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1.
N Engl J Med ; 385(11): 996-1004, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34496175

RESUMO

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. METHODS: We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. RESULTS: We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. CONCLUSIONS: In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Malformações Arteriovenosas Intracranianas/genética , Mutação , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Malformações Arteriovenosas Intracranianas/patologia , Proteína KRIT1/genética , Masculino , Meningioma/genética , Camundongos , Camundongos Endogâmicos
2.
Sci Rep ; 11(1): 11239, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045576

RESUMO

Lung cancer patients frequently develop brain metastases (BM). Despite aggressive treatment including neurosurgery and external-radiotherapy, overall survival remains poor. There is a pressing need to further characterize factors in the microenvironment of BM that may confer resistance to radiotherapy (RT), such as hypoxia. Here, hypoxia was first evaluated in 28 biopsies from patients with non­small cell lung cancer (NSCLC) BM, using CA-IX immunostaining. Hypoxia characterization (pimonidazole, CA-IX and HIF-1α) was also performed in different preclinical NSCLC BM models induced either by intracerebral injection of tumor cells (H2030-Br3M, H1915) into the cortex and striatum, or intracardial injection of tumor cells (H2030-Br3M). Additionally, [18F]-FMISO-PET and oxygen-saturation-mapping-MRI (SatO2-MRI) were carried out in the intracerebral BM models to further characterize tumor hypoxia and evaluate the potential of Hypoxia-image-guided-RT (HIGRT). The effect of RT on proliferation of BM ([18F]-FLT-PET), tumor volume and overall survival was determined. We showed that hypoxia is a major yet heterogeneous feature of BM from lung cancer both preclinically and clinically. HIGRT, based on hypoxia heterogeneity observed between cortical and striatal metastases in the intracerebrally induced models, showed significant potential for tumor control and animal survival. These results collectively highlight hypoxia as a hallmark of BM from lung cancer and the value of HIGRT in better controlling tumor growth.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Radioterapia Guiada por Imagem , Hipóxia Tumoral , Idoso , Animais , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Ratos , Sistema de Registros
3.
Mol Genet Metab Rep ; 24: 100597, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32477874

RESUMO

Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies.

4.
Open Forum Infect Dis ; 6(10): ofz374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31660340

RESUMO

In this study, we report a complete (clinical, radiological, and virological) sustained (1 year) response after nivolumab salvage therapy in a progressive multifocal leukoencephalopathy patient. Analyses of the cells infiltrate in a pretreatment brain biopsy suggest that parenchymal programmed cell death-L1+ macrophages could be the T-cells partnership in immune exhaustion and virus escape.

5.
Biochem Biophys Res Commun ; 494(1-2): 133-137, 2017 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-29054413

RESUMO

Mitochondrial (mt) DNA-associated NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) syndrome is due to mutation in the MT-ATP6 gene. We report the case of a 18-year-old man who presented with deafness, a myoclonic epilepsy, muscle weakness since the age of 10 and further developed a retinitis pigmentosa and ataxia. The whole mtDNA analysis by next-generation sequencing revealed the presence of the 2 bp microdeletion m.9127-9128 del AT in the ATP6 gene at 82% heteroplasmy in muscle and to a lower load in blood (10-20%) and fibroblasts (50%). Using the patient's fibroblasts, we demonstrated a 60% reduction of the oligomycin-sensitive ATPase hydrolytic activity, a 40% decrease in the ATP synthesis and determination of the mitochondrial membrane potential using the fluorescent probe tetramethylrhodamine, ethyl ester indicated a significant reduction in oligomycin sensitivity. In conclusion, we demonstrated that this novel AT deletion in the ATP6 gene is pathogenic and responsible for the NARP syndrome.


