Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
J Med Genet ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161153

RESUMO

BACKGROUND: Mitochondrial progressive external ophthalmoplegia (PEO) encompasses a broad spectrum of clinical and genetic disorders. We describe the phenotypic subtypes of PEO and its correlation with molecular defects and propose a diagnostic algorithm. METHODS: Retrospective analysis of the clinical, pathological and genetic features of 89 cases. RESULTS: Three main phenotypes were found: 'pure PEO' (42%), consisting of isolated palpebral ptosis with ophthalmoparesis; Kearns-Sayre syndrome (10%); and 'PEO plus', which associates extraocular symptoms, distinguishing the following subtypes: : myopathic (33%), bulbar (12%) and others (3%). Muscle biopsy was the most accurate test, showing mitochondrial changes in 95%. Genetic diagnosis was achieved in 96% of the patients. Single large-scale mitochondrial DNA (mtDNA) deletion was the most frequent finding (63%), followed by multiple mtDNA deletions (26%) due to mutations in TWNK (n=8), POLG (n=7), TK2 (n=6) or RRM2B (n=2) genes, and point mtDNA mutations (7%). Three new likely pathogenic mutations were identified in the TWNK and MT-TN genes. CONCLUSIONS: Phenotype-genotype correlations cannot be brought in mitochondrial PEO. Muscle biopsy should be the first step in the diagnostic flow of PEO when mitochondrial aetiology is suspected since it also enables the study of mtDNA rearrangements. If no mtDNA deletions are identified, whole mtDNA sequencing should be performed.

2.
Sci Transl Med ; 12(527)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969485

RESUMO

Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (MAPT), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost absent from tumors with epidermal growth factor receptor (EGFR) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.

3.
J Clin Endocrinol Metab ; 105(2)2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628455

RESUMO

CONTEXT: Glycogenin is considered to be an essential primer for glycogen biosynthesis. Nevertheless, patients with glycogenin-1 deficiency due to biallelic GYG1 (NM_004130.3) mutations can store glycogen in muscle. Glycogenin-2 has been suggested as an alternative primer for glycogen synthesis in patients with glycogenin-1 deficiency. OBJECTIVE: The objective of this article is to investigate the importance of glycogenin-1 and glycogenin-2 for glycogen synthesis in skeletal and cardiac muscle. DESIGN, SETTING, AND PATIENTS: Glycogenin-1 and glycogenin-2 expression was analyzed by Western blot, mass spectrometry, and immunohistochemistry in liver, heart, and skeletal muscle from controls and in skeletal and cardiac muscle from patients with glycogenin-1 deficiency. RESULTS: Glycogenin-1 and glycogenin-2 both were found to be expressed in the liver, but only glycogenin-1 was identified in heart and skeletal muscle from controls. In patients with truncating GYG1 mutations, neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, nonfunctional glycogenin-1 but not glycogenin-2 was identified in cardiac muscle from patients with cardiomyopathy due to GYG1 missense mutations. By immunohistochemistry, the mutated glycogenin-1 colocalized with the storage of glycogen and polyglucosan in cardiomyocytes. CONCLUSIONS: Glycogen can be synthesized in the absence of glycogenin, and glycogenin-1 deficiency is not compensated for by upregulation of functional glycogenin-2. Absence of glycogenin-1 leads to the focal accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of mutated glycogenin-1 in the heart is deleterious, and it leads to storage of abnormal glycogen and cardiomyopathy.

4.
Mitochondrion ; 50: 14-18, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31639449

RESUMO

We report the case of two members of the same family with a novel mitochondrial DNA (mtDNA) gene variant in the MT-ND5 gene associated with MELAS syndrome and discuss limitations of genetics studies. The m.13045A > G mutation was detected at very low load in the daughter's urine cells (5%) and at different levels in the skeletal muscle of both mother (50%) and daughter (84%), being absent in blood, hair and saliva. Our findings suggest that non-invasive genetic assessment in urine cells may not be a sensitive diagnostic method neither a good predictor of disease development in relatives of some families with mtDNA-associated MELAS, particularly if involving MT-ND5 gene.

