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1.
Acta Neuropathol ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444548

RESUMO

Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population.

2.
Crit Care Med ; 47(8): e685-e692, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31149963

RESUMO

OBJECTIVES: Embolic events from vegetations are commonly accepted as the main mechanism involved in neurologic complications of infective endocarditis. The pathophysiology may imply other phenomena, including vasculitis. We aimed to define the cerebral lesion spectrum in an infective endocarditis rat model. DESIGN: Experimental model of Staphylococcus aureus or Enterococcus faecalis infective endocarditis. Neurologic lesions observed in the infective endocarditis model were compared with three other conditions, namely bacteremia, nonbacterial thrombotic endocarditis, and healthy controls. SETTING: Research laboratory of a university hospital. SUBJECTS: Male Wistar rats. INTERVENTIONS: Brain MRI, neuropathology, immunohistochemistry for astrocyte and microglia, and bacterial studies on brain tissue were used to characterize neurologic lesions. MEASUREMENTS AND MAIN RESULTS: In the infective endocarditis group, MRI revealed at least one cerebral lesion in 12 of 23 rats (52%), including brain infarctions (n = 9/23, 39%) and cerebral microbleeds (n = 8/23, 35%). In the infective endocarditis group, neuropathology revealed brain infarctions (n = 12/23, 52%), microhemorrhages (n = 10/23, 44%), and inflammatory processes (i.e., cell infiltrates including abscesses, vasculitis, meningoencephalitis, and/or ependymitis; n = 11/23, 48%). In the bacteremia group, MRI studies were normal and neuropathology revealed only hemorrhages (n = 2/11, 18%). Neuropathologic patterns observed in the nonbacterial thrombotic endocarditis group were similar to those observed in the infective endocarditis group. Immunochemistry revealed higher microglial activation in the infective endocarditis group (n = 11/23, 48%), when compared with the bacteremia (n = 1/11, 9%; p = 0.03) and nonbacterial thrombotic endocarditis groups (n = 0/7, 0%; p = 0.02). CONCLUSIONS: This original model of infective endocarditis recapitulates the neurologic lesion spectrum observed in humans and suggests synergistic mechanisms involved, including thromboembolism and cerebral vasculitis, promoted by a systemic bacteremia-mediated inflammation.

3.
J Neurovirol ; 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397828

RESUMO

The role of the human cytomegalovirus (HCMV) in gliomagenesis is largely debated. Contradictory data exist regarding the sensitivity and specificity of HCMV detection techniques, including immunohistochemistry (IHC), in situ hybridization (ISH), and RNA and DNA sequencing. The aim of this study is to detect HCMV in glioblastoma (GBM) tumor samples using IHC, ISH, and real-time PCR (qPCR), as well as to correlate the findings with serological status and HCMV DNA load in blood. Forty-seven patients with histopathological diagnosis of GBM and HCMV serological status were retrospectively reviewed. HCMV DNA quantification in whole blood was performed in 31 patients. The detection of HCMV in tumor samples was performed using IHC in 42 cases, ISH in 10 cases, and qPCR in 29 cases. All but two patients were taking high steroid doses at the time of biological testing. HCMV seroprevalence was 68%. Active infection with HCMV DNA detected in blood was diagnosed in 6 out of 21 (28%) seropositive patients. HCMV was not detected in GBM samples using IHC or ISH, while qPCR was positive in one case (also positive for blood HCMV DNA). These data do not support a crucial role of HCMV in GBM tumorigenesis. HCMV might be reactivated in GBM patients, due to steroid treatment.

