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1.
Vet Pathol ; 60(2): 185-189, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36541627

RESUMO

Sebaceous carcinomas of the human ocular adnexa commonly exhibit pagetoid spread, mutations in tumor-suppressor genes, and protooncogene copy number gain. Sebaceous carcinomas are rarely reported in other species, and while the Meibomian gland (MG) represents the most common ocular adnexal structure of the canine eyelid to develop neoplasia, most are clinically and histologically benign. The objective of this study was to compare molecular features of canine MG carcinomas and adenomas. Two retrospectively identified MG carcinomas were subject to immunohistochemistry and qPCR. When compared with normal glands, MYC was upregulated in benign and malignant MG neoplasms. Aberrant p53 expression was restricted to the nuclei of intraepithelial neoplastic cells in MG carcinomas. Adipophilin expression was diminished in MG neoplasms compared with the normal MG. Our findings, if confirmed in a larger cohort of cases, could suggest that MG oncogenesis in a dog may exhibit similar molecular features as their human counterparts.


Assuntos
Adenoma , Carcinoma Basocelular , Doenças do Cão , Neoplasias das Glândulas Sebáceas , Neoplasias Cutâneas , Humanos , Cães , Animais , Glândulas Tarsais/metabolismo , Glândulas Tarsais/patologia , Proteína Supressora de Tumor p53 , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/química , Neoplasias das Glândulas Sebáceas/metabolismo , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sebáceas/veterinária , Neoplasias Cutâneas/veterinária , Carcinoma Basocelular/veterinária , Transformação Celular Neoplásica , Adenoma/patologia , Adenoma/veterinária , Mutação
2.
Nat Genet ; 29(4): 404-11, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11726927

RESUMO

Somatic inactivation of PTEN occurs in different human tumors including glioblastoma, endometrial carcinoma and prostate carcinoma. Germline mutations in PTEN result in a range of phenotypic abnormalities that occur with variable penetrance, including neurological features such as macrocephaly, seizures, ataxia and Lhermitte-Duclos disease (also described as dysplastic gangliocytoma of the cerebellum). Homozygous deletion of Pten causes embryonic lethality in mice. To investigate function in the brain, we used Cre-loxP technology to selectively inactivate Pten in specific mouse neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of human Lhermitte-Duclos disease. These results indicate that Pten regulates neuronal size in vivo in a cell-autonomous manner and provide new insights into the etiology of Lhermitte-Duclos disease.


Assuntos
Tamanho Celular/genética , Doenças Cerebelares/genética , Genes Supressores de Tumor , Neurônios/patologia , Monoéster Fosfórico Hidrolases/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ciclo Celular/genética , Divisão Celular/genética , Doenças Cerebelares/patologia , Inibidor de Quinase Dependente de Ciclina p27 , Modelos Animais de Doenças , Deleção de Genes , Proteína Glial Fibrilar Ácida/genética , Imuno-Histoquímica , Integrases/genética , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Convulsões/genética , Proteínas Supressoras de Tumor/genética , Proteínas Virais/genética
3.
Clin Neuropathol ; 30(6): 297-300, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22011734

RESUMO

Noonan syndrome, a distinctive syndrome characterized by dysmorphism, cardiac abnormalities and developmental delay, has been associated with a number of malignancies, however, only a few cases of primary glial or glioneuronal neoplasms have been reported. We report here the case of an 18-year-old with Noonan syndrome who developed a rosette forming glioneuronal tumor of the posterior fossa. The tumor demonstrated strong pERK immunoreactivity, suggesting MAPK/ERK pathway activation. Molecular testing did not reveal BRAF rearrangements (fusion transcripts) by PCR or a BRAFV600E mutation by sequencing. We review the literature regarding the molecular pathogenesis of Noonan syndrome and primary brain tumors, and consider the intriguing link between their common molecular pathways.


