10, 14 and 22. In the first recurrence, the tumour genetic profiling revealed additional LOH at chromosome 1p and atypical histopathology. During the second recurrence, an aggressive phenotype was observed and tumour progressed to an anaplastic form. Considering the appearance of the tumour relapses, the set of molecular changes overtook the histopathological progression. The genetic and histopathological imbalance in the tumour progression in secondary anaplastic MGs has not been previously described. The evolution of genetic and histopathological changes was presented in the same patient. In the future, the individualised therapy of potentially more aggressive forms of MGs could be based on certain chromosome aberrations.


Assuntos
Encéfalo/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Progressão da Doença , Humanos , Perda de Heterozigosidade , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/genética , Meningioma/diagnóstico por imagem , Meningioma/genética , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
12.
Neurol Neurochir Pol ; 50(6): 439-448, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27575681

RESUMO

Complete removal of a meningioma (MG) does not guarantee relapse-free survival. Alterations on several chromosomes responsible for MG recurrence were suggested, although their role was not validated by a systematic review. Following the analysis of own 161 cases, all previously published data has been collected for evidence synthesis. Based on own series, WHO grade >I (odds ratio (OR)=92.0; 95%CI: 19.1-443.5) and a combination of loss of heterozygosity (LOH) on 1p and 14q (OR=10.2; 95%CI: 19-55.7) were the independent recurrence-specific prognosticators. The deleterious role of LOH on 1p/14q was demonstrated in a subset of parasagittal and falcine MGs. A total of 742 cases and 10 studies were pooled for the Individual Patient Data and Aggregate Data models of meta-analysis, respectively. The prognostic role of WHO classification (OR=90.4) and anomaly of chromosome 14 (OR=3.5) was confirmed. LOH on 14 showed lesser impact on recurrence than suggested by the WHO grading (area under the curve 0.65 for LOH vs. 0.74 for WHO). Fixed effect model of meta-analysis provided high summarized OR values for 1p (OR=5.4; 95%CI: 3.6-8.1) and 14q (OR=7.6; 95%CI: 4.3-13.6), and low for chromosome 22 (OR=1.6; 95%CI: 1.1-2.4). Final appraisal of recurrence-associated chromosomal alterations indicated that arms 1p and 14q deserve attention while predicting MG recurrence.


Assuntos
Aberrações Cromossômicas , Perda de Heterozigosidade , Neoplasias Meníngeas/genética , Meningioma/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Meningioma/diagnóstico por imagem , Meningioma/patologia , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Tomografia Computadorizada por Raios X , Adulto Jovem
13.
Neurol Neurochir Pol ; 50(6): 395-402, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27480481

RESUMO

Meningiomas (MGs) are the frequent benign intracranial tumors. Their complete removal does not always guarantee relapse-free survival. Recurrence-associated chromosomal anomalies in MGs haves been proposed as prognostic factors in addition to the World Health Organisation (WHO) grading, tumor size and resection rate. The aim of this study was to evaluate the frequency of deletions on chromosomes in sporadic MGs and to correlate them with the clinical findings and tumor behaviour. Along with survival, the tumor recurrence was the main endpoint. Chromosomal loss of heterozygosity (LOH) was studied. 46 benign MGs were subjected to the analysis, complete tumor resection was intended and no early mortalities were observed. Incomplete removal was related to parasagittal location and psammomatous hisptopathology (p<0.01). Chromosomal alterations were present in 82.6% of cases; LOH at 22q (67.4%) and 1p (34.8%) were the most frequent and associated with male sex (p=0.04). Molecular findings were not specific for any of the histopathologic grade. Tumor recurrence (14 of 46) correlated with tumor size (≥35mm), LOH at 1p, 14q, coexistence of LOH at 1p/14q, 10q/14q, 'complex karyotype' status (≥2 LOHs excluding 22q), patient age (younger <35), and Simpson grading of resection rate (≥3 of worse prognosis). The last 3 variables were independent significant prognostic factors in multivariate analysis and of the same importance in recurrence prediction (Receiver Operating Characteristic curves comparison p>0.05). Among the cases of recurrence, tumor progression was observed in 3 of 14. In 2 cases, LOH on 1p and/or coexistence of LOH 1p/14q correlated with anaplastic transformation.


