Gliomas are the most common type of primary brain tumors. The most aggressive type, Glioblastoma multiforme (GBM), is one of the deadliest human diseases, with an average survival at diagnosis of about 1 year. Previous evidence suggests a link between human cytomegalovirus (HCMV) and gliomas. HCMV has been shown to be present in these tumors and several viral proteins can have oncogenic properties in glioma cells. Here we have investigated the presence of HCMV DNA, RNA and proteins in fifty-two gliomas of different grades of malignancy. The UL83 viral region, the early beta 2.7 RNA and viral protein were detected in 73%, 36% and 57% by qPCR, ISH and IHC, respectively. Positivity of the viral targets and viral load was independent of tumor type or grade suggesting no correlation between viral presence and tumor progression. Our results demonstrate high prevalence of the virus in gliomas from Brazilian patients, contributing to a better understanding of the association between HCMV infection and gliomas worldwide and supporting further investigations of the virus oncomodulatory properties.

The development of delivery systems efficiently uptaken by cells is of due importance since sites of drug action are generally localized in subcellular compartments. Herein, naked and core-shell polymeric nanoparticles (NPs) have been produced from poly(lactic-co-glycolic acid)-PLGA, poly(ethylene oxide)-b-poly(ε-caprolactone)-PEO-b-PCL, and poly(ethylene oxide)-b-poly(lactic acid)-PEO-b-PLA. The nanostructures are characterized and the cellular uptake behavior is evaluated. The data evidence that cellular uptake is enhanced as the length of the hydrophilic PEO-stabilizing shell reduces and that high negative surface charge restricts cellular uptake. Furthermore, NPs of higher degree of hydrophobicity (PEO-b-PCL) are more efficiently internalized as compared to PEO-b-PLA NPs. Accordingly, taking into account our recent published results and the findings of the current investigation, there should be a compromise regarding protein fouling and cellular uptake as resistance to nonspecific protein adsorption and enhanced cellular uptake are respectively directly and inversely related to the length of the PEO-stabilizing shell.

The relationship between human cytomegalovirus (HCMV) and tumours has been extensively investigated, mainly in glioblastoma multiforme (GBM), a malignant tumour of the central nervous system with low overall survival rates. Several reports have demonstrated the presence of HCMV in GBM, although typically restricted to a low number of cells, and studies have indicated that viral proteins have the ability to dysregulate cellular processes and increase tumour malignancy. Treatment of GBM involves the use of the chemotherapeutic agents temozolomide (TMZ) and carmustine (bis-chloroethylnitrosourea, BCNU), which lead to the attachment of adducts to the DNA backbone, causing errors during replication and consequent cell death. It is known that HCMV infection can modulate DNA repair pathways, but what effects the virus may exhibit during chemotherapy are unknown. Here we approach this question by analysing HCMV infection and viral protein accumulation in GBM cell lines with different genotypes and their response to TMZ and BCNU in the presence of the virus. We demonstrate that A172, TP365MG and U251MG GBM cells are efficiently infected by both low-passage (TB40E) and high-passage (AD169) HCMV strains. However, the GBM cell lines vary widely in their permissiveness to viral gene expression and exhibit very different patterns of immediate early, early and late protein accumulation. HCMV reduces the viability of permissive GBM cells in a multiplicity-dependent manner in both the absence and presence of TMZ or BNCU. In sum, we demonstrate that GBM cell lines are equally susceptible but differentially permissive to infection by both low- and high-passage strains of HCMV. This observation not only indicates that viral replication is largely controlled by cellular factors in this system, but also provides a possible explanation for why viral gene products are only found in a subset of cells in GBM tumours. Furthermore, we conclude that the virus does not confer increased resistance to chemotherapeutic drugs in various GBM cell lines, but instead reduces tumour cell viability. These results highlight that the oncomodulatory potential of HCMV is not limited to cancer-promoting activities, but also includes adverse effects on tumour cell proliferation or survival.

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RESUMO INTRODUÇÃOA utilização de sistemas nanoestruturados à base de matéria mole (polímeros) que têm se difundido de maneira acelerada em que pese às aplicações biomédicas e constituem sistemas que podem acomodar em seu interior um enorme número de diferentes agentes ativos. Essa tecnologia vem recebendo tamanha atenção devido à sua versatilidade, pelo fato de suas características estruturais poderem ser modificadas mediante modificação do protocolo de fabricação e pelo fato de poderem responder a estímulos externos ou fisiológicos específicos (LEE; HYEON, 2012). Geralmente, nanocarreadores (com tamanho entre 20-100nm) possuem dimensões adequadas para atravessarem a vasculatura desorganizada e porosa das regiões tumorais. Além disso, os vasos linfáticos estão ausentes ou não funcionais nestes locais, contribuindo para uma ineficiente drenagem. Este fenômeno é conhecido como efeito do aumento da permeabilidade e retenção (efeito EPR) (MAEDA; WU; MATSUMURA, 2000). A interação de nanopartículas com sistemas biológicos promovem a formação de uma nanobiointerface, onde forças de van der Waals (VDW), eletrostáticas, hidratação e efeitos solvo fóbicos desempenham papel fundamental. Principalmente o processo de interação NPmembrana celular inevitavelmente afeta o processo de absorção celular de sistemas carreadores