Assuntos
Neoplasias Encefálicas , Síndrome de Noonan , Humanos , Mutação
4.
Oncogene ; 25(3): 487-91, 2006 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-16186803

RESUMO

Notch3 has been studied in the context of brain development, but whether it plays a role in the formation of brain tumors is unclear. We demonstrate that the introduction of constitutively active Notch3 into periventricular cells of embryonic day 9.5 mice causes the formation of choroid plexus tumors (CPTs). Tumors arose in the fourth ventricles in 83% of animals and were associated with hydrocephalus. They were microscopically highly similar to choroid plexus papillomas in humans, with an ongoing proliferation rate of 4-6%. Signs of Notch pathway activity were also present in human choroid plexus lesions, and receptor mRNA levels in papillomas were elevated over those in non-neoplastic choroid plexus. Notch2 was overexpressed approximately 500-fold in one case, suggesting that the role of this pathway in CPTs may not be specific to Notch3. Our findings indicate that activated Notch3 can function as an oncogene in the developing brain, and link the Notch pathway to human CPT pathogenesis.


Assuntos
Neoplasias do Plexo Corióideo/patologia , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Notch3 , Receptores Notch/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Genetics ; 135(2): 489-505, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8244010

RESUMO

We describe 83 recessive autosomal male-sterile mutations, generated by single P element mutagenesis in Drosophila melanogaster. Each mutation has been localized to a lettered subdivision of the polytene map. Reversion analyses, as well as complementation tests using available chromosomal deficiencies, indicate that the insertions are responsible for the mutant phenotypes. These mutations represent 63 complementation groups, 58 of which are required for spermatogenesis. Phenotypes of the spermatogenesis mutants were analyzed by light microscopy. Mutations in 12 loci affect germline proliferation, spermatocyte growth, or meiosis. Mutations in 46 other loci disrupt differentiation and maturation of spermatids into motile sperm. This collection of male-sterile mutants provides the basis for a molecular genetic analysis of spermatogenesis.


Assuntos
Drosophila melanogaster/fisiologia , Mutagênese Insercional , Espermatogênese/genética , Espermatozoides/citologia , Animais , Diferenciação Celular , Mapeamento Cromossômico , Cruzamentos Genéticos , Drosophila melanogaster/genética , Feminino , Fertilidade , Genes Recessivos , Teste de Complementação Genética , Marcadores Genéticos , Hibridização In Situ , Infertilidade Masculina/genética , Masculino , Meiose/genética , Fenótipo , Glândulas Salivares/citologia
6.
Oncogene ; 34(30): 3994-4004, 2015 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-25328136

RESUMO

Cancer stem-like cells represent poorly differentiated multipotent tumor-propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor-propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor-propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT-dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated.


Assuntos
Neoplasias Encefálicas/metabolismo , DNA (Citosina-5-)-Metiltransferases/fisiologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , MicroRNAs/fisiologia , Fator 3 de Transcrição de Octâmero/fisiologia , Fatores de Transcrição SOXB1/fisiologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Epigênese Genética , Glioblastoma/patologia , Humanos , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Fenótipo
7.
J Neuropathol Exp Neurol ; 59(4): 333-7, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10759189

RESUMO

The adenomatous polyposis coli (APC) gene, a member of the Wingless/Wnt signal transduction pathway, has been implicated in the development of medulloblastomas in Turcot's syndrome. beta-catenin also functions in this highly conserved signaling pathway and is instrumental in growth and development. Mutations in either APC or beta-catenin can stabilize beta-catenin protein. Stabilized beta-catenin complexes with Tcf/Lef transcription factors and moves from the cytoplasm into the nucleus where it regulates the transcription of c-Myc and other genes. Nuclear localization of beta-catenin therefore implies activation of the signaling pathway. We have analyzed the subcellular localization of beta-catenin in 51 sporadic medulloblastomas and in 1 medulloblastoma arising in a patient with Turcot's syndrome. Nuclear beta-catenin staining was present in 9 of the sporadic tumors (18%) and in the 1 medulloblastoma from a Turcot's patient. The remaining 41 cases did not show nuclear staining. This confirms earlier observations that Wingless/Wnt signaling is involved in a subset of sporadic medulloblastomas. We also examined 48 glial and meningeal CNS tumors, all of which were negative for nuclear beta-catenin. Exon 3 of beta-catenin was sequenced in 6 of the 9 sporadic medulloblastomas with nuclear beta-catenin staining. Five of the 6 tumors sequenced had mutations affecting highly conserved beta-catenin phosphorylation sites involved in protein stability. These data suggest a simple immunohistochemical method to screen for beta-catenin mutations in medulloblastomas.


