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1.
N Engl J Med ; 372(26): 2499-508, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-26061753

RESUMO

BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).


Assuntos
Cromossomos Humanos Par 19 , Cromossomos Humanos Par 1 , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Telomerase/genética , Adulto , Idade de Início , Biomarcadores Tumorais , Análise Mutacional de DNA , DNA de Neoplasias/análise , Feminino , Mutação em Linhagem Germinativa , Glioma/classificação , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais
2.
BMC Neurol ; 15: 203, 2015 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-26467435

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome with both genetic and acquired causes characterized by elevated cytokine levels, hyperinflammation, and overactivation of lymphocytes and macrophages. It is typically a systemic disease with variable degrees of CNS involvement. Cases with predominantly central nervous system (CNS) involvement are very rare, with the vast majority of these occurring in infants and young children. This report documents a case of adult-onset CNS-HLH involving a middle-aged man. CASE PRESENTATION: A 55 year-old man developed progressive left hemiparesis and aphasia over the course of several months. Brain MRI showed multifocal, mass-like enhancing lesions with increased susceptibility consistent with blood products. An extensive workup for infectious, autoimmune, and neoplastic etiologies was significant only for a markedly elevated serum ferritin at 1456 ng/mL. Two brain biopsies showed a non-specific inflammatory process. The patient was treated empirically with steroids and plasmapheresis, but he continued to suffer a progressive neurological decline and died one year after onset of neurological symptoms. Autopsy revealed profound histiocytic infiltration, perivascular lymphocytosis, and emperipolesis, compatible with CNS-HLH. CONCLUSION: This case report describes an exceedingly rare presentation of an adult patient with CNS predominant HLH. This diagnosis should be considered in the differential diagnosis of adults presenting with progressive brain lesions, even in the absence of typical systemic signs of HLH.


Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Idade de Início , Autopsia , Biópsia , Evolução Fatal , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
3.
Clin Neuropathol ; 34(5): 258-66, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25943270

RESUMO

A 29-year-old pregnant woman developed progressively worsening encephalopathy, left hemiparesis, and hemodynamic instability over a 6-week period. Initial brain MRI and work-up for infectious and autoimmune causes were normal, although elevated IgG and oligoclonal bands were seen on analysis of the cerebrospinal fluid (CSF). After uncomplicated spontaneous delivery of a preterm healthy infant, her condition worsened. Repeat brain MRI demonstrated generalized volume loss and evidence of corticospinal tract degeneration. She underwent a brain biopsy, which showed characteristic viral inclusions of the type seen in subacute sclerosing panencephalitis (SSPE). The diagnosis was confirmed by immunohistochemistry and electron microscopy, and additional CSF analysis also showed markedly elevated IgG titer for measles. Sequence analysis of the nucleoprotein gene N-450 demonstrated a close relationship to the sequences of viruses in genotype D7. This case documents an ~ 6-month progression to death of SSPE in a pregnant woman.


Assuntos
Encéfalo/patologia , Complicações na Gravidez/patologia , Panencefalite Esclerosante Subaguda/patologia , Adulto , Encéfalo/fisiopatologia , Evolução Fatal , Feminino , Hemodinâmica/fisiologia , Humanos , Imageamento por Ressonância Magnética , Gravidez , Complicações na Gravidez/fisiopatologia , Panencefalite Esclerosante Subaguda/fisiopatologia
4.
Neuropathology ; 35(6): 575-81, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26094647

