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1.
Am J Hum Genet ; 111(3): 594-613, 2024 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-38423010

RESUMO

The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.


Assuntos
Epilepsia Generalizada , Atrofia Óptica , Animais , Humanos , Criança , Peixe-Zebra/genética , Atrofia Óptica/genética , Fenótipo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética
2.
Chembiochem ; 14(5): 607-16, 2013 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-23450708

RESUMO

Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.


Assuntos
Corantes Fluorescentes/química , Proteínas/química , Tiofenos/química , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Técnicas Biossensoriais , Humanos , Corpos de Inclusão/química , Corpos de Inclusão/metabolismo , Ligantes , Microscopia de Fluorescência , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/patologia , Proteínas/análise , Proteína Sequestossoma-1
3.
Aging (Albany NY) ; 13(2): 3146-3160, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33497354

RESUMO

Medulloblastoma is a common primary brain tumor in children but it is a rare cancer in adult patients. We reviewed the literature, searching PubMed for articles on this rare tumor entity, with a focus on tumor biology, advanced neurosurgical opportunities for safe tumor resection, and multimodal treatment options. Adult medulloblastoma occurs at a rate of 0.6 per one million people per year. There is a slight disparity between male and female patients, and patients with a fair skin tone are more likely to have a medulloblastoma. Patients present with cerebellar signs and signs of elevated intracranial pressure. Diagnostic efforts should consist of cerebral MRI and MRI of the spinal axis. Cerebrospinal fluid should be investigated to look for tumor dissemination. Medulloblastoma tumors can be classified as classic, desmoplastic, anaplastic, and large cell, according to the WHO tumor classification. Molecular subgroups include WNT, SHH, group 3, and group 4 tumors. Further molecular analyses suggest that there are several subgroups within the four existing subgroups, with significant differences in patient age, frequency of metastatic spread, and patient survival. As molecular markers have started to play an increasing role in determining treatment strategies and prognosis, their importance has increased rapidly. Treatment options include microsurgical tumor resection and radiotherapy and, in addition, chemotherapy that respects the tumor biology of individual patients offers targeted therapeutic approaches. For neurosurgeons, intraoperative imaging and tumor fluorescence may improve resection rates. Disseminated disease, residual tumor after surgery, lower radiation dose, and low Karnofsky performance status are all suggestive of a poor outcome. Extraneural spread occurs only in very few cases. The reported 5-year-survival rates range between 60% and 80% for all adult medulloblastoma patients.


Assuntos
Neoplasias Encefálicas/cirurgia , Meduloblastoma/cirurgia , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Prognóstico
4.
J Neurosci ; 29(30): 9439-49, 2009 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-19641107

RESUMO

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.


Assuntos
Comportamento Animal , Proteínas de Membrana Transportadoras/deficiência , Deficiência Intelectual Ligada ao Cromossomo X/genética , Neurônios/fisiologia , Tri-Iodotironina/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Células Cultivadas , Cadeias Leves da Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Hipertireoidismo/fisiopatologia , Hipotireoidismo/fisiopatologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Knockout , Microglia/metabolismo , Transportadores de Ácidos Monocarboxílicos , Testes Neuropsicológicos , Fenótipo , RNA Mensageiro/metabolismo , Simportadores , Síndrome
5.
J Neurooncol ; 100(3): 407-15, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20446016

RESUMO

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m(2) twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-L-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8-12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/diagnóstico por imagem , Celecoxib , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Feminino , Radioisótopos de Flúor , Seguimentos , Glioblastoma/diagnóstico por imagem , Glioblastoma/fisiopatologia , Humanos , Masculino , Metilação/efeitos dos fármacos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Estudos Retrospectivos , Temozolomida , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Tirosina/análogos & derivados
6.
J Mol Histol ; 39(5): 553-60, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18726700

RESUMO

Objective Oligodendroglial tumors with a loss of heterozygosity of 1p (LOH1p) appear to have a better prognosis than oligodendrogliomas without LOH. Previously, we reported glucose uptake in low-grade oligodendroglial tumors to be related to LOH 1p status. Here, we performed an immunohistochemical study of the common glucose transporters (GLUT) in relation to LOH1p. Material and methods We examined 17 oligodendrogliomas (O II, 11 with LOH1p), 16 oligoastrocytomas (OA II, 5 with LOH1p) and 7 astrocytomas (A II, none with LOH1p). Confocal microscopy was performed for p53, GLUT-1, -3 and -12. Immunoreaction was rated semiquantitatively by percentage of positive cells and staining intensity on immunohistological stainings. Results Confocal microscopy depicted immunoreaction for GLUT-1, -3 and -12 in the cytoplasm of the tumor cells. Oligodendrogliomas revealed a lower immunoreactivity for GLUT-1 than oligoastrocytomas and astrocytomas (P = 0.0263). No differences in immunoreactivity were found for GLUT-3 and GLUT-12. GLUT-1 expression in tumors with LOH 1p was significantly lower than in tumors with wild type 1p status (P = 0.0017). GLUT-3 and GLUT-12 immunoreactivity was not correlated with LOH 1p. Conclusion Expression of GLUT-1 is significantly reduced in low-grade oligodendroglial tumors harboring LOH 1p. Further studies should address the functional role of GLUT-1 in regard to chemosensitivity of oligodendrogliomas.


Assuntos
Neoplasias Encefálicas/metabolismo , Cromossomos Humanos Par 1/metabolismo , Glioma/metabolismo , Transportador de Glucose Tipo 1/biossíntese , Perda de Heterozigosidade , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 1/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioma/genética , Glioma/patologia , Proteínas Facilitadoras de Transporte de Glucose/biossíntese , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 3/biossíntese , Transportador de Glucose Tipo 3/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Microscopia Confocal/métodos , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética
7.
Clin Cancer Res ; 12(18): 5526-32, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17000689

RESUMO

PURPOSE: Thalidomide and its analogues have shown promise in the treatment of multiple myeloma but their therapeutic potential has not been evaluated in models of acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: We assessed the effects of the thalidomide analogue, CC-4047, on the growth and apoptosis signaling of human B cell precursor (BCP) ALL cell lines and freshly obtained childhood BCP-ALL cells grown with or without stromal cells. In addition, we studied the effects of CC-4047 on the progression and dissemination of xenotransplanted human BCP-ALL cells in nonobese diabetic/severe combined immunodeficiency mice. RESULTS: CC-4047 reduced the proliferation of human BCP-ALL cell lines in vitro. In contrast with the antileukemic effect of cytarabin, this was more pronounced when cell lines or freshly obtained childhood BCP-ALL cells were cocultured with stromal cells. CC-4047 induced the cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase in stroma-cocultured BCP-ALL cells. The inhibition of tumor growth, caspase-3 cleavage, and reduced microvessel density was observed in nonobese diabetic/severe combined immunodeficiency mice inoculated s.c. with childhood BCP-ALL cells upon CC-4047 treatment. After i.v. BCP-ALL xenotransplantation, CC-4047 reduced splenic dissemination. CONCLUSIONS: The thalidomide analogue, CC-4047, displays profound cytostatic effects on stroma-supported human ALL cells both in vitro and in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Talidomida/análogos & derivados , Animais , Vasos Sanguíneos/efeitos dos fármacos , Caspase 3/metabolismo , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Células Estromais/efeitos dos fármacos , Talidomida/farmacologia , Talidomida/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J STD AIDS ; 26(12): 912-4, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25505049

RESUMO

We report a case of a symptomatic relapse of HIV-related cryptococcal meningoencephalitis eight years after the first diagnosis on the background of immune reconstitution. The findings as well as the clinical course suggests a combination of smouldering localised infection and enhanced inflammatory reaction related to immune restoration due to antiretroviral therapy. A combination of antifungal and anti-inflammatory therapy resulted in clinical and radiological improvement. Our case challenges the concept that immune reconstitution inflammatory syndrome and microbiological relapse are dichotomous entities.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Cryptococcus neoformans/isolamento & purificação , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Meningite Criptocócica/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Antifúngicos/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Biópsia , Encéfalo/patologia , Cryptococcus neoformans/genética , Feminino , Fluconazol/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Adesão à Medicação , Meningite Criptocócica/tratamento farmacológico , Recidiva , Resultado do Tratamento
9.
J Heart Lung Transplant ; 31(11): 1171-6, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22995552

RESUMO

BACKGROUND: Continuous-flow (CF) ventricular assist devices (VAD) are an established option for treatment of end-stage heart failure. However, the effect of long-term CF with lack of peripheral arterial wall motions on blood pressure regulation and end-organ arterial wall sclerosis, especially in the case of long-term support (> 3 years), remains unclear. METHODS: Tissue samples obtained at autopsy from liver, kidney, coronary arteries, and brain from 27 VAD recipients supported for > 180 days between 2000 and 2010 were histologically examined to assess vascular alterations, including perivascular infiltrate, intravascular infiltrate, wall thickness, thrombosis, endothelial cell swelling, vessel wall necrosis, and peri-vascular fibrosis. Pulsatile-flow (PF) devices had been inserted in 9 patients and CF devices had been inserted in 16. The pathologist was blinded to the group distribution. Demographic, pharmacologic, and clinical data were retrospectively analyzed before surgery and during the follow-up period of up to 24 months. RESULTS: Median duration of support was 467 days (range, 235-1,588 days) in the PF group and 263 days (range, 182-942 days) in the CF group. Demographic and clinical data before and after surgery were similar. Amiodarone was more often used during follow-up in CF group than in the PF group (61% vs 10%, p = 0.009). Throughout the follow-up period, mean arterial pressure did not differ between recipients of the 2 pump types, nor did systolic and diastolic pressure, except at 2 weeks after VAD implantation, when systolic blood pressure was higher (p = 0.05) and diastolic lower (p = 0.03) in the PF group. Histologic studies did not identify any relevant differences in arterial wall characteristics between the 2 groups. CONCLUSION: Long-term mechanical circulatory support with CF devices does not adversely influence arterial wall properties of the end-organ vasculature.


Assuntos
Artérias Cerebrais/patologia , Vasos Coronários/patologia , Insuficiência Cardíaca/terapia , Coração Auxiliar/classificação , Artéria Hepática/patologia , Artéria Renal/patologia , Adulto , Idoso , Fenômenos Biomecânicos/fisiologia , Pressão Sanguínea/fisiologia , Artérias Cerebrais/fisiopatologia , Vasos Coronários/fisiopatologia , Feminino , Fibrose , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Artéria Hepática/fisiopatologia , Humanos , Hiperplasia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Necrose , Artéria Renal/fisiopatologia , Estudos Retrospectivos , Fatores de Tempo
10.
J Neurosurg Pediatr ; 3(5): 386-91, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19409017

RESUMO

Intracranial osteolipomas and chondromas are rare benign tumors. Forty-five chondromas, mostly supratentorial, have been reported in the literature since 1981, with origins most commonly in the sellar regions. Twenty-one osteolipomas have been described to date, usually located near the tuber cinereum or the corpus callosum. The authors present a case of an osteochondrolipoma arising from the tentorium diagnosed in a pediatric patient at the age of 9 years. The case and treatment are discussed, and a review of the literature is provided.


Assuntos
Neoplasias Infratentoriais/diagnóstico , Lipoma/diagnóstico , Ossificação Heterotópica/patologia , Osteocondroma/diagnóstico , Túber Cinéreo/patologia , Criança , Humanos , Neoplasias Infratentoriais/patologia , Neoplasias Infratentoriais/cirurgia , Lipoma/patologia , Lipoma/cirurgia , Imageamento por Ressonância Magnética , Masculino , Ossificação Heterotópica/fisiopatologia , Ossificação Heterotópica/cirurgia , Osteocondroma/patologia , Osteocondroma/cirurgia , Túber Cinéreo/fisiopatologia , Túber Cinéreo/cirurgia
11.
Spine (Phila Pa 1976) ; 33(6): E183-7, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18344848

RESUMO

STUDY DESIGN: Case report and a review of the literature. OBJECTIVE: We report the case of a young man with a short course of progressive cervical myelopathy (CM). Cervical magnetic resonance imaging (MRI) revealed a stenosis of the cervical spinal canal at C4-C6 and an atypically enlarged intramedullary high intensity extending from C1-T1 (T2-weighted) with contrast enhancement at C4-C5 (T1-weighted). Neurologic and radiologic diagnosis therefore favored a tumor of the spinal cord. SUMMARY OF BACKGROUND DATA: CM is a clinical diagnosis of mostly degenerative origin in older patients that features circumscribed high-intensity signals near the point of compression in T2-weighted MRI. Contrast enhancement in those high-intense areas is rarely described in the literature, and the differentiation from neoplastic and infective lesions might be very difficult in these cases. METHODS: Retrospective case study with follow-up examination and MRI-control 3 months after surgery. RESULTS: The patient was decompressed and stabilized from dorsally, and a biopsy was taken. The exact diagnosis of a myelopathy and an exclusion of a neoplastic origin succeeded through histopathological examination. Three months after first surgery, the patient had improved significantly and underwent an additional anterior stabilization, while the MRI remained almost unchanged. CONCLUSION: In case of a fast progressive CM with atypical radiographic appearance initial decompression with inspection of the spinal cord and a short-term clinical follow-up with an MRI control might be the procedure of choice, if a clear diagnosis for a causative treatment cannot be made. In still suspicious cases, a biopsy could be considered to exclude a neoplastic or inflammatory process.


Assuntos
Vértebras Cervicais/diagnóstico por imagem , Neoplasias da Medula Espinal/diagnóstico , Osteofitose Vertebral/diagnóstico , Adulto , Vértebras Cervicais/cirurgia , Diagnóstico Diferencial , Humanos , Masculino , Radiografia , Doenças da Medula Espinal/diagnóstico , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/cirurgia , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/cirurgia , Osteofitose Vertebral/diagnóstico por imagem , Osteofitose Vertebral/cirurgia
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