4.
Acta Neuropathol Commun ; 6(1): 109, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30340542

RESUMO

Extreme microcephaly and rhombencephalosynapsis represent unusual pathological conditions, each of which occurs in isolation or in association with various other cerebral and or extracerebral anomalies. Unlike microcephaly for which several disease-causing genes have been identified with different modes of inheritance, the molecular bases of rhombencephalosynapsis remain unknown and rhombencephalosynapsis presents mainly as a sporadic condition consistent with de novo dominant variations. We report for the first time the association of extreme microcephaly with almost no sulcation and rhombencephalosynapsis in a fœtus for which comparative patient-parent exome sequencing strategy revealed a heterozygous de novo missense variant in the ADGRL2 gene. ADGRL2 encodes latrophilin 2, an adhesion G-protein-coupled receptor whose exogenous ligand is α-latrotoxin. Adgrl2 immunohistochemistry and in situ hybridization revealed expression in the telencephalon, mesencephalon and rhombencephalon of mouse and chicken embryos. In human brain embryos and fœtuses, Adgrl2 immunoreactivity was observed in the hemispheric and cerebellar germinal zones, the cortical plate, basal ganglia, pons and cerebellar cortex. Microfluorimetry experiments evaluating intracellular calcium release in response to α-latrotoxin binding showed significantly reduced cytosolic calcium release in the fœtus amniocytes vs amniocytes from age-matched control fœtuses and in HeLa cells transfected with mutant ADGRL2 cDNA vs wild-type construct. Embryonic lethality was also observed in constitutive Adgrl2-/- mice. In Adgrl2+/- mice, MRI studies revealed microcephaly and vermis hypoplasia. Cell adhesion and wound healing assays demonstrated that the variation increased cell adhesion properties and reduced cell motility. Furthermore, HeLa cells overexpressing mutant ADGRL2 displayed a highly developed cytoplasmic F-actin network related to cytoskeletal dynamic modulation. ADGRL2 is the first gene identified as being responsible for extreme microcephaly with rhombencephalosynapsis. Increased cell adhesion, reduced cell motility and cytoskeletal dynamic alterations induced by the variant therefore represent a new mechanism responsible for microcephaly.

5.
Virchows Arch ; 473(6): 771-774, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30073405

RESUMO

Cerebral autosomal dominant arteriolopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common form of hereditary small vessel disease (SVD) of the brain. Neuronal apoptosis has been demonstrated in the cortex of patients. Whether it is associated with an activation of the pro-apoptotic protein PKR pathway is unknown. Similarly, activation of autophagy in CADASIL has never been explored. Immunostaining of four CADASIL brains previously analyzed for cortical neuronal apoptosis and five control brains for PKR (phosphoPKR) and autophagy (ATG5, LC3II) activation markers. Significant nuclear pPKR staining was observed in CADASIL neurons comparatively to controls (p = 0.001). No difference was observed between patients and controls with autophagy markers. We demonstrated the activation of PKR pathway in CADASIL. This was not associated with a detectable modulation of autophagy. These results open a new field to explore in order to better understand the mechanisms underlying cortical neurons apoptosis.

6.
World Neurosurg ; 119: 242-243, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30121405

RESUMO

Rosette-forming glioneuronal tumor has recently been included in the World Health Organization classification as a low-grade tumor. It usually occurs in young adults, arising from the fourth ventricular region. The authors describe a rare case of rosette-forming glioneuronal tumor arising from the spinal cord with cerebrospinal fluid dissemination. Magnetic resonance imaging showed a cervical spinal cord tumor, which could be easily misdiagnosed as ependyma or astrocytoma. Surgical total resection was performed, and histopathologic examination made the diagnosis, showing a biphasic neurocytic and glial tumor with neurocytic rosettes. Six months after surgery, the patient had fully recovered.