RESUMO

Distal myopathies are a group of clinically and pathologically overlapping muscle diseases that are genetically complex and can represent a diagnostic challenge. Laing early-onset distal myopathy (MPD1) is a form of distal myopathy caused by mutations in the MYH7 gene, which encodes the beta myosin heavy chain protein expressed in type 1 skeletal muscle fibers and cardiac myocytes. Here, we present a case of genetically confirmed MPD1 with a typical clinical presentation but distinctive light microscopic and ultrastructural findings on muscle biopsy. A 39-year-old professional male cellist presented with a bilateral foot drop that developed by age 8; analysis of the family pedigree showed an autosomal dominant pattern of inheritance. The physical exam demonstrated bilateral weakness of ankle dorsiflexors, toe extensors and finger extensors; creatine kinase level was normal. Biopsy of the quadriceps femoris muscle showed predominance and hypotrophy of type 1 fibers, hybrid fibers with co-expression of slow and fast myosin proteins (both in highly atrophic and normal size range), moth-eaten fibers and mini-cores, lack of rimmed vacuoles and rare desmin-positive eosinophilic sarcoplasmic inclusions. In addition to these abnormalities often observed in MPD1, the biopsy demonstrated frequent clefted fibers with complex sarcolemmal invaginations; on ultrastructural examination, these structures closely mimicked myotendinous junctions but were present away from the tendon and were almost exclusively found in type 1 fibers. Sequencing analysis of the MYH7 gene in the index patient and other affected family members demonstrated a previously described heterozygous c.4522_4524delGAG (p.Glu1508del) mutation. This case widens the pathologic spectrum of MPD1 and highlights the pathologic and clinical variability that can accompany the same genetic mutation, suggesting a significant role for modifier genes in MPD1 pathogenesis.


Assuntos
Miopatias Distais/patologia , Sarcolema/ultraestrutura , Adulto , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Músculo Esquelético/ultraestrutura , Linhagem
5.
Mod Pathol ; 26(10): 1279-87, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23702730

RESUMO

Pilocytic astrocytoma is a low-grade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Pilocytic astrocytoma of the optic nerve is an equally indolent subtype that is occasionally associated with neurofibromatosis type 1. In earlier studies, this subtype was considered within the larger category of 'optic pathway glioma,' which included infiltrating astrocytomas and other hypothalamic tumors. However, there have been suggestions that gliomas in the optic nerve, and especially pilocytic astrocytoma of the optic nerve, are biologically different from tumors within the hypothalamus and other parts of the optic tract. Furthermore, the recent discovery of BRAF duplication and fusion with the KIAA1549 gene is reported to be more typical for posterior fossa tumors, and the rate of this aberration is not well known in pilocytic astrocytoma of the optic nerve. To determine the distinction of pilocytic astrocytoma of the optic nerve from pilocytic astrocytoma of the posterior fossa and to investigate the prevalence of BRAF aberrations, we reviewed the clinicopathological and molecular features of all such patients in our institution. Our study demonstrates that BRAF duplication is more frequent in posterior fossa tumors compared with pilocytic astrocytoma of the optic nerve (P=0.011). However, the rates of phospho-MAPK1 and CDKN2A expression were high in both pilocytic astrocytoma of the optic nerve and posterior fossa pilocytic astrocytoma, suggesting that the MAPK pathway is active in these tumors. Our study supports the notion that BRAF duplication is more typical of posterior fossa pilocytic astrocytoma and that molecular alterations other than KIAA1549 fusion may underlie MAPK pathway activation in pilocytic astrocytoma of the optic nerve.


Assuntos
Astrocitoma/patologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Nervo Óptico/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/genética , Astrocitoma/metabolismo , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Masculino , Neoplasias do Nervo Óptico/genética , Neoplasias do Nervo Óptico/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo
6.
Hum Mol Genet ; 19(22): 4399-408, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20817925

RESUMO

Neurodegeneration induced by abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau defines neurodegenerative tauopathies. Destabilization of microtubules by loss of tau function and filament formation by toxic gain of function are two mechanisms suggested for how abnormal tau triggers neuronal loss. Recent experiments in kinesin-1 deficient mice suggested that axonal transport defects can initiate biochemical changes that induce activation of axonal stress kinase pathways leading to abnormal tau hyperphosphorylation. Here we show using Drosophila and mouse models of tauopathies that reductions in axonal transport can exacerbate human tau protein hyperphosphorylation, formation of insoluble aggregates and tau-dependent neurodegeneration. Together with previous work, our results suggest that non-lethal reductions in axonal transport, and perhaps other types of minor axonal stress, are sufficient to induce and/or accelerate abnormal tau behavior characteristic of Alzheimer's disease and other neurodegenerative tauopathies.