5.
Neurosurgery ; 86(3): 348-356, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173138

RESUMO

BACKGROUND: Despite some evidence for the adoption of endoscopic transnasal trans-sphenoidal surgery (ETSS) for pituitary adenomas, the advantages of this technique over the traditional approach have not been robustly confirmed. OBJECTIVE: To compare ETSS with the microscopic sublabial trans-septal trans-sphenoidal surgery (MTSS) for pituitary adenomas. METHODS: We retrospectively reviewed 2 cohorts of ETSS and MTSS performed at our institution from 1995 to 2017. Patient characteristics, surgical data, and outcomes were recorded prospectively. We performed a univariate and multivariable analysis to determine the best surgical approach. To improve the quality of the results, we matched the distribution of patient characteristics between groups by propensity score (PS) method. RESULTS: A total of 187 procedures (90 MTSS, 97 ETSS) were reviewed. We found better results in the ETSS group in terms of gross total resection (P = .002) and hormone-excess secretion control (P = .014). There was also a lower incidence of cerebrospinal fluid leakage (P = .039), transitory diabetes insipidus (P = .028), and postoperative hypopituitarism (P = .045), as well as a shorter hospital length of stay (P < .001). After PS matching, we confirmed by multivariable logistic regression analysis an increased odds ratio of gross total resection for the ETSS (3.910; 95% CI 1.720-8.889; P = .001). CONCLUSION: By PS method, our results suggest that the ETSS provides advantages over the traditional MTSS approach for tumor resection. Better control of secreting tumors and a lower rate of most complications also support the selection of the ETSS approach for the treatment of pituitary adenomas.

7.
Oxid Med Cell Longev ; 2019: 9719730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467641

RESUMO

Glioblastoma (GBM) is the most common and devastating primary brain tumor. The presence of cancer stem cells (CSCs) has been linked to their therapy resistance. Molecular and cellular components of the tumor microenvironment also play a fundamental role in the aggressiveness of these tumors. In particular, high levels of hypoxia and reactive oxygen species participate in several aspects of GBM biology. Moreover, GBM contains a large number of macrophages, which normally behave as immunosuppressive tumor-supportive cells. In fact, the presence of both, hypoxia and M2-like macrophages, correlates with malignancy and poor prognosis in gliomas. Antioxidant agents, as nutritional supplements, might have antitumor activity. Ocoxin® oral solution (OOS), in particular, has anti-inflammatory and antioxidant properties, as well as antitumor properties in several neoplasia, without known side effects. Here, we describe how OOS affects stem cell properties in certain GBMs, slowing down their tumor growth. In parallel, OOS has a direct effect on macrophage polarization in vitro and in vivo, inhibiting the protumoral features of M2 macrophages. Therefore, OOS could be a feasible candidate to be used in combination therapies during GBM treatment because it can target the highly resilient CSCs as well as their supportive immune microenvironment, without adding toxicity to conventional treatments.


Assuntos
Ácido Ascórbico/uso terapêutico , Glioblastoma/tratamento farmacológico , Macrófagos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Extratos Vegetais/uso terapêutico , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêutico , Animais , Ácido Ascórbico/farmacologia , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Extratos Vegetais/farmacologia , Vitamina B 12/farmacologia , Vitamina B 6/farmacologia
8.
Sci Rep ; 9(1): 9361, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249342

RESUMO

Calcium/Calcineurin/Nuclear Factor of Activated T cells (Ca/CN/NFAT) signalling pathway is the main calcium (Ca2+) dependent signalling pathway involved in the homeostasis of brain tissue. Here, we study the presence of NFATc members in human glioma by using U251 cells and a collection of primary human glioblastoma (hGB) cell lines. We show that NFATc3 member is the predominant member. Furthermore, by using constitutive active NFATc3 mutant and shRNA lentiviral vectors to achieve specific silencing of this NFATc member, we describe cytokines and molecules regulated by this pathway which are required for the normal biology of cancer cells. Implanting U251 in an orthotopic intracranial assay, we show that specific NFATc3 silencing has a role in tumour growth. In addition NFATc3 knock-down affects both the proliferation and migration capacities of glioma cells in vitro. Our data open the possibility of NFATc3 as a target for the treatment of glioma.

9.
Orphanet J Rare Dis ; 14(1): 100, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060578

RESUMO

BACKGROUND: TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the 'myopathic form' of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity. METHODS: We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12. RESULTS: The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients. CONCLUSIONS: The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency.


