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1.
Arch Pathol Lab Med ; 147(8): 896-906, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-36355424

RESUMO

CONTEXT.­: Despite their stromal origin, follicular dendritic cells (FDCs) share many functions with hematopoietic system cells. FDC neoplasms are currently classified by the World Health Organization along with those of a histiocytic nature. However, the molecular alterations driving oncogenesis in FDC sarcomas (FDCSs) are beginning to be unveiled and do not seem to concur with those described in histiocytic neoplasms, namely MAPK pathway activation. OBJECTIVE.­: To identify molecular alterations driving tumorigenesis in FDCS. DESIGN.­: We investigated the role of MYC and TP53 in FDC-derived tumor oncogenesis and assessed comprehensively the status of the MAPK pathway in 16 FDCSs, 6 inflammatory pseudotumor (IPT)-like FDCSs, and 8 IPTs. RESULTS.­: MYC structural alterations (both amplifications and rearrangements) were identified in 5 of 14 FDCSs (35.7%), all associated with MYC overexpression. TP53 mutations were identified in 4 of 14 FDCSs (28.6%), all of which displayed intense and diffuse p53 expression. None of these alterations were identified in any IPT-like FDCSs or in IPT cases. No MAPK pathway gene alterations were identified in any of the cases studied. CONCLUSIONS.­: The presence of MYC and TP53 alterations and the lack of association with Epstein-Barr virus segregate classical FDCS from IPT-like FDCS, pointing at different oncogenic mechanisms in both entities. Our results suggest a possible oncogenic role of MYC and TP53 alterations in FDCS. The absence of MAPK pathway alterations confirms the lack of a significant role of this pathway in the oncogenesis of FDC-derived neoplasms.


Assuntos
Sarcoma de Células Dendríticas Foliculares , Infecções por Vírus Epstein-Barr , Sarcoma , Humanos , Carcinogênese/genética , Sarcoma de Células Dendríticas Foliculares/genética , Sarcoma de Células Dendríticas Foliculares/patologia , Herpesvirus Humano 4/genética , Mutação , Proteína Supressora de Tumor p53/genética
2.
Blood ; 135(4): 274-286, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31738823

RESUMO

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.


Assuntos
Fatores Reguladores de Interferon/genética , Linfoma Difuso de Grandes Células B/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Prognóstico , Transcriptoma , Adulto Jovem
3.
Ann Neurol ; 85(6): 899-906, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30900782

RESUMO

OBJECTIVE: To clinically and pathologically characterize a cohort of patients presenting with a novel form of distal myopathy and to identify the genetic cause of this new muscular dystrophy. METHODS: We studied 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy. Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles. RESULTS: In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease. The affected members of the Swedish family carry a different ACTN2 missense variant. INTERPRETATION: ACTN2 encodes for alpha actinin2, which is highly expressed in the sarcomeric Z-disk with a major structural and functional role. Actininopathy is thus a new genetically determined distal myopathy. ANN NEUROL 2019;85:899-906.


Assuntos
Actinina/genética , Miopatias Distais/diagnóstico , Miopatias Distais/genética , Genes Dominantes/genética , Mutação de Sentido Incorreto/genética , Actinina/química , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Estrutura Secundária de Proteína
4.
Haematologica ; 104(9): 1822-1829, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30733272

RESUMO

Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.


Assuntos
Linfoma de Burkitt/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Centro Germinativo/patologia , Linfoma Difuso de Grandes Células B/genética , Adolescente , Adulto , Criança , DNA/análise , Análise Mutacional de DNA , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Fenótipo , Análise de Sequência de DNA , Resultado do Tratamento , Adulto Jovem
5.
Mod Pathol ; 32(5): 621-626, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30552415

RESUMO

The involvement of human papillomavirus (HPV) in laryngeal and hypopharyngeal lymphoepithelial carcinoma was investigated in a series of ten cases (seven laryngeal and three hypopharyngeal), retrieved from the files of three tertiary hospitals in the 2000-2017 period, through polymerase chain reaction with SPF10 primers and INNO-LiPA HPV Genotyping Extra II (Innogenetics). Epstein-Barr virus (EBV) was tested in all cases with in situ hybridization INFORM EBER Probe (Ventana Medical Systems). p16 and p53 expression were immunohistochemically analyzed. Calculated annual incidence was 0.013/100,000, and prevalence was 0.2% of laryngeal and hypopharyngeal carcinomas. All cases were EBV negative. HPV was detected in five cases, three of which also overexpressed p16. HPV16 was detected in four cases, and HPV58 in one case. Five cases were HPV negative, only one of these five overexpressed p16. No recurrence was observed in nine cases during follow-up. The 5-year disease-specific-survival rate was 100%. Mean overall survival was 87 months. Lymphoepithelial carcinoma of the larynx and hypopharynx are not related to EBV. Simultaneous HPV+/p16+ is consistent with HPV causation in a fraction of laryngeal and hypopharyngeal lymphoepithelial carcinomas.


