Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition.

BACKGROUND: Platinum-based chemotherapy remains the standard of care for most lung cancer cases. However chemoresistance is often developed during the treatment, limiting clinical utility of this drug. Recently, the ability of tumor cells to adapt their metabolism has been associated to resistance to therapies. In this study, we first described the metabolic reprogramming of Non-Small Cell Lung Cancer (NSCLC) in response to cisplatin treatment. METHODS: Cisplatin-resistant versions of the A549, H1299, and H460 cell lines were generated by continuous drug exposure. The long-term metabolic changes, as well as, the early response to cisplatin treatment were analyzed in both, parental and cisplatin-resistant cell lines. In addition, four Patient-derived xenograft models treated with cisplatin along with paired pre- and post-treatment biopsies from patients were studied. Furthermore, metabolic targeting of these changes in cell lines was performed downregulating PGC-1α expression through siRNA or using OXPHOS inhibitors (metformin and rotenone). RESULTS: Two out of three cisplatin-resistant cell lines showed a stable increase in mitochondrial function, PGC1-α and mitochondrial mass with reduced glycolisis, that did not affect the cell cycle. This phenomenon was confirmed in vivo. Post-treatment NSCLC tumors showed an increase in mitochondrial mass, PGC-1α, and a decrease in the GAPDH/MT-CO1 ratio. In addition, we demonstrated how a ROS-mediated metabolism reprogramming, involving PGC-1α and increased mitochondrial mass, is induced during short-time cisplatin exposure. Moreover, we tested how cells with increased PGC-1a induced by ZLN005 treatment, showed reduced cisplatin-driven apoptosis. Remarkably, the long-term metabolic changes, as well as the metabolic reprogramming during short-time cisplatin exposure can be exploited as an Achilles' heel of NSCLC cells, as demonstrated by the increased sensitivity to PGC-1α interference or OXPHOS inhibition using metformin or rotenone. CONCLUSION: These results describe a new cisplatin resistance mechanism in NSCLC based on a metabolic reprogramming that is therapeutically exploitable through PGC-1α downregulation or OXPHOS inhibitors.

Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke.

Endogenous neurogenesis in stroke is insufficient to replace the lost brain tissue, largely due to the lack of a proper biological structure to let new cells dwell in the damaged area. We hypothesized that scaffolds made of hyaluronic acid (HA) biomaterials (BM) could provide a suitable environment to home not only new neurons, but also vessels, glia and neurofilaments. Further, the addition of exogenous cells, such as adipose stem cells (ASC) could increase this effect. Athymic mice were randomly assigned to a one of four group: stroke alone, stroke and implantation of BM, stroke and implantation of BM with ASC, and sham operated animals. Stroke model consisted of middle cerebral artery thrombosis with FeCl3 . After 30 days, animals underwent magnetic resonance imaging (MRI) and were sacrificed. Proliferation and neurogenesis increased at the subventricular zone ipsilateral to the ventricle and neuroblasts, glial, and endothelial cells forming capillaries were seen inside the BM. Those effects increased when ASC were added, while there was less inflammatory reaction. Three-dimensional scaffolds made of HA are able to home newly formed neurons, glia, and endothelial cells permitting the growth neurofilaments inside them. The addition of ASC increase these effects and decrease the inflammatory reaction to the implant. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1598-1606, 2019.

Evaluation of the Safety and Efficacy of the Therapeutic Potential of Adipose-Derived Stem Cells Injected in the Cerebral Ischemic Penumbra.

INTRODUCTION: Stroke represents an attractive target for cell therapy. Although different types of cells have been employed in animal models with variable results, the human adipose-derived stem cells (hASCs) have demonstrated favorable characteristics in the treatment of diseases with inflammatory substrate, but experience in their intracerebral administration is lacking. The purpose of this study is to evaluate the effect and safety of the intracerebral application of hASCs in a stroke model. METHODS: A first group of Athymic Nude mice after stroke received a stereotactic injection of hASCs at a concentration of 4 × 104/µL at the penumbra area, a second group without stroke received the same cell concentration, and a third group had only stroke and no cells. After 7, 15, and 30 days, the animals underwent fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging; subsequently, they were sacrificed for histological evaluation (HuNu, GFAP, IBA-1, Ki67, DCX) of the penumbra area and ipsilateral subventricular zone (iSVZ). RESULTS: The in vitro studies found no alterations in the molecular karyotype, clonogenic capacity, and expression of 62 kDa transcription factor and telomerase. Animals implanted with cells showed no adverse events. The implanted cells showed no evidence of proliferation or differentiation. However, there was an increase of capillaries, less astrocytes and microglia, and increased bromodeoxyuridine and doublecortin-positive cells in the iSVZ and in the vicinity of ischemic injury. CONCLUSIONS: These results suggest that hASCs in the implanted dose modulate inflammation, promote endogenous neurogenesis, and do not proliferate or migrate in the brain. These data confirm the safety of cell therapy with hASCs.

Math anxiety and its relationship to inhibitory abilities and perceived emotional intelligence / Ansiedad matemática y su relación con capacidades inhibitorias e inteligencia emocional percibida

Math anxiety has been found to be an emotional problem that has a negative effect on students’ academic performance across different levels of education. This type of anxiety could be related to certain cognitive and emotional processes. A first objective was to examine the relationship between math anxiety and certain inhibitory abilities responsible of eliminating intrusive thoughts or preventing them access to consciousness. A second aim was to determine the extent in which math anxiety and students’ self-perceptions of their own emotional abilities are related. To this end, 187 first-year undergraduate psychology students were administered different measures to assess math anxiety, statistics anxiety, inhibitory abilities, and perceived emotional intelligence. The results showed that students with high math anxiety were more likely to experience intrusive thoughts, were less effective at suppressing these thoughts, and reported lower scores in understanding and regulating their emotions. These cognitive mechanisms and emotional abilities are of relevance to better understand the nature of this type of anxiety

La ansiedad a las matemáticas es un problema emocional que repercute negativamente en el rendimiento académico de los estudiantes en distintos niveles educativos. El presente estudio analiza la relación entre este tipo de ansiedad y ciertos procesos cognitivos y emocionales. En primer lugar se pretendía determinar la relación entre la ansiedad a las matemáticas y ciertas habilidades inhibitorias dirigidas a eliminar o evitar el acceso a la conciencia de pensamientos intrusivos. En segundo lugar, interesaba comprobar la posible relación de la ansiedad a las matemáticas con la propia percepción del estudiante de sus habilidades emocionales. A tal fin se administraron a 187 estudiantes de primer curso del Grado de Psicología diferentes medidas de ansiedad a las matemáticas, a la estadística, de habilidades inhibitorias y de inteligencia emocional percibida. Los resultados mostraron que los estudiantes con puntuaciones más altas en ansiedad a las matemáticas presentaban una mayor susceptibilidad a experimentar pensamientos intrusivos, una menor eficacia a la hora de suprimirlos así como puntuaciones inferiores en comprensión y regulación de sus emociones. Los procesos inhibitorios y emocionales estudiados pueden resultar útiles para entender la naturaleza de la ansiedad matemática

Age differences in working memory updating: the role of interference, focus switching and substituting information.

Working memory updating (WMU) tasks require different elements in working memory (WM) to be maintained simultaneously, accessing one of these elements, and substituting its content. This study examined possible developmental changes from childhood to adulthood both in focus switching and substituting information in WM. In addition, possible age-related changes in interference due to representational overlap between the different elements simultaneously held in these tasks were examined. Children (8- and 11-year-olds), adolescents (14-year-olds) and younger adults (mean age=22 years) were administered a numerical updating memory task, in which updating and focus switching were manipulated. As expected, response times decreased and recall performance increased with age. More importantly, the time needed for focus switching was longer in children than in adolescents and younger adults. On the other hand, substitution of information and interference due to representational overlap were not affected by age. These results suggest that age-related changes in focus switching might mediate developmental changes in WMU performance.

The role of similarity in updating numerical information in working memory: decomposing the numerical distance effect.

The present study investigates the process of updating representations in working memory (WM) and how similarity between the information involved influences this process. In WM updating tasks, the similarity in terms of numerical distance between the number to be substituted and the new one facilitates the updating process. We aimed to disentangle the possible effect of two dimensions of similarity that may contribute to this numerical effect: numerical distance itself and common digits shared between the numbers involved. Three experiments were conducted in which different ranges of distances and the coincidence between the digits of the two numbers involved in updating were manipulated. Results showed that the two dimensions of similarity had an effect on updating times. The greater the similarity between the information maintained in memory and the new information that substituted it, the faster the updating. This is consistent both with the idea of distributed representations based on features, and with a selective updating process based on a feature overwriting mechanism. Thus, updating in WM can be understood as a selective substitution process influenced by similarity in which only certain parts of the representation stored in memory are changed.

The distance effect in numerical memory-updating tasks.

Two experiments examined the role of numerical distance in updating numerical information in working memory. In the first experiment, participants had to memorize a new number only when it was smaller than a previously memorized number. In the second experiment, updating was based on an external signal, which removed the need to perform any numerical comparison. In both experiments, distance between the memorized number and the new one was manipulated. The results showed that smaller distances between the new and the old information led to shorter updating times. This graded facilitation suggests that the process by which information is substituted in the focus of attention involves maintaining the shared features between the new and the old number activated and selecting other new features to be activated. Thus, the updating cost may be related to amount of new features to be activated in the focus of attention.