7.
Cereb Cortex ; 28(7): 2458-2478, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29722804

RESUMO

Neuropathological conditions might affect adult granulogenesis in the adult human dentate gyrus. However, radial glial cells (RGCs) have not been well characterized during human development and aging. We have previously described progenitor and neuronal layer establishment in the hippocampal pyramidal layer and dentate gyrus from embryonic life until mid-gestation. Here, we describe RGC subtypes in the hippocampus from 13 gestational weeks (GW) to mid-gestation and characterize their evolution and the dynamics of neurogenesis from mid-gestation to adulthood in normal and Alzheimer's disease (AD) subjects. In the pyramidal ventricular zone (VZ), RGC density declined with neurogenesis from mid-gestation until the perinatal period. In the dentate area, morphologic and antigenic differences among RGCs were observed from early ages of development to adulthood. Density and proliferative capacity of dentate RGCs as well as neurogenesis were strongly reduced during childhood until 5 years, few DCX+ cells are seen in adults. The dentate gyrus of both control and AD individuals showed Nestin+ and/or GFAPδ+ cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present in the human hippocampus from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems negligible in the adult.

8.
Clin Neuropathol ; 37(5): 209-216, 2018 Sep/Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29809131

RESUMO

Numerous molecular alterations have been described in supratentorial high-grade gliomas (1p19q co-deletion, IDH1/2, histone H3, hTERT promotor mutations, loss of ATRX) which have led to a new histomolecular classification of diffuse gliomas. We aimed at describing these alterations in a series of 19 adults with pure cerebellar high-grade gliomas. Systematic immunohistochemical analyses, including that of IDH1R132H, ATRX, p53, PTEN, EGFR, p16, FGFR3, BRAFV600E, mismatch repair proteins, H3K27me3, H3K36me3, and H3K27M; molecular analyses of IDH1/2, hTERT, BRAF, H3F3A, and HIST1H3B mutation hotspots; and EGFR, PTEN FISH were retrospectively performed in a multicentric study. We histopathologically identified 14 glioblastomas, 4 grade III astrocytomas and 1 gliosarcoma. Two cases showed a H3F3A K27M mutation. Only one case harbored a classical profile of glioblastoma with hTERT mutation, EGFR gain and 10q loss. The most frequent alteration was the absence of p16 immunoexpression. We report a histomolecular analysis of pure cerebellar high grade gliomas. The histomolecular profile appears to be different from that of supratentorial gliomas, with no IDH1/2 gene mutations and only 1 case with a classic profile of de novo glioblastoma. In 2 cases, we identified H3F3A K27M mutation, classically described in pediatric midline gliomas.
.

10.
J Neuropathol Exp Neurol ; 77(3): 207-215, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29361006

RESUMO

Pediatric chordomas are rare malignant neoplasms, and few data are available for optimizing therapeutic strategies and outcome. This study aimed at evaluating how best to manage them and to identify prognostic factors. This multicentric retrospective study included 40 children diagnosed with chordomas between 1966 and 2012. Clinical, radiological, and histopathological data, treatment modalities, and outcomes were reviewed. The median age was 12 years old. Most chordomas were histologically classical forms (45.5%) and were mostly located at the skull base (72.5%). The overall survival (OS) was 66.6% and 58.6%, and progression-free survival (PFS) was 55.7% and 52% at 5 and 10 years, respectively. Total resection was correlated with a better outcome (p = 0.04 for OS and PFS, log-rank). A histopathological/immunohistochemical grading system recently crafted for adults was applied. In a multivariate analysis, it significantly correlated with outcome (PFS and OS, p = 0.004), and the loss of BAF47 immunoexpression appeared to be a significant independent prognostic factor (PFS, p = 0.033). We also identified clinical and histopathological parameters that correlated with prognosis. A new grading system combined with the quality of surgical resection could help classify patients to postpone radiotherapy in case of low risk. Targeted therapy and reirradiation at recurrence may be considered as potential therapeutic strategies.