Assuntos
Núcleo Celular/metabolismo , Neoplasias do Sistema Nervoso Central/genética , Proteínas do Citoesqueleto/genética , Meduloblastoma/genética , Transativadores , Proteínas de Peixe-Zebra , Idoso , Sítios de Ligação/genética , Núcleo Celular/patologia , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Citoplasma/metabolismo , Citoplasma/patologia , Proteínas do Citoesqueleto/metabolismo , Análise Mutacional de DNA , Éxons/genética , Doenças Fetais/patologia , Doenças Fetais/fisiopatologia , Humanos , Imuno-Histoquímica , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Pessoa de Meia-Idade , Mutação , Fosforilação , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Taxa de Sobrevida , Proteínas Wnt , beta Catenina
8.
J Neuropathol Exp Neurol ; 60(5): 462-9, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11379821

RESUMO

Nodular/desmoplastic medulloblastomas are a well-established histopathological subtype containing reticulin-free nodules or "pale islands' that are comprised of cells with round "neurocytic" nuclei and abundant cytoplasm. Significant neuronal maturation occurs within nodules. We used immunohistochemistry to evaluate neuronal differentiation in the nodules of 6 of these tumors. The neuronal markers NeuN, synaptophysin, and MAP-2 were identified in the "pale islands" of all 6 nodular medulloblastomas examined, and high and medium molecular weight nonphosphorylated neurofilaments were detected in 2 of the 6 cases. We also observed collections of apoptotic cells within nodules. Given the known role of neurotrophin signaling in neuronal maturation and apoptosis, we analyzed immunohistochemically the distribution of neurotrophin receptors TrkA and TrkC and their primary ligands NGF and NT3 in 14 nodular medulloblastomas. TrkA and TrkC were detected in 13 and 10 cases, respectively, and were predominantly localized within nodules. NGF and NT3 were distributed diffusely with some nodular accentuation. The localized expression of Trk receptors within nodules of desmoplastic medulloblastomas suggests neurotrophin signaling is involved in the apoptosis and neuronal differentiation in medulloblastomas. We also examined expression of p53 and BCL-2 in these tumors; both were prominent in internodular regions but only weakly expressed within nodules. Trk receptors, p53, and BCL-2 are all expressed during development of the normal cerebellum. Interestingly, the immunohistochemical expression profile of these proteins in the differentiating nodules of medulloblastomas is in many ways similar to their expression in the developing cerebellum. Thus similar signaling pathways may be operational in cerebellar development and medulloblastoma tumor differentiation.


Assuntos
Apoptose , Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/fisiologia , Adolescente , Adulto , Diferenciação Celular , Senescência Celular , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/patologia , Neurônios/patologia , Receptores de Fator de Crescimento Neural/metabolismo
9.
Am J Surg Pathol ; 24(8): 1159-64, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10935658