Assuntos
Deleção Cromossômica , Perda de Heterozigosidade/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Recidiva Local de Neoplasia/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Progressão da Doença , Feminino , Humanos , Masculino , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/cirurgia , Meningioma/patologia , Meningioma/cirurgia , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Curva ROC , Fatores Sexuais , Taxa de Sobrevida , Adulto Jovem
14.
BMC Cancer ; 15: 778, 2015 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-26497896

RESUMO

BACKGROUND: Pilocytic astrocytoma is the most common type of brain tumor in the pediatric population, with a generally favorable prognosis, although recurrences or leptomeningeal dissemination are sometimes also observed. For tumors originating in the supra-or infratentorial location, a different molecular background was suggested, but plausible correlations between the transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features, and the clinical pattern of the disease. METHODS: Eighty six children (55 males and 31 females) with histologically verified pilocytic astrocytoma were included in this study. Their age at the time of diagnosis ranged from fourteen months to seventeen years, with a mean age of seven years. There were 40 cerebellar, 23 optic tract/hypothalamic, 21 cerebral hemispheric, and two brainstem tumors. According to the radiological features presented on MRI, all cases were divided into four subtypes: cystic tumor with a non-enhancing cyst wall; cystic tumor with an enhancing cyst wall; solid tumor with central necrosis; and solid or mainly solid tumor. In 81 cases primary surgical resection was the only and curative treatment, and in five cases progression of the disease was observed. In 47 cases the analysis was done by using high density oligonucleotide microarrays (Affymetrix HG-U133 Plus 2.0) with subsequent bioinformatic analyses and confirmation of the results by independent RT-qPCR (on 39 samples). RESULTS: Bioinformatic analyses showed that the gene expression profile of pilocytic astrocytoma is highly dependent on the tumor location. The most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression even within different compartments of the supratentorial region. Analysis of the genes potentially associated with radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression. CONCLUSIONS: Here we have shown that pilocytic astrocytomas of three different locations can be precisely differentiated on the basis of their gene expression level, but their transcriptional profiles does not strongly reflect the radiological appearance of the tumor or the course of the disease.


Assuntos
Astrocitoma/genética , Neoplasias do Sistema Nervoso Central/genética , Adolescente , Astrocitoma/diagnóstico por imagem , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Recidiva Local de Neoplasia , Prognóstico , Radiografia , Transcriptoma
15.
Int J Neurosci ; 125(10): 755-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25385508

RESUMO

BACKGROUND: Mutations in the THAP1 gene are associated with a broad spectrum of dystonia including focal and generalized forms. Missense, nonsense and frameshift mutations, including small insertions/deletions within the THAP1 gene, have been reported and majority of them cause autosomal dominant disease with limited penetrance of approximately 60%. Here, we describe a novel THAP1 mutation. MATERIALS AND METHODS: Blood samples were collected from consenting family members for extraction of genomic DNA. As controls, we analyzed 150 individuals without neurological disorders. THAP1 coding sequences were amplified with PCR and sequenced. RESULTS: We describe a Polish family with a novel heterozygous substitution: c.167A>G (p.Glu56Gly) in THAP1 exon 2. This is the largest reported family with the mutation in THAP1 exon 2. The mutation was found in four of five genetically studied family members, including two clinically affected male individuals and two asymptomatic carriers (male and female). Data on one deceased male symptomatic subject were available and two assumed carriers were identified. The substitution was not present in any of the analyzed healthy controls. The high variability of phenotype included age of onset, localization of the initial symptom as well as the rate and degree of generalization. CONCLUSIONS: Our findings strongly suggest the role of other genetic factors or environmental triggers in the pathogenesis of dystonia related to mutations in THAP1 gene.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação a DNA/genética , Distonia/genética , Distonia/fisiopatologia , Proteínas Nucleares/genética , Adulto , Estudos de Casos e Controles , Distonia/diagnóstico , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Polônia , Análise de Sequência de DNA , População Branca/genética
16.
PLoS Pathog ; 8(11): e1002985, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23133383

RESUMO

Prions cause neurodegeneration in vivo, yet prion-infected cultured cells do not show cytotoxicity. This has hampered mechanistic studies of prion-induced neurodegeneration. Here we report that prion-infected cultured organotypic cerebellar slices (COCS) experienced progressive spongiform neurodegeneration closely reproducing prion disease, with three different prion strains giving rise to three distinct patterns of prion protein deposition. Neurodegeneration did not occur when PrP was genetically removed from neurons, and a comprehensive pharmacological screen indicated that neurodegeneration was abrogated by compounds known to antagonize prion replication. Prion infection of COCS and mice led to enhanced fodrin cleavage, suggesting the involvement of calpains or caspases in pathogenesis. Accordingly, neurotoxicity and fodrin cleavage were prevented by calpain inhibitors but not by caspase inhibitors, whereas prion replication proceeded unimpeded. Hence calpain inhibition can uncouple prion replication from its neurotoxic sequelae. These data validate COCS as a powerful model system that faithfully reproduces most morphological hallmarks of prion infections. The exquisite accessibility of COCS to pharmacological manipulations was instrumental in recognizing the role of calpains in neurotoxicity, and significantly extends the collection of tools necessary for rigorously dissecting prion pathogenesis.


