RESUMO
BACKGROUND: Vagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors. VPGLs arise from the vagus nerve and are less common than carotid paragangliomas. Both diagnostics and therapy of the tumors raise significant challenges. Besides, the genetic and molecular mechanisms behind VPGL pathogenesis are poorly understood. METHODS: The collection of VPGLs obtained from 8 patients of Russian population was used in the study. Exome library preparation and high-throughput sequencing of VPGLs were performed using an Illumina technology. RESULTS: Based on exome analysis, we identified pathogenic/likely pathogenic variants of the SDHx genes, frequently mutated in paragangliomas/pheochromocytomas. SDHB variants were found in three patients, whereas SDHD was mutated in two cases. Moreover, likely pathogenic missense variants were also detected in SDHAF3 and SDHAF4 genes encoding for assembly factors for the succinate dehydrogenase (SDH) complex. In a patient, we found a novel variant of the IDH2 gene that was predicted as pathogenic by a series of algorithms used (such as SIFT, PolyPhen2, FATHMM, MutationTaster, and LRT). Additionally, pathogenic/likely pathogenic variants were determined for several genes, including novel genes and some genes previously reported as associated with different types of tumors. CONCLUSIONS: Results indicate a high heterogeneity among VPGLs, however, it seems that driver events in most cases are associated with mutations in the SDHx genes and SDH assembly factor-coding genes that lead to disruptions in the SDH complex.
Assuntos
Neoplasias dos Nervos Cranianos/genética , Mutação , Paraganglioma/genética , Doenças do Nervo Vago/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Succinato Desidrogenase/genéticaRESUMO
Remote nano-magneto-mechanical actuation of magnetic nanoparticles (MNPs) by non-heating extremely low frequency magnetic field (ELF MF) is explored as a tool for non-invasive modification of bionanomaterials in pharmaceutical and medical applications. Here we study the effects of ELF MF (30-160 Hz, 8-120 kA/m) on the activity and release of a model enzyme, superoxide dismutase 1 (SOD1) immobilized by polyion coupling on dispersed MNPs aggregates coated with poly(L-lysine)-block-poly(ethylene glycol) block copolymer (s-MNPs). Such fields do not cause any considerable heating of MNPs but promote their rotating-oscillating mechanical motion that produces mechanical forces and deformations in adjacent materials. We observed the changes in the catalytic activity of immobilized SOD1 as well as its release from the s-MNPs/SOD1 polyion complex upon application of the ELF MF for 5 to 15 min. At longer exposures (25 min) the s-MNPs/SOD1 dispersion destabilizes. The bell-shaped effect of the field frequency with maximum at f = 50 Hz and saturation effect of field strength (between 30 kA/m and 120 kA/m at f = 50 Hz) are reported and explained. The findings are significant as one early indication of the nano-magneto-mechanical disruption by ELF MF of cooperative polyion complexes that are widely used for design of current functional healthcare bionanomaterials.