RESUMO

Benign mixed tumors of the salivary glands are generally regarded as indolent and harmless neoplasms. A subset of benign mixed tumors, however, can undergo carcinomatous transformation (that is, carcinoma ex-mixed tumor). Even more rarely, a mixed tumor that is seemingly benign at the microscopic level will metastasize like a true carcinoma (that is, metastasizing mixed tumor [MZMT]). Despite the benign appearance of the metastatic implants, there is usually little doubt regarding their true nature and origin. Patients invariably have had a mixed tumor removed from the parotid or some other salivary gland, and metastatic spread is usually preceded by multiple episodes of local tumor recurrence. We report a case of MZMT that presented as a solitary kidney mass. In the absence of a previous or concurrent salivary gland tumor, its metastatic nature was not appreciated and it was regarded as an unusual but benign kidney adenoma. One year after removal of the kidney mass, the patient presented with signs and symptoms of an aggressive parotid tumor. Pathologic examination of the tumor in the parotid demonstrated a high-grade carcinoma arising from a mixed tumor. This case underscores the importance of considering MZMT when a seemingly benign mixed tumor is encountered at a nonsalivary site, even in patients without a supportive history. Failure to do so may cause an unnecessary delay in primary tumor diagnosis and management, allow the primary tumor to progress toward a more malignant phenotype, and deny the patient a high expectation for a complete cure.


Assuntos
Adenoma Pleomorfo/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Renais/secundário , Neoplasias Parotídeas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Renais/patologia , Pessoa de Meia-Idade
10.
Am J Surg Pathol ; 25(10): 1252-60, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11688459

RESUMO

Neurocytic neoplasms usually arise within the lateral ventricles, generally as circumscribed, slowly growing masses curable by total resection. Both subtotal resection and histologic atypia are associated with an increased risk of recurrence. In contrast, neurocytic neoplasms situated within brain parenchyma, so-called "extraventricular neurocytomas" (EVNs), are not as well characterized. The relationships between histologic features and extent of resection versus clinical behavior have not been defined. We evaluated pathologic features, clinical data, and neuroimaging of 35 examples. The tumors occurred in 18 males and 17 females, age 5-76 years (median 34 years). All tumors involved the cerebrum. On imaging, EVNs were solitary, variably contrast-enhancing, and often (57%) cystic. Tumor cells were arranged in sheets, clusters, ribbons, or rosettes, in association with fine neuropil dispersed in broad zones that separated cell aggregates. Ganglion cell differentiation was seen in 66%. All tumors showed strong synaptophysin immunoreactivity. Despite the lack of apparent astrocytes in hematoxylin and eosin-stained sections, focal glial fibrillary acidic protein reactivity was seen in 46%. Eleven EVNs were designated "atypical" based on the presence of necrosis, vascular proliferation, or elevated mitotic activity (> or = 3 mitoses/10 high power fields). Nineteen tumors were subtotally resected or biopsied, whereas 14 were totally resected grossly. Seventeen patients underwent radiotherapy (mean 55 Gy). In 30 cases with follow-up, 10 tumors recurred, 3 causing death at 6, 14, and 43 months. All 10 recurrences followed subtotal resection. No totally resected tumors recurred. Thus, the majority of EVNs are well differentiated and appear unlikely to recur after gross total resection. Subtotal resection, atypical histologic features, and high cell proliferation rates correlate with recurrence.


Assuntos
Neoplasias Encefálicas/patologia , Neurocitoma/patologia , Telencéfalo/patologia , Adolescente , Adulto , Idoso , Antígenos Nucleares , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Recidiva Local de Neoplasia , Neurocitoma/metabolismo , Neurocitoma/mortalidade , Neurocitoma/terapia , Proteínas Nucleares/análise , Radioterapia Adjuvante , Taxa de Sobrevida , Resultado do Tratamento
11.
Clin Neurol Neurosurg ; 103(3): 160-7, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11532556

RESUMO

Subacute diencephalic angioencephalopathy (SDAE) is a rare and fatal disease of unknown etiology that involves the thalami bilaterally. To date, there have been four cases reported, in which the diagnosis was established only after post mortem examination of the brain. We report two male patients, ages 69 and 41 years, who presented with progressive dementia and somnolence. Radiological evaluation revealed enhancing lesions involving both thalami. The differential diagnosis included a number of neoplastic, inflammatory and vascular processes. In both cases, pathological evaluation of biopsy specimens suggested the diagnosis of SDAE. Despite supportive care, the disease progressed rapidly and both patients died within weeks after initial presentation. The diagnosis was confirmed at autopsy in both cases. SDAE is a rare cause of bithalamic disease that can be mistaken for a neoplasm as well as a number of conditions that necessitate different treatment choices. The histopathological findings can establish the diagnosis when combined with radiological and clinical information. This report emphasizes the utility of stereotactic biopsy in early diagnosis of SDAE.