Assuntos
Cerebelo/metabolismo , Doenças Priônicas/metabolismo , Príons/metabolismo , Príons/patogenicidade , Animais , Calpaína/genética , Calpaína/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Caspases/genética , Caspases/metabolismo , Cerebelo/patologia , Camundongos , Camundongos Transgênicos , Microdissecção/métodos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Doenças Priônicas/genética , Doenças Priônicas/patologia , Príons/genética , Proteólise
17.
Cancer Cell Int ; 14: 82, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25788865

RESUMO

BACKGROUND: The molecular heterogeneity of high-grade astrocytomas underlies the difficulties in the development of representative and valuable in vitro experimental models for their studies. The purpose of our study was to estimate the value of astrocytoma-associated antigens (AAAs) - IL13Rα2, Fra-1, EphA2 - and the most common molecular aberrations typical for astrocytomas as potential markers to screen the status of tumour-derived cell cultures in vitro. METHODS: The tumour-derived cell cultures were established from high-grade astrocytomas. The expression analyses of the tested genes were performed via semi-quantitative real-time PCR and subsequently verified by immunohistochemical and immunocytochemical technique. The analyses of molecular aberrations at DNA level included gene dosage status evaluation based on real-time PCR, sequencing analysis, and loss of heterozygosity (LOH) assay. RESULTS: The expression analyses based on semi-quantitative real-time PCR showed that in the final stage of culture the expression level of all tested AAAs was significantly higher or at least comparable to that of primary tumours; however, two expression patterns were observed during cell culture establishment. Analysis at the single cell level via immunocytochemistry also demonstrated an increase of the level of tested proteins and/or selection of tumour cell populations strongly positive for AAAs vs. other cell types including admixed non-tumoural cells. Confrontation of AAA expression data with the results of molecular analyses at DNA level seems to support the latter, revealing that the expression pattern of astrocytoma-associated antigens in tumour-derived cells in subsequent stages of culture is convergent with changes in the molecular profile of examined cell populations. CONCLUSIONS: The consistency of the obtained results seems to support the use of the selected AAAs, in particular IL13Rα2 and Fra-1, as tools facilitating the establishment of tumour-derived cultures. However, the intratumoural heterogeneity of high-grade astrocytomas may require further detailed characterisation of the molecular profile of a tumour in order to evaluate the value of the experimental model in relation to the individual context of particular studies.

18.
PLoS One ; 19(7): e0304528, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39079175

RESUMO

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.


Assuntos
Idade de Início , Síndrome de Creutzfeldt-Jakob , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Humanos , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , Idoso , Pessoa de Meia-Idade , Feminino , Masculino , Fenótipo , Genótipo
19.
Acta Neuropathol ; 125(5): 659-69, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23417712

RESUMO

Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15% of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15% of pediatric HGGs (11/73) and 8% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Mutação/genética , Adolescente , Adulto , Fatores Etários , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Exoma , Glioma/metabolismo , Glioma/patologia , Histona Metiltransferases , Humanos , Lactente , Metilação , Pessoa de Meia-Idade , Gradação de Tumores , Adulto Jovem
20.
Virol J ; 10: 160, 2013 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-23693084

RESUMO

BACKGROUND: Guided by decades-old reports of hantaviral antigens in the Eurasian common shrew (Sorex araneus) and the Eurasian water shrew (Neomys fodiens) in European Russia, we employed RT-PCR to analyze lung tissues of soricine shrews, captured in Boginia, Huta Dlutowska and Kurowice in central Poland during September 2010, 2011 and 2012. FINDINGS: In addition to Seewis virus (SWSV), which had been previously found in Eurasian common shrews elsewhere in Europe, a genetically distinct hantavirus, designated Boginia virus (BOGV), was detected in Eurasian water shrews captured in each of the three villages. Phylogenetic analysis, using maximum likelihood and Bayesian methods, showed that BOGV formed a separate lineage distantly related to SWSV. CONCLUSIONS: Although the pathogenic potential of BOGV and other recently identified shrew-borne hantaviruses is still unknown, clinicians should be vigilant for unusual febrile diseases and clinical syndromes occurring among individuals reporting exposures to shrews.


Assuntos
Eulipotyphla/virologia , Orthohantavírus/classificação , Orthohantavírus/isolamento & purificação , Animais , Análise por Conglomerados , Genótipo , Orthohantavírus/genética , Pulmão/virologia , Dados de Sequência Molecular , Filogenia , Polônia , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Homologia de Sequência
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa