Targeting sphingolipid metabolism with the sphingosine kinase inhibitor SKI-II overcomes hypoxia-induced chemotherapy resistance in glioblastoma cells: effects on cell death, self-renewal, and invasion.

BACKGROUND: Glioblastoma patients commonly develop resistance to temozolomide chemotherapy. Hypoxia, which supports chemotherapy resistance, favors the expansion of glioblastoma stem cells (GSC), contributing to tumor relapse. Because of a deregulated sphingolipid metabolism, glioblastoma tissues contain high levels of the pro-survival sphingosine-1-phosphate and low levels of the pro-apoptotic ceramide. The latter can be metabolized to sphingosine-1-phosphate by sphingosine kinase (SK) 1 that is overexpressed in glioblastoma. The small molecule SKI-II inhibits SK and dihydroceramide desaturase 1, which converts dihydroceramide to ceramide. We previously reported that SKI-II combined with temozolomide induces caspase-dependent cell death, preceded by dihydrosphingolipids accumulation and autophagy in normoxia. In the present study, we investigated the effects of a low-dose combination of temozolomide and SKI-II under normoxia and hypoxia in glioblastoma cells and patient-derived GCSs. METHODS: Drug synergism was analyzed with the Chou-Talalay Combination Index method. Dose-effect curves of each drug were determined with the Sulforhodamine B colorimetric assay. Cell death mechanisms and autophagy were analyzed by immunofluorescence, flow cytometry and western blot; sphingolipid metabolism alterations by mass spectrometry and gene expression analysis. GSCs self-renewal capacity was determined using extreme limiting dilution assays and invasion of glioblastoma cells using a 3D spheroid model. RESULTS: Temozolomide resistance of glioblastoma cells was increased under hypoxia. However, combination of temozolomide (48 µM) with SKI-II (2.66 µM) synergistically inhibited glioblastoma cell growth and potentiated glioblastoma cell death relative to single treatments under hypoxia. This low-dose combination did not induce dihydrosphingolipids accumulation, but a decrease in ceramide and its metabolites. It induced oxidative and endoplasmic reticulum stress and triggered caspase-independent cell death. It impaired the self-renewal capacity of temozolomide-resistant GSCs, especially under hypoxia. Furthermore, it decreased invasion of glioblastoma cell spheroids. CONCLUSIONS: This in vitro study provides novel insights on the links between sphingolipid metabolism and invasion, a hallmark of cancer, and cancer stem cells, key drivers of cancer. It demonstrates the therapeutic potential of approaches that combine modulation of sphingolipid metabolism with first-line agent temozolomide in overcoming tumor growth and relapse by reducing hypoxia-induced resistance to chemotherapy and by targeting both differentiated and stem glioblastoma cells.

Exploring Corymbia torelliana hydrochar combustion kinetics through thermogravimetric analysis, peak deconvolution and reaction profile modelling.

This study aims to conduct an applied and innovative investigation to enhance the energy quality of wood residues through hydrothermal carbonization pretreatment. For this purpose, the treatment was carried out at three different temperatures: 180, 220, and 240 °C under autogenous pressure. The in natura material and the hydrochars were characterized, and thermogravimetric analyses were performed in an O2 atmosphere with heating rates of 2.5, 5, 10, and 20 °C min-1. The global activation energy for natura biomass combustion was determined to be 112.49 kJ.mol-1. On the other hand, the hydrothermal carbonization process promoted a reduction in this value for the 94.85 kJ.mol-1. The conversion function for the in natura biomass was characterized as 1 - α , order 1, while the hydrochars was 2(1-α) [-ln(1-α)] (1/2), Avrami-Erofe'ev I. Triple kinetic parameters were ascertained, and the conversion curves along with their respective derivatives were modeled, exhibiting minimal deviations between theoretical and experimental data. This facilitated the mathematical representation of the reaction processes and allowed for a comprehensive comparison of the results.

Intervenções de Enfermagem na prevenção de extubação não programada em recém-nascidos: bundle de boas práticas / Nursing interventions for the prevention of non scheduled extubation in newborns: bundle of good practice

OBJETIVOS: identificar o conhecimento da equipe de Enfermagem acerca da extubação não programada (ENP), os fatores relacionados, as complicações/agravos e as intervenções de Enfermagem como medidas preventivas juntos ao recém-nascido de risco. METODOLOGIA: Pesquisa descritiva, qualitativa realizada na Unidade de Terapia Intensiva Neonatal de um hospital pediátrico de Fortaleza-Ceará, no período de julho a setembro de 2018. RESULTADOS: Evidenciou-se a necessidade de pactuação sobre o conceito de ENP entre a equipe. Dentre os principais fatores relacionados teve-se: excesso de manuseio e ausência de comunicação efetiva na equipe. Como intervenções preventivas ressaltou-se o posicionamento do RN e a fixação adequada do tubo. CONCLUSÃO: a equipe de enfermagem tem preciosos saberes e intervenções que puderam ser visualizados como medidas de boas práticas na prevenção das ENP para construção de um Bundle. (AU)

Objective: To identify the knowledge of the Nursing team about non-programmed extubation (ENP), related factors, complications/injuries and Nursing interventions as preventive measures together with the newborn at risk. Methodology: Descriptive and qualitative research performed at the Neonatal Intensive Care Unit of a pediatric hospital in Fortaleza, Ceará, from July to September, 2018. Results: The need for agreement on the concept of PNS among the team was evidenced. Among the main related factors were: excessive handling and lack of effective communication in the team. As preventive interventions, the positioning of the newborn and adequate tube fixation were emphasized. Conclusion: the nursing team has valuable knowledge and interventions that could be visualized as measures of good practices in the prevention of NPS for the construction of a Bundle. (AU)

Objetivo: identificar el conocimiento del equipo de Enfermería acerca de la extubación no programada (ENP), los factores relacionados, las complicaciones / agravios y las intervenciones de Enfermería como medidas preventivas junto al recién nacido de riesgo. Metodologia: Investigación descriptiva, cualitativa realizada en la Unidad de Terapia Intensiva Neonatal de un hospital pediátrico de Fortaleza-Ceará, en el período de julio a septiembre de 2018. Resultados: Se evidenció la necesidad de pactación sobre el concepto de ENP entre el equipo. Entre los principales factores relacionados se tuvo: exceso de manejo y ausencia de comunicación efectiva en el equipo. Como intervenciones preventivas se resaltó el posicionamiento del RN y la fijación adecuada del tubo. Conclusión: el equipo de enfermería tiene preciosos saberes e intervenciones que pudieron ser visualizados como medidas de buenas prácticas en la prevención de las ENP para la construcción de un Bundle. (AU)