Assuntos
Cinesinas/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Tauopatias/metabolismo , Proteínas tau/metabolismo , Animais , Animais Geneticamente Modificados , Transporte Axonal/fisiologia , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Drosophila , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Mutantes , Camundongos Transgênicos , Fosforilação , Tauopatias/patologia , Tauopatias/fisiopatologia
7.
Brain Pathol ; 29(1): 75-84, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30417460

RESUMO

Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved 14 anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: ≥5 mitoses per 10 high power fields, Ki-67 labeling index (LI) ≥10%, microvascular proliferation (MVP) and spontaneous necrosis. These features were typically encountered in the foci of hypercellularity and reduced mucin. There were eight male and six female patients (age range 6-57 years, median = 16.5). Ten tumors displayed anaplasia at initial resection, and 4 were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8% and 40% in the anaplastic foci and <3% in the foci of classic MPE. There was documented cerebrospinal fluid (CSF) dissemination in seven cases, recurrence following an anaplastic diagnosis in three cases and bone or soft tissue invasion in two cases. One patient suffered lung metastases. Two cases evaluated by targeted next-generation sequencing and one evaluated by fluorescence in situ hybridization (FISH) showed nonspecific chromosomal gains. We conclude that although rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, closer follow-up is recommended, given the concern for aggressive biologic potential. Further study is needed to determine WHO grading criteria and genetic indicators of tumor progression.


Assuntos
Ependimoma/diagnóstico , Ependimoma/patologia , Neoplasias da Medula Espinal/patologia , Adolescente , Adulto , Antígenos Nucleares , Criança , Feminino , Humanos , Hibridização in Situ Fluorescente , Antígeno Ki-67 , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia
9.
Am J Surg Pathol ; 42(4): 506-511, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29324471

RESUMO

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Epigênese Genética , Neoplasias Hipofisárias/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Adulto , Fatores Etários , Idoso , Feminino , Deleção de Genes , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Neoplasias Hipofisárias/patologia , Mutação Puntual , Tumor Rabdoide/patologia , Teratoma/patologia , Adulto Jovem
10.
Cell Rep ; 22(13): 3672-3683, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29590631

RESUMO

Meningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. Using 280 human meningioma samples and RNA sequencing, immunohistochemistry, whole-exome sequencing, DNA methylation arrays, and targeted gene expression profiling, we comprehensively define the molecular profile of aggressive meningioma. Transcriptomic analyses identify FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, we discover genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, we define a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. In summary, we find that multiple molecular mechanisms converge on a FOXM1/Wnt signaling axis in aggressive meningioma.


Assuntos
Proteína Forkhead Box M1/genética , Meningioma/genética , Proliferação de Células/genética , Metilação de DNA , Feminino , Proteína Forkhead Box M1/biossíntese , Proteína Forkhead Box M1/metabolismo , Expressão Gênica , Humanos , Masculino , Meningioma/metabolismo , Meningioma/patologia , Transfecção , Células Tumorais Cultivadas , Via de Sinalização Wnt
11.
J Neuropathol Exp Neurol ; 75(10): 925-935, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27539476

RESUMO

Glioblastomas (GBM) are aggressive brain tumors that inevitably recur despite surgical resection, chemotherapy, and radiation. The degree to which recurrent GBM retains its initial immunophenotype is incompletely understood. We generated tissue microarrays of paired initial and posttreatment GBM (3 pairs positive and 17 negative for IDH1R132H) from the same patients and made comparisons in the IDH1R132H-negative group for immunohistochemical and gene expression differences between primary and recurrent tumors. In initial tumors, immunopositivity for Ki-67 in > 20% of tumor cells was associated with shorter progression-free and overall survival. Recurrent tumors showed decreased staining for CD34 suggesting lower vessel density. A subset of tumors showed increased staining for markers associated with the mesenchymal gene expression pattern, including CD44, phosphorylated STAT3, and YKL40. Recurrent tumors with the greatest increase in mesenchymal marker expression had rapid clinical progression, but no difference in overall survival after second surgery. Comparison of protein and gene expression data from the same samples revealed a poor correlation. A subset of tumors (15%) showed loss of neurofibromin protein in both initial and recurrent tumors. These data support the notion that GBM progression is associated with a shift toward a mesenchymal phenotype in a subset of tumors and this may portend a more aggressive behavior.