11.
Brain Struct Funct ; 223(3): 1501-1518, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29168008

RESUMO

The function, regulation and cellular distribution of GABAA receptor subunits have been extensively documented in the adult rodent brain and are linked to numerous neurological disorders. However, there is a surprising lack of knowledge on the cellular (sub-) distribution of GABAA receptor subunits and of their expressional regulation in developing healthy and diseased foetal human brains. To propose a role for GABAA receptor subunits in neurodevelopmental disorders, we studied the developing hippocampus of normal and Down syndrome foetuses. Among the α1-3 and γ2 subunits probed, we find significantly altered expression profiles of the α1, α3 and γ2 subunits in developing Down syndrome hippocampi, with the α3 subunit being most affected. α3 subunits were selectively down-regulated in all hippocampal subfields and developmental periods tested in Down syndrome foetuses, presenting a developmental mismatch by their adult-like distribution in early foetal development. We hypothesized that increased levels of the amyloid precursor protein (APP), and particularly its neurotoxic ß-amyloid (1-42) fragment, could disrupt α3 gene expression, likely by facilitating premature neuronal differentiation. Indeed, we find increased APP content in the hippocampi of the Down foetuses. In a corresponding cellular model, soluble ß-amyloid (1-42) administered to cultured SH-SY5Y neuroblastoma cells, augmented by retinoic acid-induced differentiation towards a neuronal phenotype, displayed a reduction in α3 subunit levels. In sum, this study charts a comprehensive regional and subcellular map of key GABAA receptor subunits in identified neuronal populations in the hippocampus of healthy and Down syndrome foetuses and associates increased ß-amyloid load with discordant down-regulation of α3 subunits.

12.
Brain Pathol ; 28(4): 466-474, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28474749

RESUMO

Clear cell meningioma (CCM) is a rare grade II histopathological subtype that usually occurs in young patients and displays high recurrence rate. Germline SMARCE1 mutations have been described in hereditary forms of this disease and more recently in small syndromic and sporadic CCM series. The diagnostic value of SMARCE1 in distinguishing between CCM and other meningioma variants has not been yet established. The aim of our study was to investigate the status of SMARCE1 in a series of CCMs and its morphological mimickers. We compared the performance of an anti-SMARCE1 antibody and the molecular analysis of the SMARCE1 gene in a retrospective multicenter series of CCMs. All CCMs lossed SMARCE1 immunoexpression. Bi-allelic inactivating events were found by NGS-based sequencing in all of these cases, except for one, which was incompletely explored, but had a wild-type sequence. We then validated the anti-SMARCE1 antibody specificity by analyzing additional 305 pediatric and adult meningiomas of various subtypes and 15 non-meningioma clear cell tumors by SMARCE1 immunohistochemistry. A nuclear immunostaining was preserved in all other meningioma variants, as well as non-meningioma clear cell tumors. In conclusion, our series showed, for the first time, that SMARCE1 immunostaining is a highly sensitive biomarker for CCM, useful as a routine diagnostic biomarker.

13.
Pract Neurol ; 18(2): 159-161, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29208730

RESUMO

IgG4-related disease is now recognised as an important cause of intracranial and spinal hypertrophic pachymeningitis. Treatment with corticosteroids generally leads to significant clinical improvement. We present two cases of IgG4 pachymeningitis unresponsive to corticosteroids who improved with rituximab.


Assuntos
Imunoglobulina G , Fatores Imunológicos/uso terapêutico , Meningite/tratamento farmacológico , Rituximab/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Meningite/imunologia , Pessoa de Meia-Idade , Recidiva
14.
Handb Clin Neurol ; 145: 51-78, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28987191

RESUMO

This chapter briefly describes the normal development of the nervous system, the neuropathology and pathophysiology of acquired and secondary disorders affecting the embryo, fetus, and child. They include CNS manifestations of chromosomal change; forebrain patterning defects; disorders of the brain size; cell migration and specification disorders; cerebellum, hindbrain and spinal patterning defects; hydrocephalus; secondary malformations and destructive pathologies; vascular malformations; arachnoid cysts and infectious diseases. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling.


Assuntos
Encefalopatias/etiologia , Encéfalo , Doenças Fetais/fisiopatologia , Malformações do Sistema Nervoso/complicações , Encéfalo/anormalidades , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez
15.
Acta Neuropathol Commun ; 5(1): 36, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28460636

RESUMO

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.


Assuntos
Proteínas de Transporte/genética , Epêndima/anormalidades , Doenças Fetais/genética , Hidrocefalia/genética , Mutação com Perda de Função , Adulto , Epêndima/diagnóstico por imagem , Família , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/etiologia , Doenças Fetais/patologia , Homozigoto , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/patologia
16.
Neurosurgery ; 80(5): 793-799, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28387870

RESUMO

BACKGROUND: Biophysical modeling of glioma is gaining more interest for clinical practice. The most popular model describes aggressivity of tumor cells by two parameters: net proliferation rate (ρ) and propensity to migrate (D). The ratio ρ/D, which can be estimated from a single preoperative magnetic resonance imaging (MRI), characterizes tumor invasiveness profile (high ρ/D: nodular; low ρ/D: diffuse). A recent study reported, from a large series of glioblastoma multiforme (GBM) patients, that gross total resection (GTR) would improve survival only in patients with nodular tumors. OBJECTIVE: To replicate these results, that is to verify that benefit of GTR would be only observed for nodular tumors. METHODS: Between 2005 and 2012, we considered 234 GBM patients with pre- and postoperative MRI. Stereotactic biopsy (BST) was performed in 109 patients. Extent of resection was assessed on postoperative MRI and classified as GTR or partial resection (PR). Invasiveness ρ/D was estimated from the preoperative tumor volumes on T1-Gadolinium-enhanced and fluid-attenuated inversion recovery sequences. RESULTS: We demonstrate that patients with diffuse GBM (low ρ/D), as well as more nodular (mid and high ρ/D) GBM, presented significant survival benefit from GTR over PR/BST ( P < .001). CONCLUSION: Whatever the degree of tumor invasiveness, as estimated from MRI-driven biophysical modeling, GTR improves survival of GBM patients, compared to PR or BST. This conflicting result should motivate further studies.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Tomada de Decisão Clínica/métodos , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Modelos Teóricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biofísicos , Feminino , Gadolínio , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estudos Retrospectivos , Carga Tumoral , Adulto Jovem
17.
Cereb Cortex ; 27(1): 358-372, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-26443441

RESUMO

The molecular mechanisms that orchestrate the development of the human dentate gyrus are not known. In this study, we characterized the formation of human dentate and fimbrial progenitors and postmitotic neurons from 9 gestational weeks (GW9) to GW25. PAX6+ progenitor cells remained proliferative until GW16 in the dentate ventricular zone. By GW11, the secondary dentate matrix had developed in the intermediate zone, surrounding the dentate anlage and streaming toward the subpial layer. This secondary matrix contained proliferating PAX6+ and/or TBR2+ progenitors. In parallel, SOX2+ and PAX6+ fimbrial cells were detected approaching the dentate anlage, representing a possible source of extra-dentate progenitors. By GW16, when the granule cell layer could be delineated, a hilar matrix containing PAX6+ and some TBR2+ progenitors had become identifiable. By GW25, when the 2 limbs of the granule cell layer had formed, the secondary dentate matrix was reduced to a pool of progenitors at the fimbrio-dentate junction. Although human dentate development recapitulates key steps previously described in rodents, differences seemed to emerge in neuron layer markers expression. Further studies are necessary to better elucidate their role in dentate formation and connectivity.


Assuntos
Giro Denteado/embriologia , Fórnice/embriologia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Biomarcadores/análise , Humanos
18.
Brain Pathol ; 27(5): 567-579, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27543943

RESUMO

The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3id ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3id . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3id overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3id is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3id recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3id and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3id . A better understanding of spatial and temporal intratumor cell heterogeneity in O3id will open new therapeutic avenues overcoming resistance to current antitumor treatments.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 1 , Células-Tronco Neurais/patologia , Oligodendroglioma/genética , Oligodendroglioma/patologia , Adulto , Deleção Cromossômica , Biologia Computacional , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neurais/metabolismo , Neurogênese , Fenótipo , Proteínas Repressoras/metabolismo , Estudos Retrospectivos , Fatores de Transcrição SOX9/metabolismo
19.
Ann Pathol ; 36(4): 245-51, 2016 Aug.
Artigo em Francês | MEDLINE | ID: mdl-27475007

RESUMO

Rhino-sinusal infections are serious diseases and possibly lethal. When they are invasive, we easily discuss apergilloses and mucormycoses. The confirmation of the diagnosis of mucormycosis need an extensive surgery for precise histopathological and mycological evaluation. The pathologist may be faced to other rare mycoses such as phaeohyphomycoses, which present different morphological features than mucormycoses and Aspergillus. Once the diagnosis is established, an appropriate antifungal treatment is quickly started. The aim of our work is to report two observations of phaeohyphomycoses, to describe their histopathological features, to discuss complementary diagnostic methods and to present the main differential diagnoses.


Assuntos
Alternaria/isolamento & purificação , Alternariose/microbiologia , Feoifomicose/microbiologia , Rinite/microbiologia , Sinusite/microbiologia , Adulto , Alternaria/ultraestrutura , Alternariose/diagnóstico , Alternariose/patologia , Alternariose/terapia , Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Terapia Combinada , Desbridamento , Diagnóstico Diferencial , Diagnóstico Precoce , Evolução Fatal , Feminino , Humanos , Lipossomos , Mastoidite/tratamento farmacológico , Mastoidite/microbiologia , Mastoidite/cirurgia , Feoifomicose/diagnóstico , Feoifomicose/patologia , Feoifomicose/terapia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Rinite/diagnóstico , Rinite/patologia , Rinite/terapia , Choque Séptico/etiologia , Sinusite/diagnóstico , Sinusite/patologia , Sinusite/terapia
20.
PLoS One ; 11(7): e0160176, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27472761

RESUMO

BACKGROUND: Congenital cytomegalovirus infections are a leading cause of neurodevelopmental disorders in human and represent a major health care and socio-economical burden. In contrast with this medical importance, the pathophysiological events remain poorly known. Murine models of brain cytomegalovirus infection, mostly neonatal, have brought recent insights into the possible pathogenesis, with convergent evidence for the alteration and possible involvement of brain immune cells. OBJECTIVES AND METHODS: In order to confirm and expand those findings, particularly concerning the early developmental stages following infection of the fetal brain, we have created a model of in utero cytomegalovirus infection in the developing rat brain. Rat cytomegalovirus was injected intraventricularly at embryonic day 15 (E15) and the brains analyzed at various stages until the first postnatal day, using a combination of gene expression analysis, immunohistochemistry and multicolor flow cytometry experiments. RESULTS: Rat cytomegalovirus infection was increasingly seen in various brain areas including the choroid plexi and the ventricular and subventricular areas and was prominently detected in CD45low/int, CD11b+ microglial cells, in CD45high, CD11b+ cells of the myeloid lineage including macrophages, and in CD45+, CD11b- lymphocytes and non-B non-T cells. In parallel, rat cytomegalovirus infection of the developing rat brain rapidly triggered a cascade of pathophysiological events comprising: chemokines upregulation, including CCL2-4, 7 and 12; infiltration by peripheral cells including B-cells and monocytes at E17 and P1, and T-cells at P1; and microglia activation at E17 and P1. CONCLUSION: In line with previous findings in neonatal murine models and in human specimen, our study further suggests that neuroimmune alterations might play critical roles in the early stages following cytomegalovirus infection of the brain in utero. Further studies are now needed to determine which role, whether favorable or detrimental, those putative double-edge swords events actually play.


Assuntos
Encéfalo/embriologia , Infecções por Citomegalovirus/patologia , Microglia/patologia , Muromegalovirus/patogenicidade , Animais , Linhagem da Célula , Infecções por Citomegalovirus/imunologia , Citometria de Fluxo , Ativação de Macrófagos , Microglia/imunologia , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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