Assuntos
Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Diencéfalo/diagnóstico por imagem , Diencéfalo/patologia , Doenças Talâmicas/diagnóstico por imagem , Doenças Talâmicas/patologia , Adulto , Idoso , Autopsia , Biópsia , Demência/diagnóstico por imagem , Demência/patologia , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino , Radiografia
12.
Arch Pathol Lab Med ; 125(8): 1024-30, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11473451

RESUMO

CONTEXT: Although most fatal brain tumors are diagnosed well before a patient's death, occasionally medical examiners and coroners encounter cases in which the presence of a primary tumor of the central nervous system (CNS) was not suspected prior to death. Analysis of such cases can shed light on specific pitfalls hindering the diagnosis of brain tumors. In addition, by analyzing the incidence of these cases in a large autopsy series, one can draw conclusions about the evolving effectiveness of medical diagnosis. OBJECTIVE: To determine the incidence of deaths due to undiagnosed primary CNS tumors in the era of advanced neuroimaging techniques. DESIGN: Records from forensic autopsies performed during a 20-year period (1980-1999) at the Office of the Chief Medical Examiner of the State of Maryland were reviewed to identify cases in which death was caused by primary CNS tumors undiagnosed prior to the patient's death. RESULTS: We present 11 cases of undiagnosed primary CNS tumors resulting in sudden death that were identified among 54 873 forensic autopsies. Sudden deaths due to undiagnosed CNS neoplasms account for a significantly lower percentage of cases in our study (0.02%) than in similar series reported prior to 1980 (> or =0.16%). CONCLUSIONS: We hypothesize that improvements in imaging techniques, notably the introduction of computed tomography and magnetic resonance imaging, have resulted in increased early detection of CNS neoplasms. However, vague or short-term symptoms and limited health care access can dissuade patients from seeking medical attention and result in failure to diagnose these tumors correctly.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias da Medula Espinal/diagnóstico , Adulto , Idoso , Autopsia , Neoplasias Encefálicas/patologia , Diagnóstico por Imagem , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Medula Espinal/patologia
13.
Oncogene ; 33(35): 4433-41, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-24077291

RESUMO

Hypoxic regions are frequent in glioblastoma (GBM), the most common type of malignant adult brain tumor, and increased levels of tumor hypoxia have been associated with worse clinical outcomes. To unmask genes important in hypoxia, we treated GBM neurospheres in hypoxia and identified monocarboxylate transporter-4 (MCT4) as one of the most upregulated genes. To investigate the clinical importance of MCT4 in GBM, we examined clinical outcomes and found that MCT4 overexpression is associated with shorter patient survival. Consistent with this, MCT4 upregulation correlated with the aggressive mesenchymal subset of GBM, and MCT4 downregulation correlated with the less aggressive G-CIMP (Glioma CpG Methylator Phenotype) subset of GBM. Immunohistochemical analysis of tissue microarrays confirmed that MCT4 protein levels were increased in high-grade as compared with lower-grade astrocytomas, further suggesting that MCT4 is a clinically relevant target. To test the requirement for MCT4 in vitro, we transduced neurospheres with lentiviruses encoding short-hairpin RNAs (shRNAs) against MCT4, resulting in growth inhibition of 50-80% under hypoxia in two lines. MCT4 knockdown was associated with a decreased percentage of cells expressing the stem-cell marker CD133 and increased apoptotic fraction. We also found that flow-sorted CD133-positive cells had almost sixfold higher MCT4 levels than CD133-negative cells, suggesting that the stem-like population might have a greater requirement for MCT4. Most importantly, MCT4 silencing also slowed GBM intracranial xenograft growth in vivo. Interestingly, whereas MCT4 is a well-characterized lactate exporter, we found that both intracellular and extracellular lactate levels did not change following MCT4 silencing, suggesting a novel lactate export-independent mechanism for growth inhibition in GBMs. To identify this potential mechanism, we performed microarray analysis on control and shMCT4-expressing neurospheres and found a dramatic reduction in the expression of multiple Hypoxia-Inducible Factor (HIF)-regulated genes following MCT4 knockdown. The overall reduction in HIF transcriptional response was further validated using a hypoxia response element (HRE)-dependent green-fluorescent protein (GFP) reporter line.