Assuntos
Carcinoma/virologia , DNA Viral/genética , Papillomavirus Humano 16/genética , Neoplasias Hipofaríngeas/virologia , Neoplasias Laríngeas/virologia , Infecções por Papillomavirus/virologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma/química , Carcinoma/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Intervalo Livre de Doença , Interações Hospedeiro-Patógeno , Humanos , Neoplasias Hipofaríngeas/química , Neoplasias Hipofaríngeas/patologia , Neoplasias Hipofaríngeas/terapia , Neoplasias Laríngeas/química , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/terapia , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/terapia , Espanha , Fatores de Tempo , Proteína Supressora de Tumor p53/análise
8.
BMJ Case Rep ; 20142014 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-25199185

RESUMO

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL) whereby individual lymphoma cells infiltrate the cerebral white matter without causing a mass effect. The disease characteristically presents as a rapidly progressive dementia, which opens an ample differential diagnosis of toxic, metabolic, neurodegenerative and infective causes. Other presentations also include changes in personality, myoclonus and psychotic symptoms. Here we report a patient who presented with a rapidly progressive dementia with a unique surgical history of a dural mater graft in the 1970s. The diagnosis of iatrogenic Creutzfeldt-Jakob disease (iCJD) was initially considered. However, the patient's clinical status deteriorated rapidly with no response to symptomatic treatment and she died 2 months after symptom onset. A diagnosis of T-type LC was reached at autopsy.


Assuntos
Neoplasias Encefálicas/diagnóstico , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/diagnóstico , Demência/diagnóstico , Linfoma não Hodgkin/diagnóstico , Demência/etiologia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Doença Iatrogênica , Linfoma não Hodgkin/complicações , Pessoa de Meia-Idade , Complicações Pós-Operatórias
9.
Proc Natl Acad Sci U S A ; 109(26): 10534-9, 2012 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-22689981

RESUMO

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.


Assuntos
Caspases/genética , Células-Tronco Hematopoéticas/metabolismo , Linfoma/patologia , Proteínas de Neoplasias/genética , Oncogenes , Animais , Humanos , Camundongos , Camundongos Transgênicos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B/metabolismo , Transcrição Gênica
10.
J Alzheimers Dis ; 30(4): 909-17, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22495343

RESUMO

The standard for differentiating between dementia subtypes is currently based on neuropathological changes and follows traditional nosological classifications. However, the high incidence of comorbid neuropathologies complicates the differentiation between dementia diagnoses in the clinic. The aim of this study was to investigate the grades of agreement between clinical and neuropathological diagnoses in neurodegenerative disorders, to compare them with rates found in previous studies, and to propose implications for dementia diagnostics. Patients, who donated their brains to the Brain Bank of Navarre (Pamplona, Spain), had been diagnosed with a neurodegenerative disorder during life (clinical diagnosis) and postmortem (neuropathological diagnosis). We studied a sample of patients with a short average time interval between the last clinical assessment and death (4.6 months). Overall, there was a mean grade of agreement of 44.0% between the clinical diagnosis and the pure neuropathological diagnosis (i.e., without co-morbid neuropathological disorders). This grade of agreement differed between dementia subtypes: e.g., 85% for prion disease, 49% for Alzheimer's disease, and 0% for Lewy body dementia. Our data confirm that co-occurrence of multiple neuropathological disorders is very common in individuals with dementia, and that the underlying neuropathology often differs from the neuropathology implied by the clinical diagnosis. These findings support a multidimensional approach to diagnosing dementia, in which dementia syndromes are not categorized into diagnostic subtypes, but are seen as syndromes characterized by a combination of various neuropathological dimensions.


Assuntos
Demência/diagnóstico , Demência/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Comorbidade , Demência/complicações , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Humanos , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/epidemiologia , Doenças Priônicas/complicações , Doenças Priônicas/diagnóstico , Doenças Priônicas/epidemiologia , Adulto Jovem
11.
Muscle Nerve ; 44(5): 710-4, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22006685

RESUMO

INTRODUCTION: Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain-3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported. METHODS: We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation. RESULTS: The benign phenotype observed in association with the combined pG222R and pR748Q mutations suggested that it may result from a compensatory effect of compound heterozygosity rather than the individual mutations themselves. Our analyses revealed that these two mutations exert different effects on the protease activity of calpain-3, suggesting "molecular complementation" in these patients. CONCLUSION: We propose several hypotheses to explain how this specific combination of mutations may rescue the normal proteolytic activity of calpain-3, resulting in an exceptionally benign phenotype.