Assuntos
Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Retinose Pigmentar/enzimologia , Retinose Pigmentar/genética , Deleção de Sequência , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Sequência de Bases , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Análise Mutacional de DNA , DNA Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Oligomicinas/farmacologia , Síndrome , Adulto Jovem
6.
Neurology ; 82(21): 1919-26, 2014 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-24789864

RESUMO

OBJECTIVE: To clarify the phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathies. METHODS: We screened for TRPV4 mutations in 169 French unrelated patients with inherited axonal peripheral neuropathy. Ninety-five patients had dominant Charcot-Marie-Tooth type 2 (CMT2) disease, and 74 patients, including 39 patients with distal hereditary motor neuropathy, 14 with congenital spinal muscular atrophy and arthrogryposis, 13 with CMT2, and 8 with scapuloperoneal spinal muscular atrophy, presented with additional vocal cord paralysis and/or skeletal dysplasia. RESULTS: No deleterious TRPV4 mutation was identified in the 95 patients with "pure" CMT2 (0/95). In contrast, 12 of 74 patients (16%) with neuropathy and vocal cord paralysis and/or skeletal dysplasia presented pathogenic TRPV4 mutations, including 7 patients with distal hereditary motor neuropathy, 2 with scapuloperoneal spinal muscular atrophy, 2 with congenital spinal muscular atrophy and arthrogryposis, and one with CMT2. Investigation of affected relatives allowed us to study 17 patients. All patients had childhood-onset motor neuropathy and showed a variety of associated findings, including foot deformities (100% of cases), kyphoscoliosis (100%), elevated serum creatine kinase levels (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Eight missense mutations were observed in these 12 families, including 2 previously unreported. Six mutations were de novo events, and 2 asymptomatic carriers were identified. CONCLUSION: With 16% of patients affected in our series, this study demonstrates that TRPV4 mutations are a major cause of inherited axonal neuropathy associated with a large spectrum of additional features.


Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Mutação , Fenótipo , Canais de Cátion TRPV/genética , Adolescente , Adulto , Idoso , Doenças Ósseas/patologia , Criança , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Adulto Jovem
7.
J Mol Neurosci ; 53(2): 171-5, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24604296

RESUMO

Idiopathic basal ganglia calcification (IBGC) is a progressive cerebral disorder with diverse motor, cognitive, and psychiatric expression. It is inherited as an autosomal dominant trait. Three IBGC-causing genes have been identified in the past 2 years: SLC20A2, PDGFRB, and PDGFB. Biological and genetic evidence showed that loss of function of either SLC20A2 or the PDGFB/PDGFRB pathway was the mechanism underlying calcification in patients with a mutation. Recently, in a study focusing on SLC20A2, a large deletion at this locus was reported. No study has systematically searched for copy number variants (CNV) involving these three genes. We designed a quantitative PCR assay of multiple short fluorescent fragments (QMPSF) to detect CNVs involving one of these three genes in a single assay. Among the 27 unrelated patients from our IBGC case series with no mutation in SLC20A2, PDGFRB, and PDGFB, we identified in one patient a heterozygous partial deletion involving exons 2 to 5 of PDGFB. This patient exhibited both strio-pallido-dentate calcification and white matter hyperintensity of presumed vascular origin, associated with mood disorder, subtle cognitive decline, and gait disorder. We confirmed by RT-PCR experiments that the allele carrying the deletion was transcribed. The resulting cDNA lacks sequence for several critical functional domains of the protein. Intragenic deletion of PDGFB is a new and rare mechanism causing IBGC. CNVs involving the three IBGC-causing genes should be investigated in patients with no point mutation.


Assuntos
Doenças dos Gânglios da Base/genética , Calcinose/genética , Deleção de Genes , Leucoencefalopatias/genética , Doenças Neurodegenerativas/genética , Proteínas Proto-Oncogênicas c-sis/genética , Idoso , Doenças dos Gânglios da Base/diagnóstico , Calcinose/diagnóstico , Éxons , Feminino , Heterozigoto , Humanos , Leucoencefalopatias/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética
8.
Histol Histopathol ; 29(8): 1071-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24574040

RESUMO

Cerebral cavernous malformations (CCMs) are described as vascular lesions consisting of endothelial-lined dilated vessels embedded in a connective tissue sheath without intervening parenchyma between them. Their anatomical connections with the normal blood vessels are still enigmatic and the fine three-dimensional (3-D) organization of these vascular lesions remains to be established. Two stacks of serial histological slices, obtained from two brainstem CCM lesions (from the necropsy of a CCM2 male patient), were stained using Masson's trichrome method and then digitized. Stacks of regions of interest underwent quasi-automatic processing: 1) propagative registering using blockmatching algorithms and Brain Visa programs; 2) 3-D segmentation using Aphelion; 3) display with Anatomist or ImageVis3D. These first histological 3-D reconstructions show the external limits of the caverns defined as the external limit of their collagen sheath. These pictures not only reveal the gross spatial organization of the lesions, but due to their high resolution (4 µm) and with the help of simple anaglyphic 3-D rendering, they also allow the visualization of connections between caverns and very small blood vessels.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Autopsia , Humanos , Masculino
9.
J Neurol Neurosurg Psychiatry ; 85(3): 345-53, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23606733

RESUMO

OBJECTIVE: Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort. METHODS: DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations. RESULTS: All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin. CONCLUSIONS: We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.


Assuntos
Doenças Genéticas Inatas/epidemiologia , Doenças Musculares/epidemiologia , Insuficiência Respiratória/epidemiologia , Adulto , Idoso , Conectina/genética , Exoma/genética , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Ligação Genética/genética , Predisposição Genética para Doença/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação/genética , Linhagem , Fenótipo , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia
10.
Neuromuscul Disord ; 23(12): 992-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24095155

RESUMO

The slow α-tropomyosin gene (TPM3) has been associated with three distinct histological entities: nemaline myopathy (NM, NEM1), congenital fibre-type disproportion (CFTD), and cap disease (CD). Here we describe a patient presenting an early-onset congenital myopathy associated with a combination of well separated cap structures and nemaline bodies in his muscle biopsy. Exome sequencing analysis allowed us to identify a de novo missense mutation in the TPM3 gene. Our study confirms the extreme variability of morphological findings in TPM3-related myopathies, and proves that cap and nemaline bodies are two sides of the same 'coin'.


Assuntos
Mutação/genética , Miopatias da Nemalina/genética , Tropomiosina/genética , Adulto , Análise Mutacional de DNA , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Miopatias da Nemalina/complicações , Miopatias da Nemalina/patologia , Miopatias Congênitas Estruturais/complicações , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia
11.
Nature ; 498(7455): 492-6, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23748444

RESUMO

Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-ß and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-ß and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.


Assuntos
Progressão da Doença , Transição Epitelial-Mesenquimal , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Animais , Proteína Morfogenética Óssea 6/antagonistas & inibidores , Proteína Morfogenética Óssea 6/metabolismo , Proteína Morfogenética Óssea 6/farmacologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Proteína KRIT1 , Camundongos , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
12.
Joint Bone Spine ; 80(2): 208-10, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22999899

RESUMO

Eosinophilic fasciitis is a rare connective tissue disorder, which can be associated with hematological complications in 10% of cases, such as aplastic anemia or acquired amegakaryocytic thrombocytopenia. Paroxysmal nocturnal hemoglobinuria had never been described in a patient suffering from eosinophilic fasciitis. We report an original case of a 59-year-old patient who developed a moderate aplastic pancytopenia while he was treated for a biopsy-proven eosinophilic fasciitis. A complete set of investigations was carried out and was found to be negative, including a first research of paroxysmal nocturnal hemoglobinuria. Two years after disease onset, while pancytopenia remained stable, occurrence of morning dark urine led to found a paroxysmal nocturnal hemoglobinuria clone. We discuss a potential link between the two conditions and hypothesize that paroxysmal nocturnal hemoglobinuria blood cells may pre-exist for a long time and take a survival advantage in the setting of marrow injury, as observed in eosinophilic fasciitis with hematological complications. We finally suggest that paroxysmal nocturnal hemoglobinuria should be included as a hematological complication of eosinophilic fasciitis.


Assuntos
Eosinofilia/complicações , Eosinofilia/patologia , Fasciite/complicações , Fasciite/patologia , Hemoglobinúria Paroxística/etiologia , Leucemia Mieloide Aguda/complicações , Pancitopenia/complicações , Fáscia/patologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade
13.
Cancer ; 118(18): 4545-54, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22359215

RESUMO

BACKGROUND: O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation status was proposed as a prognostic biomarker for patients with glioblastoma. However, the prognostic impact of MGMT in patients with newly diagnosed glioblastoma who receive carmustine-releasing wafers (Gliadel) along with temozolomide (TMZ) is still unknown. METHODS: MGMT promoter methylation status and protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received the Gliadel wafers followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy while they were enrolled in a French multicenter prospective study. RESULTS: For the whole cohort, the median overall survival (OS) was 17.5 months, and the progression-free survival was 10.3 months. Patients with tumors that harbored MGMT methylation had a significantly longer OS compared with patients who had wild-type MGMT (21.7 months vs 15.1 months; P = .025). Similarly, patients who had low MGMT protein expression (≤15%) had a significantly improved OS compared with patients who had high MGMT expression (27.0 months vs 15.1 months; P = .021). The extent of resection was the strongest clinical predictor of outcome. In multivariate Cox models that were adjusted for sex, performance status, and extent of surgery, both MGMT methylation and protein expression were identified as independent prognosticators, and the finding was validated internally using a bootstrap resampling technique. Discrepancies were identified between protein expression and MGMT methylation status, thus suggesting that the 2 assays probably assess different biologic features. CONCLUSIONS: MGMT promoter methylation status and low MGMT expression both were identified as positive prognosticators in patients with newly diagnosed glioblastoma who underwent surgical resection and received Gliadel wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol).


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Metilação de DNA , Glioblastoma/genética , Glioblastoma/terapia , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais , Carmustina/uso terapêutico , Quimiorradioterapia , Quimioterapia Adjuvante , Terapia Combinada , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , O(6)-Metilguanina-DNA Metiltransferase/biossíntese , Prognóstico , Temozolomida
14.
J Transplant ; 2011: 865957, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21559262

RESUMO

Lymphomatoid granulomatosis (LYG) in renal transplant recipients is rare multisystemic angiocentric lymphoproliferative disorder with significant malignant potential. Here, we describe LYG in a 70-year-old renal allograft recipient who, 4 years after transplantation, on tacrolimus and mycophenolate mofetil and prednisone maintenance immunosuppression, complained of low-grade fever, persistent headache and gait disturbance. The MRI of the brain revealed diffuse periventricular cerebral and cerebellar contrast-enhanced lesions. The CT scan of the thorax showed multiple pulmonary nodular opacities in both lung fields. The patient was diagnosed LYG based on the cerebral biopsy showing perivascular infiltration of CD20-positive B-lymphocytes with granulomatous lesions and immunofluorescence staining with anti-EBV antibodies. With careful reduction of the immunossuppression combined with the use of rituximab, our patient showed a complete disappearance of LYG, and she is clinically well more than 4 years after the diagnosis, with good kidney function. No recurrence has been observed by radiological imaging until now. This is the first report of a durable (>4 years) complete remission of LYG after treatment with rituximab in renal transplantation.

15.
J Cell Sci ; 123(Pt 7): 1073-80, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20332120

RESUMO

Little is known about the molecular mechanisms that regulate the organization of vascular lumen. In this paper we show that lumen formation correlates with endothelial polarization. Adherens junctions (AJs) and VE-cadherin (VEC, encoded by CDH5) are required for endothelial apicobasal polarity in vitro and during embryonic development. Silencing of CDH5 gene expression leads to abrogation of endothelial polarity accompanied by strong alterations in lumenal structure. VEC co-distributes with members of the Par polarity complex (Par3 and PKCzeta) and is needed for activation of PKCzeta. CCM1 is encoded by the CCM1 gene, which is mutated in 60% of patients affected by cerebral cavernous malformation (CCM). The protein interacts with VEC and directs AJ organization and AJ association with the polarity complex, both in cell-culture models and in human CCM1 lesions. Both VEC and CCM1 control Rap1 concentration at cell-cell junctions. We propose that VEC, CCM1 and Rap1 form a signaling complex. In the absence of any of these proteins, AJs are dismantled, cell polarity is lost and vascular lumenal structure is severely altered.


Assuntos
Neoplasias Encefálicas/genética , Células Endoteliais/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas/metabolismo , Junções Aderentes/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias Encefálicas/patologia , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Polaridade Celular/genética , Células Endoteliais/patologia , Predisposição Genética para Doença , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Proteína KRIT1 , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Complexos Multiproteicos/metabolismo , Polimorfismo Genético , Ligação Proteica/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismo
16.
Cancer ; 115(17): 3955-68, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19536879

