Regulation of cAMP and GSK3 signaling pathways contributes to the neuronal conversion of glioma

Glioma is the most malignant type of primary central nervous system tumors, and has an extremely poor prognosis. One potential therapeutic approach is to induce the terminal differentiation of glioma through the forced expression of pro-neural factors. Our goal is to show the proof of concept of the neuronal conversion of C6 glioma through the combined action of small molecules. We investigated the various changes in gene expression, cell-specific marker expression, signaling pathways, physiological characteristics, and morphology in glioma after combination treatment with two small molecules (CHIR99021, a glycogen synthase kinase 3 [GSK3] inhibitor and forskolin, a cyclic adenosine monophosphate [cAMP] activator). Here, we show that the combined action of CHIR99021 and forskolin converted malignant glioma into fully differentiated neurons with no malignant characteristics; inhibited the proliferation of malignant glioma; and significantly down-regulated gene ontology and gene expression profiles related to cell division, gliogenesis, and angiogenesis in small molecule-induced neurons. In vivo, the combined action of CHIR99021 and forskolin markedly delayed neurological deficits and significantly reduced the tumor volume. We suggest that reprogramming technology may be a potential treatment strategy replacing the therapeutic paradigm of traditional treatment of malignant glioma, and a combination molecule comprising a GSK3 inhibitor and a cAMP inducer could be the next generation of anticancer drugs

The vasoactive peptide urotensinII: A chemokine exhibiting migration/adhesion properties in glioma

International audienc

Signaling switch of a vasoactive peptide GPCR: Prototypic chemotaxic mechanism involved in glioma

International audienc

Signaling switch of a vasoactive peptide GPCR: Prototypic chemotaxic mechanism involved in glioma

International audienc

Photoelastic analysis of stress distribution on parallel and angled implants after installation of fixed prostheses Análise fotoelástica de distribuição de tensões em implantes paralelos e angulados após a instalação de próteses fixas

The longevity of implant-supported prosthetic rehabilitation depends largely on how the masticatory forces are transferred to the implants and surrounding bone. Anatomical conditions, bone morphology and aesthetics usually dictate implant placement in less than ideal positions for prosthetic rehabilitation and sometimes it is possible to find them with different inclinations. The purpose of this paper was to compare, through photoelastic analysis, the stress distribution in a fixed prosthesis with 3 parallel implants, to the stress distribution in the same prosthesis in the existence of an angled central implant. Two photoelastic resin models were made and a polariscope was used in the visualization of isochromatic fringes formed in the models when axial loads of 2 kg, 5 kg and 10 kg were applied to a unique central point of the prosthesis. The presence of inducted tensions (preloads) was observed in the models after applying torque to the retention screws. Preloads were intensified with the incidence of occlusal forces. In the parallel implants, the force dissipation followed the long axis. The angled implant had a smaller quantity of fringes and the stresses were located mostly around the apical region of the lateral implants.<br>A longevidade das reabilitações orais implanto-suportadas depende, em grande parte, de como as forças mastigatórias são transferidas aos implantes e ao osso que os circunda. Condições anatômicas, morfologia óssea e estética muitas vezes ditam a colocação de implantes em posições que não são ideais para a reabilitação protética, e podemos encontrá-los com diferentes inclinações. A proposta deste trabalho foi comparar, através de análise fotoelástica, a dissipação de tensões em uma prótese fixa com 3 implantes paralelos entre si com a dissipação de tensões na mesma prótese na existência do implante central angulado. Foram confeccionados dois modelos de resina fotoelástica. Utilizou-se um polariscópio para visualização das franjas isocromáticas que se formaram nos modelos fotoelásticos quando cargas axiais de 2 kg, 5 kg e 10 kg foram aplicadas em um mesmo ponto central da prótese. Verificou-se a indução de tensões (pré-tensões) nos modelos após o apertamento dos parafusos de retenção das próteses. As pré-tensões foram agravadas com a incidência de forças oclusais. Nos implantes paralelos, a dissipação de forças seguiu os longos eixos. No implante angulado houve menor quantidade de franjas, e as tensões estavam localizadas principalmente ao redor da região apical dos implantes laterais