Assuntos
Calpaína/genética , Triagem de Portadores Genéticos , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Índice de Gravidade de Doença , Adulto , Animais , Células COS , Chlorocebus aethiops , Feminino , Humanos , Masculino , Distrofia Muscular do Cíngulo dos Membros/diagnóstico
12.
Rev Neurol (Paris) ; 167(1): 51-6, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21193208

RESUMO

CNS/PNS interfaces constitute cell boundaries, since they delimit territories with different neuronal and glial contents. Despite their potential interest in regenerative medicine, the mechanisms restricting oligodendrocytes and astrocytes to the CNS, and Schwann cells to the PNS in mammals are not known. To investigate the involvement of peripheral glia and myelin in the maintenance of the CNS/PNS boundary, we have first made use of different mouse mutants. We show that inactivation of Krox20/Egr2, a master regulatory gene for myelination in Schwann cells, results in transgression of the CNS/PNS boundary by astrocytes and oligodendrocytes and in myelination of nerve root axons by oligodendrocytes. In contrast, such migration does not occur with the Trembler(J) mutation, which prevents PNS myelination without affecting Krox20 expression. Altogether these data suggest that maintenance of the CNS/PNS boundary requires a new Krox20 function separable from myelination control. Finally, we have analyzed a human patient affected by a congenital amyelinating neuropathy, associated with the absence of the KROX20 protein in Schwann cells. In this case, the nerve roots were also invaded by oligodendrocytes and astrocytes. This indicates that transgression of the CNS/PNS boundary by central glia can occur in pathological situations in humans and suggests that the underlying mechanisms are common with the mouse.


Assuntos
Proteína 2 de Resposta de Crescimento Precoce/antagonistas & inibidores , Proteína 2 de Resposta de Crescimento Precoce/deficiência , Neuroglia/fisiologia , Raízes Nervosas Espinhais/patologia , Animais , Astrócitos/fisiologia , Galinhas , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/fisiologia , Humanos , Lactente , Camundongos , Camundongos Mutantes Neurológicos , Mutação de Sentido Incorreto , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Doenças do Sistema Nervoso Periférico/congênito , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Células de Schwann/patologia , Peixe-Zebra/genética
13.
Int J Cancer ; 128(12): 2853-64, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20734389

RESUMO

Squamous cell carcinoma (SCC) of the vulva is a heterogeneous disease, associated or not with vulvar lichen sclerosus (LS). The precursor role of LS in vulvar cancer is unclear. We studied the epigenetic alterations of RASSF1A, RASSF2A, p16, TSP-1 and MGMT genes in vulvar SCCs, LS associated with SCC, isolated LS and normal vulvar skin. Gene hypermethylation and human papillomavirus presence were evaluated by methylation-specific PCR and PCR/reverse line blot, respectively. High-risk human papillomavirus types were present in 16.7% of the patients with vulvar SCC. There were increasing percentages of hypermethylation of genes from isolated LS to LS associated with vulvar SCC and vulvar SCC. The genes were hypermethylated more frequently in vulvar SCC associated with LS than in those not associated with LS, MGMT and RASSF2A being unmethylated in LS not associated with vulvar SCC. TSP-1 hypermethylation was related to recurrence in patients with vulvar cancer. Conclusions are as follows: (i) the epigenetic inactivation of genes is a common event in vulvar SCC and is also present in adjacent lesions, implying a possible precursor role for these alterations; (ii) MGMT and RASSF2A hypermethylation are present exclusively in vulvar SCC and LS associated with SCC, and absent from isolated LS; and (iii) TSP-1 hypermethylation is a bad prognosis factor in vulvar SCC.


Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA , Líquen Escleroso e Atrófico/genética , Neoplasias Vulvares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Epigênese Genética , Feminino , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
14.
Neuromuscul Disord ; 20(11): 701-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20637616

RESUMO

A novel myopathy characterized by hexagonally cross-linked tubular arrays has been reported in five patients. We studied the clinical and histopathological features of five additional unrelated patients with this myopathy. Patients experienced exercise intolerance with exercise-induced myalgia and weakness, without rhabdomyolysis. One patient additionally presented mild permanent pelvic girdle muscle weakness. Age at onset varied between 13 and 56 years. The inclusions were eosinophilic on H and E, bright red with modified Gomori's trichrome stains, present in type 2 fibers, and revealed immunoreactivity selectively for a caveolin-3-antibody. Ultrastructurally, the inclusions showed a highly organized, hexagonally cross-linked crystalloid structure. Mutations in the caveolin-3 encoding gene were excluded. Biochemical assessment of glycogenolysis in muscle was normal. Inherited or sporadic myopathy with hexagonally cross-linked tubular arrays is associated with a homogeneous clinical and histopathological phenotype. This myopathy should be included in the differential diagnosis of patients with exercise intolerance and myalgia.