Assuntos
Hipóxia Celular , Glioblastoma/patologia , Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioblastoma/metabolismo , Humanos , Fator 1 Induzível por Hipóxia/genética , Camundongos Nus , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Neoplasias Experimentais , Células-Tronco Neoplásicas/imunologia , Prognóstico
14.
Artigo em Inglês | MEDLINE | ID: mdl-19022772

RESUMO

The Notch pathway has a fundamental role during cell-fate specification in the developing mammalian nervous system. During neocortical development, Notch signaling inhibits neuronal differentiation and maintains the neural stem/progenitor cell pool to permit successive waves of neurogenesis, which are followed by gliogenesis. In addition, recent evidence suggests that Notch signaling is not uniformly used among distinct proliferative neural cells types, with the canonical cascade functional in neural stem cells but attenuated in neurogenic progenitors. Although the role of Notch in neural development is increasingly well understood, it has recently become evident that Notch also has a role in brain tumor biology. Notch receptors are overexpressed in many different brain tumor types, and they may have an initiating role in some. Stem-like cells in brain tumors share many similarities with neural stem/progenitor cells and may require Notch for their survival and growth. Understanding the role of Notch signaling in neoplastic and non-neoplastic stem/progenitor populations will advance our understanding of basic principles regulating developmental and stem cell biology and may also lead to more effective therapies for brain tumors.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neurônios/citologia , Neurônios/metabolismo , Receptores Notch/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Astrocitoma/metabolismo , Astrocitoma/patologia , Diferenciação Celular , Ependimoma/metabolismo , Ependimoma/patologia , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Modelos Neurológicos , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neurogênese , Transdução de Sinais
15.
Mol Psychiatry ; 12(3): 283-91, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17199132

RESUMO

The beta2-adrenergic receptor is part of the catecholamine system, and variants at two polymorphic sites in the gene coding for the receptor (ADRB2) confer increased activity. Overstimulation of this receptor may alter brain development, and has been linked to autism in non-identical twins. The objective of this study was to determine whether alleles in ADRB2 are associated with diagnosis of autism in the Autism Genetic Resource Exchange (AGRE) population. Three hundred and thirty-one independent autism case-parent trios were included in the analysis. Subjects were genotyped at activity-related polymorphisms rs1042713 (codon 16) and rs1042714 (codon 27). Association between autism and genotypes at each polymorphic site was tested using genotype-based transmission disequilibrium tests, and effect modification by family and pregnancy characteristics was evaluated. Sensitivity to designation of the proband in each family was assessed by performing 1000 repeats of the analysis selecting affected children randomly. A statistically significant OR of 1.66 for the Glu27 homozygous genotype was observed. Increased associations with this genotype were observed among a subset of Autism Diagnostic Observation Schedule confirmed cases and a subset reporting experience of pregnancy-related stressors. In conclusion, the Glu27 allele of the ADRB2 gene may confer increased risk of autism and shows increased strength with exposure to pregnancy related stress.


Assuntos
Transtorno Autístico/genética , Predisposição Genética para Doença , Polimorfismo Genético , Receptores Adrenérgicos beta 2/genética , Risco , Criança , Estudos de Coortes , Saúde da Família , Feminino , Frequência do Gene , Genótipo , Ácido Glutâmico/genética , Humanos , Desequilíbrio de Ligação , Masculino , Razão de Chances , Gravidez
16.
Development ; 121(10): 3477-86, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7588080

RESUMO

During Drosophila spermatogenesis, germ cells undergo four rounds of mitosis, an extended premeiotic G2 phase and two meiotic divisions. In males homozygous for mutations in pelota, the germline mitotic divisions are normal, but the cell cycle arrests prior to the first meiotic division; pelota males are therefore sterile. Chromosomes begin to condense in these mutants, but other meiotic processes, including nuclear envelope breakdown and spindle formation, do not occur. The arrest phenotype closely resembles that of mutations in the Drosophila cdc25 homolog twine. Although meiosis is blocked in pelota and twine homozygotes, spermatid differentiation continues. pelota is also required for patterning in the eye and mitotic divisions in the ovary. We have cloned the pelota locus and show it encodes a 44 x 10(3) M(r) protein with yeast, plant, worm and human homologs.


Assuntos
Proteínas de Drosophila , Drosophila/fisiologia , Meiose/genética , Proteínas Nucleares , Proteínas/genética , Espermatogênese/genética , Sequência de Aminoácidos , Animais , Arabidopsis , Sequência de Bases , Caenorhabditis elegans , Drosophila/genética , Olho/ultraestrutura , Feminino , Fase G2 , Masculino , Microscopia Eletrônica de Varredura , Mitose , Dados de Sequência Molecular , Saccharomyces , Alinhamento de Sequência , Espermatozoides/citologia
17.
Pediatr Dev Pathol ; 4(4): 351-7, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11441336

RESUMO

The Wnt signaling pathway is involved in both normal development and tumorigenesis. Activation of the pathway results in stabilization and nuclear translocation of beta-catenin protein. Nuclear localization of beta-catenin has been used to identify tumors in which mutations in APC or beta-catenin activate Wnt signaling. We analyzed the subcellular localization of beta-catenin immunohistochemically in human fetal and postnatal tissues to identify activation of Wnt signaling during development. Nuclear beta-catenin is present in capillary endothelium, mesenchyme surrounding renal tubules, adrenal cortex, cartilage anlage, placental cytotrophoblast, and pulmonary acinar buds. These investigations suggest a defined role for Wnt signaling in human fetal development and provide a catalogue of non-neoplastic tissues with nuclear beta-catenin staining.


Assuntos
Núcleo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Desenvolvimento Embrionário e Fetal/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Transativadores , Proteínas de Peixe-Zebra , Glândulas Suprarrenais/embriologia , Glândulas Suprarrenais/metabolismo , Adulto , Capilares/embriologia , Capilares/metabolismo , Cartilagem/embriologia , Cartilagem/metabolismo , Feminino , Idade Gestacional , Humanos , Técnicas Imunoenzimáticas , Lactente , Rim/embriologia , Rim/metabolismo , Pulmão/embriologia , Pulmão/metabolismo , Masculino , Placenta/metabolismo , Transdução de Sinais , Distribuição Tecidual , Proteínas Wnt , beta Catenina
18.
Nature ; 381(6585): 783-5, 1996 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-8657280

RESUMO

Infertility resulting from a severe defect in sperm production affects 2% of men worldwide. Of these men with azoospermia, the absence of sperm in semen, one in eight carry de novo deletions for a specific region of the Y chromosome. A candidate gene for the Y-chromosome azoospermia factor (AZF) has been identified and named Deleted in Azoospermia (DAZ). Here we describe the cloning and characterization of the Drosophila gene boule, which is a homologue of DAZ. The two genes encode closely related proteins that contain a predicted RNA-binding motif, and both loci are expressed exclusively in the testis. Loss of boule function results in azoospermia; meiotic divisions are blocked, although limited spermatid differentiation occurs. Histological examination of boule testes with cell-cycle markers indicates that the primary defect is at the meiotic G2/M transition. These results support the hypothesis that DAZ is the human AZF, and indicate that Boule and DAZ have an essential meiotic function in fly and human spermatogenesis.