RESUMO

BACKGROUND: Ependymomas derive from ependymal cells that cover the cerebral ventricles and the central canal of the spinal cord. The molecular alterations leading to ependymomal oncogenesis are not completely understood. METHODS: The authors performed array-based expression profiling on a series of 34 frozen ependymal tumors with different localizations and histologic grades. Data were analyzed by nonsupervised and supervised clustering methods along with Gene Ontology and Pathway Analyzer tools. RESULTS: Class discovery experiments indicated a strong correlation between profiles and tumor localization as well as World Health Organization (WHO) tumor grades. On the basis of supervised clustering, intracranial ependymomas were associated with high expression levels of Notch, Hedgehog, and bone morphogenetic protein pathway members. In contrast, most of the homeobox-containing genes manifested high expression in extracranial ependymomas. The results also revealed that WHO grade 2 ependymomas differed from WHO grade 3 ependymomas by genes implicated in Wnt/beta-catenin signaling, cell cycle, E2F transcription factor 1 destruction, angiogenesis, apoptosis, remodeling of adherens junctions, and mitotic spindle formation. CONCLUSIONS: Taken together, the tumor localization-related gene sets mainly implicated in stem cell maintenance, renewal, and differentiation suggest the dysregulation of localized cancer stem cells during ependymoma development. The WHO grade differentiating pathways suggested that alteration of the Wnt/beta-catenin signaling pathway is a key event in the tumorigenesis of WHO grade 3 ependymomas. On the basis of the current data, the authors suggest a developmental scheme of ependymomas that integrates tumor localization and tumor grades, and that pinpoints new targets for the development of future therapeutic approaches.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Ependimoma/genética , Ependimoma/patologia , Perfilação da Expressão Gênica , Adolescente , Adulto , Idoso , Transformação Celular Neoplásica , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade
17.
Hum Mutat ; 30(2): E345-75, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18853459

RESUMO

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc.


Assuntos
Proteínas de Membrana/genética , Proteínas Musculares/genética , Mutação/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Disferlina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética
18.
Mol Cancer ; 6: 47, 2007 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-17626628

RESUMO

Ependymal tumors constitute a clinicopathologically heterogeneous group of brain tumors. They vary in regard to their age at first symptom, localization, morphology and prognosis. Genetic data also suggests heterogeneity. We define a newly recognized subset of ependymal tumors, the trisomy 19 ependymoma. Histologically, they are compact lesions characterized by a rich branched capillary network amongst which tumoral cells are regularly distributed. When containing clear cells they are called clear cell ependymoma. Most trisomy 19 ependymomas are supratentorial WHO grade III tumors of the young. Genetically, they are associated with trisomy 19, and frequently with a deletion of 13q21.31-31.2, three copies of 11q13.3-13.4, and/or deletions on chromosome 9. These altered chromosomal regions are indicative of genes and pathways involved in trisomy 19 ependymoma tumorigenesis. Recognition of this genetico-histological entity allows better understanding and dissection of ependymal tumors.


Assuntos
Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 19/genética , Ependimoma/patologia , Trissomia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 9/genética , Ependimoma/genética , Feminino , Genoma Humano , Humanos , Lactente , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico/métodos , Polimorfismo de Nucleotídeo Único , Análise Serial de Tecidos/métodos , Fixação de Tecidos/métodos
20.
Biochem Biophys Res Commun ; 329(3): 1152-4, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15752774

RESUMO

We describe a lethal mitochondrial disease in a 10-month-old child who presented with encephalomyopathy. Histochemical and electron microscopy examinations of skeletal muscle biopsy revealed abnormal mitochondria associated with a combined deficiency of complexes I and IV. After excluding mitochondrial DNA deletions and depletion, direct sequencing was used to screen for mutation in all transfer RNA (tRNA) genes. A T-to-C substitution at position 5693 in the tRNA(Asn) gene was found in blood and muscle. Microdissection of muscle biopsy and its analysis revealed the highest level of this mutation in cytochrome c oxidase (COX)-negative fibres. We suggest that this novel mutation would affect the anticodon loop structure of the tRNA(Asn) and cause a fatal mitochondrial disease.


Assuntos
Deficiência de Citocromo-c Oxidase/genética , Deficiência de Citocromo-c Oxidase/patologia , Complexo IV da Cadeia de Transporte de Elétrons/genética , Predisposição Genética para Doença/genética , Mitocôndrias Musculares/patologia , Músculo Esquelético/patologia , RNA de Transferência de Asparagina/genética , Deficiência de Citocromo-c Oxidase/complicações , Humanos , Lactente , Masculino , Encefalomiopatias Mitocondriais/complicações , Encefalomiopatias Mitocondriais/etiologia , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/patologia , Mutação
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