Assuntos
Miopatias Mitocondriais/enzimologia , Timidina Quinase/deficiência , Adolescente , Adulto , Criança , DNA Mitocondrial/genética , Feminino , Humanos , Transtornos de Início Tardio/enzimologia , Transtornos de Início Tardio/metabolismo , Transtornos de Início Tardio/patologia , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/genética , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/enzimologia , Doenças Musculares/genética , Mutação/genética , Estudos Retrospectivos , Timidina Quinase/genética , Adulto Jovem
10.
Neuromuscul Disord ; 29(3): 247-250, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30732915

RESUMO

In a previous report of a new phenotype with predominant scapulo-humeral-peroneal-distal myopathy associated with the Glu197Asp mutation in ACTA1, muscle biopsies did not show nemaline rods, nor could nemaline rods formation be demonstrated in an exhaustive functional in vivo or in vitro study. However, muscle biopsy in members of our family, carrying a similar clinical phenotype of some members of the original family and the same ACTA1 mutation, revealed the presence of numerous nemaline rods, suggesting that there must be other factors that explain the absence of nemaline rods.

11.
J Neurol ; 266(4): 934-941, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706156

RESUMO

BACKGROUND: Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations. METHODS: A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing. RESULTS: The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation. CONCLUSIONS: Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.


Assuntos
Contratura/genética , Distrofias Musculares/congênito , Mutação , Adulto , Idoso , Colágeno Tipo VI/genética , Contratura/diagnóstico por imagem , Contratura/patologia , Creatina Quinase/metabolismo , Feminino , Seguimentos , Genes Dominantes , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofias Musculares/diagnóstico por imagem , Distrofias Musculares/genética , Distrofias Musculares/patologia , Fenótipo , Estudos Retrospectivos , Adulto Jovem
12.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 30(1): 11-18, ene.-feb. 2019. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-181456

RESUMO

Background and purpose: Our objectives were: (1) compare dynamic susceptibility-weighted (DSC) and dynamic contrast-enhanced (DCE) permeability parameters, (2) evaluate diagnostic accuracy of DSC and DCE discriminating high- and low-grade tumors, (3) analyze relationship of permeability parameters with overall (OS) and progression-free survival (PFS) and (4) assess differences in high-grade tumors classified according to molecular biomarkers. Materials and methods: 49 patients with histologically proved diffuse gliomas underwent DSC and DCE imaging. Parametric maps of cerebral blood volume (CBV), CBV-leakage corrected, volume transfer coefficient (Ktrans), fractional volume of the extravascular extracellular space (EES) (Ve), fractional blood plasma volume (Vp) and rate constant between EES and blood plasma (Kep) were calculated. High-grade gliomas were also classified according to isocitrate dehydrogenase (IDH), alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and O6-methylguanine-dna-methyltransferase promoter methylation (MGMT) status. Results: There is correlation between parameters leakage, Ktrans and Vp. ROC curve analysis showed significance in both Ktrans and Ve for glioma grading. Threshold value of 0.075 for Ve generated the best combination of sensitivity (80%) and specificity (75%) in tumor gradation. Leakage was the only permeability parameter related to OS (P=0.006) and PFS (0.012); with prolonged survival for leakage values lower than 1.2. IDH-mutated high-grade tumors showed lower leakage and Ktrans values. High-grade tumors with loss of ATRX presented lower leakage and Vp values. Conclusions: Both DSC and DCE permeability parameters serve as non-invasive method for glioma grading. Leakage was the unique permeability parameter related to survival and the best discriminating high-grade gliomas classified according to IDH and ATRX status


Introducción y objetivos: 1) Evaluar la utilidad de los parámetros de permeabilidad para clasificar gliomas de alto y bajo grado; 2) Analizar diferencias de permeabilidad de glioblastomas clasificados según marcadores moleculares; 3) Analizar la relación de la permeabilidad con la supervivencia global (SG) y libre de progresión (SLP), y 4) Comparar parámetros de perfusión T1 y T2*. Material y métodos: Cuarenta y nueve pacientes con gliomas difusos confirmados histológicamente fueron estudiados con perfusión T1 y T2*. Calculamos los mapas paramétricos del volumen sanguíneo cerebral (CBV), CBV-leakage corregido, constante de permeabilidad (Ktrans), fracción de volumen vascular (Vp), fracción de volumen del espacio intersticial (Ve) y coeficiente de extracción (Kep). El análisis histológico se basó en criterios OMS 2007 y los glioblastomas se clasificaron según mutación de genes isocitrato deshidrogenasa (IDH), Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) y metilguanidina-ADN metiltransferasa (MGMT). Resultados: Incluimos 28 varones y 21 mujeres (16-78 años). Los gliomas se clasificaron en 41 tumores de alto grado y 8 de bajo grado. Leakage se correlacionó con SG y SLP; y mostró correlación lineal con Ktrans y Vp. Los gliomas de alto y de bajo grado mostraron diferencias en los valores de leakage, Ktrans, Vp y Ve. Leakage fue el parámetro que mejor discriminó los glioblastomas clasificados según mutación IDH y ATRX. Conclusión: La perfusión T1 y T2* sirven para clasificar a los gliomas difusos en función del grado tumoral. Leakage se relaciona con la SG y SLP y es el parámetro que mejor discrimina glioblastomas clasificados en función de IDH y ATRX


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais , Glioma/diagnóstico por imagem , Espectroscopia de Ressonância Magnética/métodos , Permeabilidade , Glioma/classificação , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Neoplasias Neuroepiteliomatosas/patologia , Imuno-Histoquímica , Curva ROC , Estimativa de Kaplan-Meier
13.
J Oncol Pharm Pract ; 25(4): 998-1002, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29690814

RESUMO

Progressive multifocal leukoencephalopathy rarely occurs in patients with multiple myeloma. Intracranial central nervous system invasion is also an uncommon event in multiple myeloma, occurring in less than 1% of cases. We describe herein an exceptional case of coexisting progressive multifocal leukoencephalopathy and intraparenchymal central nervous system myeloma infiltration. A 73-year-old woman with relapsed multiple myeloma was treated with 15 cycles of lenalidomide and dexamethasone, but therapy had to be stopped because of a hip fracture after a fall. During hospitalization, the patient developed progressive multifocal leukoencephalopathy caused by John Cunningham virus, and a prominent intra-parenchymal CD138-positive infiltrate was detected. VDJ rearrangements of the immunoglobulin heavy chain gene and the mutational profile of plasma cells in bone marrow at the time of diagnosis and in brain biopsy after progression were analyzed by next generation sequencing, showing genetic differences between medullary and extramedullary myeloma cells. The role of long-term treatment with lenalidomide and dexamethasone in the development progressive multifocal leukoencephalopathy or intraparenchymal central nervous system myeloma infiltration remains unknown. However, our results suggest that both events may have arisen as a consequence of treatment-related immunosuppression. Thus, an appropriate clinical approach compatible with the simultaneous treatment of progressive multifocal leukoencephalopathy and multiple myeloma should be developed.


Assuntos
Encéfalo/patologia , Leucoencefalopatia Multifocal Progressiva/etiologia , Mieloma Múltiplo/complicações , Idoso , Encéfalo/diagnóstico por imagem , Dexametasona/uso terapêutico , Feminino , Humanos , Vírus JC , Lenalidomida/efeitos adversos , Imagem por Ressonância Magnética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Invasividade Neoplásica
14.
Neurocirugia (Astur) ; 30(1): 11-18, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30143443

RESUMO

BACKGROUND AND PURPOSE: Our objectives were: (1) compare dynamic susceptibility-weighted (DSC) and dynamic contrast-enhanced (DCE) permeability parameters, (2) evaluate diagnostic accuracy of DSC and DCE discriminating high- and low-grade tumors, (3) analyze relationship of permeability parameters with overall (OS) and progression-free survival (PFS) and (4) assess differences in high-grade tumors classified according to molecular biomarkers. MATERIALS AND METHODS: 49 patients with histologically proved diffuse gliomas underwent DSC and DCE imaging. Parametric maps of cerebral blood volume (CBV), CBV-leakage corrected, volume transfer coefficient (Ktrans), fractional volume of the extravascular extracellular space (EES) (Ve), fractional blood plasma volume (Vp) and rate constant between EES and blood plasma (Kep) were calculated. High-grade gliomas were also classified according to isocitrate dehydrogenase (IDH), alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and O6-methylguanine-dna-methyltransferase promoter methylation (MGMT) status. RESULTS: There is correlation between parameters leakage, Ktrans and Vp. ROC curve analysis showed significance in both Ktrans and Ve for glioma grading. Threshold value of 0.075 for Ve generated the best combination of sensitivity (80%) and specificity (75%) in tumor gradation. Leakage was the only permeability parameter related to OS (P=0.006) and PFS (0.012); with prolonged survival for leakage values lower than 1.2. IDH-mutated high-grade tumors showed lower leakage and Ktrans values. High-grade tumors with loss of ATRX presented lower leakage and Vp values. CONCLUSIONS: Both DSC and DCE permeability parameters serve as non-invasive method for glioma grading. Leakage was the unique permeability parameter related to survival and the best discriminating high-grade gliomas classified according to IDH and ATRX status.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Permeabilidade Capilar , Glioma/diagnóstico por imagem , Angiografia por Ressonância Magnética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/análise , Enzimas Reparadoras do DNA/análise , Feminino , Glioma/química , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/análise , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Retrospectivos , Taxa de Sobrevida , Proteínas Supressoras de Tumor/análise , Proteína Nuclear Ligada ao X/análise , Adulto Jovem
16.
J Neurol Sci ; 394: 63-67, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30218921