Assuntos
Proteínas de Drosophila , Fertilidade/genética , Meiose/genética , Proteínas de Ligação a RNA/genética , Sequência de Aminoácidos , Animais , Clonagem Molecular , Ciclinas/metabolismo , Proteína 1 Suprimida em Azoospermia , Drosophila , Feminino , Genes de Insetos , Humanos , Masculino , Meiose/fisiologia , Camundongos , Dados de Sequência Molecular , Oligospermia/genética , Proteínas de Ligação a RNA/fisiologia , Homologia de Sequência de Aminoácidos , Espermatogênese/genética , Testículo/citologia , Testículo/metabolismo , Cromossomo Y
19.
Acta Neurochir (Wien) ; 146(3): 299-302; discussion 302, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15015054

RESUMO

Spinal angiolipomas are rare lesions usually found in the epidural space of the thoracic spine. This report presents a case of and reviews the literature on this rare entity. The etiology, clinical presentation, imaging, and treatment are discussed. In 92 reported cases of spinal angiolipoma 56 occurred in women (61%), and 36 in men (39%). Mean age of occurrence is 42.9 years (range 10 days-85 years) with most patients presenting with slowly progressive symptoms of spinal cord compression. Most cases occur in the extradural compartment, and are of the non-invasive subtype. This rare clinical entity must be considered in the differential diagnosis of spinal epidural lesions. In most cases complete removal is possible, however, prognosis is good even for infiltrating lesions. Thus, one must not risk neurological damage to attain complete resection.


Assuntos
Angiolipoma/patologia , Neoplasias Epidurais/patologia , Angiolipoma/etiologia , Angiolipoma/cirurgia , Neoplasias Epidurais/etiologia , Neoplasias Epidurais/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Vértebras Torácicas
20.
Pediatr Dev Pathol ; 3(4): 346-52, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10890250

RESUMO

We have encountered a series of seven unusual neuroblastic pediatric central nervous system (CNS) neoplasms with a unique constellation of histologic, immunohistochemical, and ultrastructural features. The tumors presented in five girls and two boys, ages 1 to 3 years. In six cases the lesions involved the frontoparietal region, in one case the tectal plate. The tumors consisted of small to medium-sized, round to oval, hyperchromatic cells with poorly defined cytoplasmic borders. Cells were found in clusters and cords set in a paucicellular fibrillar neuropil matrix. Distinctive, virtually anuclear regions of neuropil were scattered throughout the lesions. True rosettes with well-formed central lumens often filled with granular debris were present, along with perivascular pseudorosettes and occasional Homer-Wright rosettes. Mitoses and apoptosis were frequent, but large regions of confluent necrosis were absent. Immunohistochemically, the neuropil-like areas as well as the perinuclear cytoplasm of many embryonal tumor cells were positive for synaptophysin and neurofilament protein. Ultrastructurally, the tumor cells showed microtubule-containing neuronal processes, some with neurosecretory granules. While the lesions were largely glial fibrillary acidic protein (GFAP) negative, there was focal GFAP positivity consistent with divergent differentiation in one case. The clinical outcome was poor, with five patients dead from their disease 5 to 14 months after initial presentation and one patient with recurrent disease 7 months after resection and chemotherapy. The final patient is alive without recurrent disease 30 months after initial presentation. These lesions present distinctive histological features within the group of primitive neuroectodermal tumors.


Assuntos
Neoplasias Encefálicas/patologia , Tumores Neuroectodérmicos Primitivos/patologia , Apoptose , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Feminino , Proteína Glial Fibrilar Ácida/análise , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Neutrófilos , Formação de Roseta , Resultado do Tratamento
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