RESUMEN
BACKGROUND: A range of different neurological manifestations has been reported in fetuses and adults after Zika virus (ZIKV) infection. OBJECTIVE: We describe a detection of the ZIKV in the brain tissue from a multiple sclerosis (MS) patient with acute disseminated encephalomyelitis (ADEM)-like event in Rio de Janeiro, Brazil. METHODS: Biological samples collected during the hospitalization were tested by serology and molecular diagnostic for various infectious agents. Histopathological analysis was performed using the anti-flavivirus group 4G2 monoclonal antibody, anti-ZIKV non-structural 1 (NS1) monoclonal antibody, and anti-CD4, CD8, and CD11b antibodies. RESULTS: Anti-ZIKV IgM and IgG antibodies were positive in the serum and urine. A brain biopsy showed ZIKV protein in brain cells and T CD8 infiltration in brain tissue. CONCLUSION: Our data describe the coexistence of a recent central nervous system (CNS) ZIKV infection accompanied by a severe ADEM-like syndrome outcome in a patient with clinical history of MS. A de novo immune response concomitant with ZIKV infection might be involved in the mechanism of the ADEM-like syndrome and response to immunotherapy. The present report reinforces the importance of providing the differential diagnosis of acute episodes of MS exacerbation in an environment prone to ZIKV expression.
Asunto(s)
Encéfalo/microbiología , Encefalomielitis Aguda Diseminada/diagnóstico , Esclerosis Múltiple Recurrente-Remitente , Infección por el Virus Zika/diagnóstico , Virus Zika/aislamiento & purificación , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/orina , Encefalomielitis Aguda Diseminada/microbiología , Femenino , Humanos , Infección por el Virus Zika/sangre , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/orinaRESUMEN
Glioblastoma is the most life-threatening tumour of the central nervous system. Temozolomide (TMZ) is the first-choice oral drug for the treatment of glioblastoma, although it shows low efficacy. Silver nanoparticles (AgNPs) have been shown to exhibit biocidal activity in a variety of microorganisms, including some pathogenic microorganisms. Herein, the antiproliferative effect of AgCl-NPs on glioblastoma cell lines (GBM02 and GBM11) and on astrocytes was evaluated through automated quantitative image-based analysis (HCA) of the cells. The cells were treated with 0.1-5.0 µg/ml AgCl-NPs or with 9.7-48.5 µg/ml TMZ. Cells that received combined treatment were also analysed. At a maximum tested concentration of AgCl-NPs, GBM02 and GBM11, the growth decreased by 93% and 40%, respectively, following 72 h of treatment. TMZ treatment decreased the proliferation of GBM02 and GBM11 cells by 58% and 34%, respectively. Combinations of AgCl-NPs and TMZ showed intermediate antiproliferative effects; the lowest concentrations caused an inhibition similar to that obtained with TMZ, and the highest concentrations caused inhibition similar to that obtained with AgCl-NPs alone. No significant changes in astrocyte proliferation were observed. The authors' findings showed that HCA is a fast and reliable approach that can be used to evaluate the antiproliferative effect of the nanoparticles at the single-cell level and that AgCl-NPs are promising agents for glioblastoma treatment.
Asunto(s)
Glioblastoma , Nanopartículas del Metal , Línea Celular Tumoral , Cloruros , Glioblastoma/tratamiento farmacológico , Humanos , Plata/farmacología , Compuestos de PlataRESUMEN
Despite advances in treatment of lethal prostate cancer, the incidence of prostate cancer brain metastases is increasing. In this sense, we analyzed the molecular profile, as well as the functional consequences involved in the reciprocal interactions between prostate tumor cells and human astrocytes. We observed that the DU145 cells, but not the LNCaP cells or the RWPE-1 cells, exhibited more pronounced, malignant and invasive phenotypes along their interactions with astrocytes. Moreover, global gene expression analysis revealed several genes that were differently expressed in our co-culture models with the overexpression of GLIPR1 and SPARC potentially representing a molecular signature associated with the invasion of central nervous system by prostate malignant cells. Further, these results were corroborated by immunohistochemistry and in silico analysis. Thus, we conjecture that the data here presented may increase the knowledge about the molecular mechanisms associated with the invasion of CNS by prostate malignant cells.
Asunto(s)
Neoplasias Encefálicas/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Osteonectina/genética , Osteonectina/metabolismo , Neoplasias de la Próstata/genética , Células A549 , Animales , Astrocitos/química , Astrocitos/citología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Células Cultivadas , Técnicas de Cocultivo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Neoplasias de la Próstata/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Familial cerebral cavernous malformations (CCM) are among the most common vascular malformations of the central nervous system (CNS) and are linked to mutations on the specific genes CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. We present the first report in the literature of a pharmaco-resistant epileptic patient harboring co-occurring pathogenic mutations within CCM2/MGC4607 and CCM1/KRIT1. CASE DESCRIPTION: A 51-year-old patient first presented at age of 33 years with episodes of seizures. Magnetic resonance imaging including a susceptibility-weighted imaging sequence had shown multiple cerebral cavernous malformation lesions. She had partial response of symptoms and remained in routine follow-up needing progressive pharmacological improvement. Direct sequencing allowed the detection of 1 nonsense pathogenic mutation in CCM2/MGC4607 (c.118C>T; p.Arg40Ter) and 1 unclassified frameshift insertion variant in CCM1/KRIT1 (c.1687_1688insT; p.Tyr563LeufsTer5). CONCLUSIONS: Although the CCM2/MGC460 variant seems to be the major contributor for the patient's CCM phenotype, the mutated CCM1/KRIT1 seems to act as a booster to CCM overall pathogenicity.
Asunto(s)
Proteínas Portadoras/genética , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Proteína KRIT1/genética , Epilepsia Refractaria/etiología , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Humanos , Imagen por Resonancia Magnética , Persona de Mediana EdadRESUMEN
BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular capillary anomalies with a dysfunctional endothelial adherent junction profile, depicting hemorrhage and epilepsy as the main clinical features. With the advent of an increasingly personalized medicine, better comprehension of genetic mechanisms behind CCM represents an important key in the management of the patients and risk rating in relatives. In this context, genetic factors that might influence clinical expressiveness of CCM need to be identified. CASE DESCRIPTION: A 33-year-old woman harboring multiple CCM lesions with a CCM1 mutational profile already being treated conservatively for a right mesial temporal lobe CCM presented with refractory seizures. Magnetic resonance imaging showed no bleeding in the lesion, and the patient was submitted to complete resection of the CCM. Histopathology of the CCM samples depicted an extensive inflammatory reaction and colocalization of CD20+ and CD68+ cells. Genetic analyses of the patient and her mother demonstrated a novel CCM1 (KRIT1) frameshift mutation (c.1661_1662insT; p.Leu554PhefsTer14). Furthermore, variants in CD14 (rs778588), TLR-4 (rs10759930), SOD2 (rs4880), APEX1 (rs1130409), and OGG1 (rs1052133), known as polymorphisms related to disease aggressiveness, were detected in the patient and not in her oligosymptomatic mother harboring the same CCM1 mutation. CONCLUSIONS: Heterogeneity of clinical manifestations among individuals with familial CCM with the same genotype adds mechanistic involvement of modifier factors as phenotypic markers. We describe a novel CCM1/KRIT1 familial mutation in which the coexistence of genetic variants in inflammation and oxidative stress may be related to variable expressiveness of the disease.
Asunto(s)
Mutación del Sistema de Lectura , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Proteína KRIT1/genética , Adulto , Anticonvulsivantes/uso terapéutico , Brasil , ADN Glicosilasas/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Femenino , Genotipo , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Hemangioma Cavernoso del Sistema Nervioso Central/cirugía , Humanos , Inflamación/genética , Receptores de Lipopolisacáridos/genética , Imagen por Resonancia Magnética , Madres , Estrés Oxidativo/genética , Fenotipo , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Índice de Severidad de la Enfermedad , Superóxido Dismutasa/genética , Receptor Toll-Like 4/genéticaRESUMEN
Neurological complications affecting the central nervous system have been reported in adult patients infected by Zika virus (ZIKV) but the underlying mechanisms remain unknown. Here, we report that ZIKV replicates in human and mouse adult brain tissue, targeting mature neurons. ZIKV preferentially targets memory-related brain regions, inhibits hippocampal long-term potentiation and induces memory impairment in adult mice. TNF-α upregulation, microgliosis and upregulation of complement system proteins, C1q and C3, are induced by ZIKV infection. Microglia are found to engulf hippocampal presynaptic terminals during acute infection. Neutralization of TNF-α signaling, blockage of microglial activation or of C1q/C3 prevent synapse and memory impairment in ZIKV-infected mice. Results suggest that ZIKV induces synapse and memory dysfunction via aberrant activation of TNF-α, microglia and complement. Our findings establish a mechanism by which ZIKV affects the adult brain, and point to the need of evaluating cognitive deficits as a potential comorbidity in ZIKV-infected adults.