RESUMO

INTRODUCTION: Sarcoglycanopathies (LGMD 2C2F) are a subgroup of limb-girdle muscular dystrophies (LGMD), caused by mutations in sarcoglycan genes. They usually have a childhood onset and rapidly progressive course with loss of ability to walk over 12-16 years. METHODS: Next generation sequencing (NGS) targeted gene panel was performed in three adult patients with progressive muscle weakness in which routine muscle histology and immunohistochemistry were not diagnostic. RESULTS: Genetic analysis revealed homozygous or compound heterozygous mutations in SGCA gene and Western Blot demonstrated protein reduction confirming the diagnosis of α-sarcoglicanopathy. DISCUSSION: Our cases evidence that the diagnosis of mild forms of alfa sarcoglicanopathy could be a challenge and suggest the possibility that they could be underdiagnosed. The use of Next generation Sequencing targeted gene panels is very helpful in the diagnosis of these patients.


Assuntos
Testes Genéticos/métodos , Mutação/genética , Sarcoglicanopatias/diagnóstico , Sarcoglicanopatias/genética , Sarcoglicanas/genética , Adulto , Biologia Computacional , Creatina Quinase/sangue , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Estudos Retrospectivos , Sarcoglicanopatias/sangue , Sarcoglicanopatias/complicações , Sarcoglicanas/metabolismo
17.
Clin Neuropathol ; 37(5): 217-220, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30079885

RESUMO

The radiological diagnosis of glioma progression is still challenging. A 33-year-old woman diagnosed with a frontal tumor underwent awake craniotomy with total tumor resection. The diagnosis was IDH-mutated diffuse astrocytoma, WHO grade II. The patient did not receive additional radiotherapy or chemotherapy. Periodic MRI scans showed a T2/FLAIR nodular enlargement which appeared de novo and grew slowly and gradually until 4 years post surgery. The patient underwent a second craniotomy to completely resect the T2/FLAIR hyperintensity. In the histological and molecular study of the second resection, no tumor cells were identified. We could hypothesize that the reactive changes favored by surgery could explain the ongoing radiologic findings.
.


Assuntos
Astrocitoma/diagnóstico por imagem , Astrocitoma/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Isocitrato Desidrogenase/genética , Adulto , Astrocitoma/genética , Neoplasias Encefálicas/genética , Craniotomia , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética , Mutação/genética , Gradação de Tumores , Reoperação , Resultado do Tratamento
18.
J Neuropathol Exp Neurol ; 77(8): 710-716, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010995

RESUMO

Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS ≥36 months) and 45 non-LTS. Using next-generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients.


Assuntos
Neoplasias Encefálicas/genética , Sobreviventes de Câncer , Marcação de Genes/métodos , Glioblastoma/genética , Mutação/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Feminino , Glioblastoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade
19.
Nat Med ; 24(7): 1024-1035, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29892069

RESUMO

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/secundário , Fator de Transcrição STAT3/metabolismo , Animais , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Sobrevivência Celular , Marcação de Genes , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imunidade Inata , Camundongos , Fosforilação , Microambiente Tumoral
20.
Nat Med ; 24(9): 1481, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29921958

RESUMO

In the version of this article originally published, the names of three authors were incorrect. The authors were listed as "Coral Fustero-Torres", "Elena Pineiro" and "Melchor Sánchez-Martínez". Their respective names are "Coral Fustero-Torre", "Elena Piñeiro-Yáñez" and "Melchor Sanchez-Martinez". The errors have been corrected in the print, HTML and PDF versions of this article.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA