Cancer cell lines are widely used as in vitro models of tumorigenesis, facilitating fundamental discoveries in cancer biology and translational medicine. Currently, there are few options for glioblastoma (GBM) treatment and limited in vitro models with accurate genomic and transcriptomic characterization. Here, a detailed characterization of a new GBM cell line, namely AHOL1, was conducted in order to fully characterize its molecular composition based on its karyotype, copy number alteration (CNA), and transcriptome profiling, followed by the validation of key elements associated with GBM tumorigenesis. Large numbers of CNAs and differentially expressed genes (DEGs) were identified. CNAs were distributed throughout the genome, including gains at Xq11.1-q28, Xp22.33-p11.1, Xq21.1-q21.33, 4p15.1-p14, 8q23.2-q23.3 and losses at Yq11.21-q12, Yp11.31-p11.2, and 15q11.1-q11.2 positions. Nine druggable genes were identified, including HCRTR2, ETV1, PTPRD, PRKX, STS, RPS6KA6, ZFY, USP9Y, and KDM5D. By integrating DEGs and CNAs, we identified 57 overlapping genes enriched in fourteen pathways. Altered expression of several cancer-related candidates found in the DEGs-CNA dataset was confirmed by RT-qPCR. Taken together, this first comprehensive genomic and transcriptomic landscape of AHOL1 provides unique resources for further studies and identifies several druggable targets that may be useful for therapeutics and biologic and molecular investigation of GBM.

Resumo Justificativa: A cirurgia cardíaca pode produzir déficit persistente na razão entre oferta de oxigênio (DO2) e consumo de oxigênio (VO2). A Saturação venosa central de Oxigênio (SvcO2) é uma medida acessível e indireta da razão DO2/VO2. Objetivo: Monitorar a SvcO2 perioperatória e avaliar sua correlação com a mortalidade em cirurgia cardíaca. Método: Este estudo observacional prospectivo avaliou 273 pacientes submetidos a cirurgia cardíaca. Coletamos amostras de sangue para medir a SvcO2 em três momentos: T0 (após indução anestésica), T1 (final da cirurgia) e T2 (24 horas após a cirurgia). Os pacientes foram divididos em dois grupos (sobreviventes e não sobreviventes). Os seguintes desfechos foram analisados: mortalidade intra-hospitalar, tempo de permanência na Unidade de Terapia Intensiva (UTI) e de internação hospitalar, e variação na SvcO2. Resultados: Dos 273 pacientes, 251 (92%) sobreviveram e 22 (8%) não. Houve queda significante da SvcO2 perioperatória nos sobreviventes (T0 = 78% ± 8,1%, T1 = 75,4% ± 7,5% e T2 = 68,5% ± 9%; p< 0,001) e nos não sobreviventes (T0 = 74,4% ± 8,7%, T1 = 75,4% ± 7,7% e T2 = 66,7% ± 13,1%; p< 0,001). No T0, a porcentagem de pacientes com SvcO2< 70% foi maior no grupo não sobrevivente (31,8% vs. 13,1%; p = 0,046) e a regressão logística múltipla mostrou que a SvcO2 é um fator de risco independente associado ao óbito, OR = 2,94 (95% IC 1,10 − 7,89) (p = 0,032). O tempo de permanência na UTI e de hospitalização foi de 3,6 ± 3,1 e 7,4 ± 6,0 dias, respectivamente, e não foi significantemente associado à SvcO2. Conclusões: Valores precoces de SvcO2 intraoperatória < 70% indicaram maior risco de óbito em pacientes submetidos à cirurgia cardíaca. Observamos redução perioperatória da SvcO2, com altos níveis no intraoperatório e mais baixos no pós-operatório.

Abstract Background: Cardiac surgery can produce persistent deficit in the ratio of Oxygen Delivery (DO2) to Oxygen Consumption (VO2). Central venous oxygen Saturation (ScvO2) is an accessible and indirect measure of DO2/VO2 ratio. Objective: To monitor perioperative ScvO2 and assess its correlation with mortality during cardiac surgery. Methods: This prospective observational study evaluated 273 patients undergoing cardiac surgery. Blood gas samples were collected to measure ScvO2 at three time points: T0 (after anesthetic induction), T1 (end of surgery), and T2 (24 hours after surgery). The patients were divided into two groups (survivors and nonsurvivors). The following outcomes were analyzed: intrahospital mortality, length of Intensive Care Unit (ICU) and hospital stay (LOS), and variation in ScvO2. Results: Of the 273 patients, 251 (92%) survived and 22 (8%) did not. There was a significant perioperative reduction of ScvO2 in both survivors (T0 = 78% ± 8.1%, T1 = 75.4% ± 7.5%, and T2 = 68.5% ± 9%; p< 0.001) and nonsurvivors (T0 = 74.4% ± 8.7%, T1 = 75.4% ± 7.7%, and T2 = 66.7% ± 13.1%; p < 0.001). At T0, the percentage of patients with ScvO2< 70% was greater in the nonsurvivor group (31.8% vs. 13.1%; p= 0.046) and the multiple logistic regression showed that ScvO2 is an independent risk factor associated with death, OR = 2.94 (95% CI 1.10−7.89) (p= 0.032). The length of ICU and LOS were 3.6 ± 3.1 and 7.4 ± 6.0 days respectively and was not significantly associated with ScvO2. Conclusions: Early intraoperative ScvO2 < 70% indicated a higher risk of death. A perioperative reduction of ScvO2 was observed in patients undergoing cardiac surgery, with high intraoperative and lower postoperative levels.

Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary cancer predisposition disorder. In Brazil, the p.R337H TP53 founder mutation causes the variant form of LFS, Li-Fraumeni-like syndrome. The occurrence of cancer and age of disease onset are known to vary, even in patients carrying the same mutation, and several mechanisms such as genetic and epigenetic alterations may be involved in this variability. However, the extent of involvement of such events has not been clarified. It is well established that p53 regulates several pathways, including the thymine DNA glycosylase (TDG) pathway, which regulates the DNA methylation of several genes. This study aimed to identify the DNA methylation pattern of genes potentially related to the TDG pathway (CDKN2A, FOXA1, HOXD8, OCT4, SOX2, and SOX17) in 30 patients with germline TP53 mutations, 10 patients with wild-type TP53, and 10 healthy individuals. We also evaluated TDG expression in patients with adrenocortical tumors (ADR) with and without the p.R337H TP53 mutation. Gene methylation patterns of peripheral blood DNA samples assessed by pyrosequencing revealed no significant differences between the three groups. However, increased TDG expression was observed by quantitative reverse transcription PCR in p.R337H carriers with ADR. Considering the rarity of this phenotype and the relevance of these findings, further studies using a larger sample set are necessary to confirm our results.