12.
Nat Cell Biol ; 18(12): 1336-1345, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27820599

RESUMO

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.


Assuntos
Neoplasias Encefálicas/patologia , Retroalimentação Fisiológica , Glioblastoma/metabolismo , Glioblastoma/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isocitrato Desidrogenase/metabolismo , Tenascina/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Imunofluorescência , Humanos , Isocitrato Desidrogenase/genética , Mecanotransdução Celular , MicroRNAs/metabolismo , Mutação/genética , Invasividade Neoplásica , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Semin Pediatr Neurol ; 22(1): 23-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25976257

RESUMO

Pilocytic astrocytoma (PA) is the most common astrocytic neoplasm of childhood. Patients have an extremely favorable prognosis after surgical resection, qualifying tumors for a grade I designation by the World Health Organization. The molecular data on PA support a key role for the BRAF oncogene in the pathogenesis of these tumors, with the KIAA1549-BRAF fusion being the most common alteration identified in sporadic cases, particularly those occurring in the posterior fossa. Constitutive activation of BRAF leads to downstream activation of the MEK/MAPK/ERK/p16 pathway, which interestingly is also used by cells to activate oncogene-induced senescence (OIS). In fact, the presence of an active OIS pathway might explain the periods of dormancy or spontaneous regression or both, that can be seen in PA. In addition to reviewing the historical evolution, clinicopathologic, predictive, prognostic, and molecular features of PA, we discuss current therapeutic strategies and the caveats that should be considered for the development of therapies that could be used to more effectively treat challenging cases. Individualized treatment requires identification of the type of MAPK alteration, as several alterations in BRAF have been described in addition to the KIAA1549-BRAF fusion. Combination regimens would also appear crucial to achieve tumor eradication and prevent the development of drug resistance. Balancing mitogen-activated protein kinases (MAPK) pathway inhibition with abrogation of an active OIS should be carefully considered as well to preserve any existing protective pathways. Importantly, PAs are largely indolent tumors, and care should be taken to avoid overtreatment, as aggressive therapy could cause more harm than good.


Assuntos
Astrocitoma/genética , Astrocitoma/terapia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/terapia , Testes Genéticos , Humanos
14.
Surg Pathol Clin ; 8(1): 63-71, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25783822

RESUMO

The pilocytic astrocytoma is predominantly a tumor of childhood and the most common type of circumscribed astrocytoma. The indolent nature of this tumor allows for prolonged survival for most patients, rendering the disease a rather "chronic" one, with potential long-term sequelae that are occasionally related to treatment. Two critical features of this tumor are its tendency to remain dormant, or involute even after subtotal resection, and the exceptional anaplastic transformation, sometimes following adjuvant therapy. The biological behavior of pilocytic astrocytoma can often be related to molecular alterations in the MAPK pathway.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Astrocitoma/classificação , Astrocitoma/diagnóstico por imagem , Astrocitoma/terapia , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Senescência Celular , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Proto-Oncogênicas B-raf/genética , Radiografia
15.
J Neuropathol Exp Neurol ; 74(5): 442-52, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25853694

RESUMO

Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.


Assuntos
Astrocitoma/metabolismo , Astrocitoma/mortalidade , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Adulto , Biomarcadores Tumorais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , Análise de Sobrevida
16.
Cancer Cell ; 28(3): 307-317, 2015 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-26373278

RESUMO

The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Mutação/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Glioma/genética , Humanos , Filogenia , Regiões Promotoras Genéticas/genética , Transcrição Gênica/genética , Regulação para Cima/genética
17.
Rare Tumors ; 6(2): 5313, 2014 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-25002947

RESUMO

Tumor-to-tumor metastasis of breast carcinoma to meningioma is a rare phenomenon. It is likely underdiagnosed given the relatively high prevalence and comorbidity of these two primary tumor types, the lack of standardized methodologies for its diagnosis, and the tendency to obfuscate this lesion with simple meningioma or cerebral metastasis of breast carcinoma. Careful histopathologic study of the resected meningioma is the cornerstone of diagnosis of these lesions, although certain conventional radiological features along with specialized modalities may clue the diagnosis. Vigilance for this lesion is appropriate in selected patients with known breast cancer or meningioma, as the two are often coexistent in the same patient, permitting tumor-to-tumor metastasis. Detection of this rare disease process may alter the treatment plan and prognosis. Here, we report a case of breast carcinoma-to-meningioma metastasis in a patient who developed subacute neurological decline while undergoing long-term treatment of her primary, late-stage breast cancer.

18.
Mol Biol Cell ; 23(9): 1700-14, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22398725

RESUMO

Bidirectional axonal transport driven by kinesin and dynein along microtubules is critical to neuronal viability and function. To evaluate axonal transport mechanisms, we developed a high-resolution imaging system to track the movement of amyloid precursor protein (APP) vesicles in Drosophila segmental nerve axons. Computational analyses of a large number of moving vesicles in defined genetic backgrounds with partial reduction or overexpression of motor proteins enabled us to test with high precision existing and new models of motor activity and coordination in vivo. We discovered several previously unknown features of vesicle movement, including a surprising dependence of anterograde APP vesicle movement velocity on the amount of kinesin-1. This finding is largely incompatible with the biophysical properties of kinesin-1 derived from in vitro analyses. Our data also suggest kinesin-1 and cytoplasmic dynein motors assemble in stable mixtures on APP vesicles and their direction and velocity are controlled at least in part by dynein intermediate chain.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Transporte Axonal/fisiologia , Dineínas/metabolismo , Cinesinas/metabolismo , Vesículas Transportadoras/metabolismo , Animais , Transporte Biológico , Biologia Computacional , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Complexo Dinactina , Dineínas/genética , Cinesinas/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Atividade Motora/fisiologia
20.
J Neurophysiol ; 93(6): 3381-9, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15911893

RESUMO

Beta-adrenergic receptors and the cyclic AMP signaling pathway play an important role in neuronal plasticity and in learning and memory and are known to change with aging. We examined the effects of beta-adrenergic stimulation paired with 5-Hz low frequency stimulation (LFS) of Schaffer collateral-commissural afferents on population spike amplitude in area CA1 of hippocampal slices from young (3 mo) and aged (22 mo) Fischer 344 rats. Application of the beta-adrenergic agonist isoproterenol (1 microM) for 10 min followed immediately by 3 min LFS produced long-lasting potentiation in young hippocampi, but the magnitude of potentiation in aged rats was significantly attenuated and was not long-lasting. In slices prepared from young rats, long-term potentiation (LTP) induced by this protocol occludes subsequent attempts to produce conventional high frequency stimulation-induced LTP, and vice versa, suggesting that these two forms of potentiation share one or more molecular mechanisms. Age-related differences in response to LFS alone were not observed, but significant differences in response to beta-adrenergic stimulation were apparent. Similarly, significant age-related differences in response to direct activation of adenylate cyclase with forskolin (10 microM) were observed. In both age groups, this enhancement produced by isoproterenol or forskolin is only transient, returning to baseline within 60 or 90 min, respectively. Taken together, these studies of adenylate cyclase-mediated forms of potentiation in area CA1 suggest that there is an age-related defect, either upstream or downstream of adenylate cyclase activation, in this important signaling system. Such changes may contribute to the compromised performance on memory tasks that is often observed with normal aging.


Assuntos
Adenilil Ciclases/metabolismo , Envelhecimento/fisiologia , Hipocampo/citologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Fatores Etários , Análise de Variância , Animais , Colforsina/farmacologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Estimulação Elétrica/métodos , Ativação Enzimática/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Isoproterenol/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Potenciação de Longa Duração/efeitos da radiação , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo
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