Assuntos
Debilidade Muscular/patologia , Músculo Esquelético/patologia , Doenças Musculares/patologia , Adolescente , Adulto , Idade de Início , Western Blotting , Caveolina 3/genética , Caveolina 3/metabolismo , Creatina Quinase/sangue , Exercício Físico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/genética , Doenças Musculares/metabolismo , Fenótipo
15.
J Neurosci ; 30(17): 5958-67, 2010 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-20427655

RESUMO

CNS/PNS interfaces constitute cell boundaries, because they delimit territories with different neuronal and glial contents. Despite their potential interest in regenerative medicine, the mechanisms restricting oligodendrocytes and astrocytes to the CNS and Schwann cells to the PNS in mammals are not known. To investigate the involvement of peripheral glia and myelin in the maintenance of the CNS/PNS boundary, we have first made use of different mouse mutants. We show that depletion of Schwann cells and boundary cap cells or inactivation of Krox20/Egr2, a master regulatory gene for myelination in Schwann cells, results in transgression of the CNS/PNS boundary by astrocytes and oligodendrocytes and in myelination of nerve root axons by oligodendrocytes. In contrast, such migration does not occur with the Trembler(J) mutation, which prevents PNS myelination without affecting Krox20 expression. Altogether, these data suggest that maintenance of the CNS/PNS boundary requires a Krox20 function separable from myelination control. Finally, we have analyzed a human patient affected by a congenital amyelinating neuropathy, associated with the absence of the KROX20 protein in Schwann cells. In this case, the nerve roots were also invaded by oligodendrocytes and astrocytes. This indicates that transgression of the CNS/PNS boundary by central glia can occur in pathological situations in humans and suggests that the underlying mechanisms are common with the mouse.


Assuntos
Sistema Nervoso Central/fisiologia , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Neuroglia/fisiologia , Sistema Nervoso Periférico/fisiologia , Animais , Astrócitos/fisiologia , Astrócitos/ultraestrutura , Axônios/fisiologia , Axônios/ultraestrutura , Movimento Celular/fisiologia , Sistema Nervoso Central/ultraestrutura , Proteína 2 de Resposta de Crescimento Precoce/genética , Humanos , Lactente , Camundongos , Camundongos Transgênicos , Bainha de Mielina/fisiologia , Bainha de Mielina/ultraestrutura , Neuroglia/ultraestrutura , Oligodendroglia/fisiologia , Oligodendroglia/ultraestrutura , Sistema Nervoso Periférico/ultraestrutura , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Células de Schwann/fisiologia , Células de Schwann/ultraestrutura , Raízes Nervosas Espinhais/fisiologia , Raízes Nervosas Espinhais/ultraestrutura
16.
Neuromuscul Disord ; 20(4): 229-37, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20227276

RESUMO

Mutations in dynamin-2 (DNM2) cause autosomal dominant centronuclear myopathy (CNM). We report a series of 12 patients from eight families with CNM in whom we have identified a number of novel features that expand the reported clinicopathological phenotype. We identified two novel and five recurrent missense mutations in DNM2. Early clues to the diagnosis include relative weakness of neck flexors, external ophthalmoplegia and ptosis, although these are not present in all patients. Pes cavus was present in two patients, and in another two members of one family there was mild slowing of nerve conduction velocities. Whole-body MRI examination in two children and one adult revealed a similar pattern of involvement of selective muscles in head (lateral pterygoids), neck (extensors), trunk (paraspinal) and upper limbs (deep muscles of forearm). Findings in lower limbs and pelvic region were similar to that previously reported in adults with DNM2 mutations. Two patients presented with dystrophic changes as the predominant pathological feature on muscle biopsies; one of whom had a moderately raised creatine kinase, and both patients were initially diagnosed as congenital muscular dystrophy. DNM2 mutation analysis should be considered in patients with a suggestive clinical phenotype despite atypical histopathology, and MRI findings can be used to guide genetic testing. Subtle neuropathic features in some patients suggest an overlap with the DNM2 neuropathy phenotype. Missense mutations in the C-terminal region of the PH domain appear to be associated with a more severe clinical phenotype evident from infancy.


Assuntos
Dinamina II/genética , Predisposição Genética para Doença/genética , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Deformidades do Pé/genética , Deformidades do Pé/patologia , Marcadores Genéticos/genética , Testes Genéticos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Mutação de Sentido Incorreto/genética , Miopatias Congênitas Estruturais/fisiopatologia , Condução Nervosa/genética , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fenótipo , Estrutura Terciária de Proteína/genética
17.
Bull Acad Natl Med ; 194(4-5): 743-4, 2010.
Artigo em Francês | MEDLINE | ID: mdl-21568047

RESUMO

CNS/PNS interfaces constitute cell boundaries, defining territories with different neuronal and glial contents. Despite their potential implications for regenerative medicine, the mechanisms that restrict oligodendrocytes and astrocytes to the CNS and Schwann cells to the PNS are not known in mammals. To investigate the involvement of peripheral glia and myelin in CNS/PNS boundary maintenance, we first studied mutant mice. We found that inactivation of Krox20/Egr2, a master regulatory gene for myelination in Schwann cells, resulted in CNS/PNS boundary transgression by astrocytes and oligodendrocytes, and in myelination of nerve root axons by oligodendrocytes. In contrast, no such migration was observed in mice with the Trembler(J) mutation, which prevents PNS myelination without affecting Krox20 expression. These findings suggest that CNS/PNS boundary maintenance requires a new Krox20 function independent of myelination control. We also examined a patient with congenital amyelinating neuropathy, whose Schwann cells lack KROX20 protein. Interestingly, the patient's nerve roots were also invaded by oligodendrocytes and astrocytes, indicating that CNS/PNS boundary transgression by central glia can occur in human pathological situations and that the underlying mechanisms are the same as in mutant mice.


Assuntos
Sistema Nervoso Central/fisiologia , Proteína 2 de Resposta de Crescimento Precoce/fisiologia , Sistema Nervoso Periférico/fisiologia , Humanos
18.
PLoS One ; 3(11): e3750, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19015733

RESUMO

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens), cell adhesion (fibronectin), muscle development (myosins and melusin) and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB) is upregulated in LGMD2A muscle samples, it could be hypothesized that beta-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1). Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Calpaína/genética , Feminino , Glicoproteínas/metabolismo , Humanos , Interleucinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Músculos/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
19.
BJU Int ; 102(6): 747-55, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18336597

RESUMO

OBJECTIVE: To evaluate the presence of human papillomavirus (HPV) infection, the methylation status in the promoter region of thrombospondin-1 (TSP-1), RAS association domain family 1A (RASSF1-A) and p16 genes, and the expression of TSP-1, CD31, p16 and p53 proteins in patients diagnosed with penile cancer, and the possible associations between these variables and clinical and pathological features. PATIENTS AND METHODS: HPV types, gene promoter hypermethylation and protein expression were analysed by reverse line blot, methylation-specific polymerase chain reaction, and immunohistochemistry, respectively, in 24 penile squamous cell carcinomas. RESULTS: HPV infection was detected in 11 of 24 cases (46%), and TSP-1, RASSF1-A and p16 genes were hypermethylated in 46%, 42% and 38% of the tumours, respectively. TSP-1 hypermethylation was associated with unfavourable histological grade (grade 3; P = 0.033), vascular invasion (P = 0.023), weak expression of TSP-1 protein (P = 0.041), and shorter overall survival (P = 0.04). TSP-1 expression was not associated with microvessel density. However, RASSF1-A hypermethylation was more frequent in T1 tumours (P = 0.01), and p16 hypermethylation was not associated with any of the tested variables except for absence of p16 expression (P = 0.022). CONCLUSION: In summary, the epigenetic inactivation of TSP-1 and RASSF1-A genes is associated with pathological variables and seems to be of prognostic significance in penile cancer.


Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA , Neoplasias Penianas/genética , Trombospondina 1/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Genes p16 , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Penianas/patologia , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos
20.
Cir Esp ; 82(6): 358-60, 2007 Dec.
Artigo em Espanhol | MEDLINE | ID: mdl-18053506

RESUMO

Basaloid-squamous carcinoma is a poorly-differentiated variety of squamous cell carcinoma. The most common location is the upper aerodigestive tract and the incidence of this entity in the esophagus is low. Despite advances in knowledge of the biology of these tumors, their recent description and their low frequency has hampered consensus on the therapeutic approach. We present a case of basaloid-squamous cell of the esophagus a 54 year-old man who underwent an esophagectomy with lymphadenectomy and has been followed-up for 5 years with no evidence of disease recurrence. We also provide a literature review of this entity.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade
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