Functional changes in prefrontal cortex following frequency-specific training

Altres ajuts: European ANR (COEN4007-18, COEN-0003-01); PHRC grants from the French Ministry of Health and research funding; France Parkinson and ARSLA charity.Numerous studies indicate a significant role of pre-frontal circuits (PFC) connectivity involving attentional and reward neural networks within attention deficit hyperactivity disorder (ADHD) pathophysiology. To date, the neural mechanisms underlying the utility of non-invasive frequency-specific training systems in ADHD remediation remain underexplored. To address this issue, we created a portable electroencephalography (EEG)-based wireless system consisting of a novel headset, electrodes, and neuro program, named frequency specific cognitive training (FSCT). In a double-blind, randomized, controlled study we investigated the training effects in N = 46 school-age children ages 6-18 years with ADHD. 23 children in experimental group who underwent FCST training showed an increase in scholastic performance and meliorated their performance on neuropsychological tests associated with executive functions and memory. Their results were compared to 23 age-matched participants who underwent training with placebo (pFSCT). Electroencephalogram (EEG) data collected from participants trained with FSCT showed a significant increase in 14-18 Hz EEG frequencies in PFC brain regions, activities that indicated brain activation in frontal brain regions, the caudate nucleus, and putamen. These results demonstrate that FSCT targets specific prefrontal and striatal areas in children with ADHD, suggesting a beneficial modality for non-invasive modulation of brain areas implicated in attention and executive functions

Secado a presión reducida de naranjas (<i>Cv. Valencia Late</i>) pre-tratadas osmóticamente

Se ha estudiado la deshidratación de naranjas (cv. Valencia Late) empleando técnicas de osmosis (DO) y secado a presión reducida (SPR) –individuales y combinadas (DO seguida de SPR) – bajo diferentes condiciones: DO: tipo de agente osmótico (sacarosa, glucosa), concentración (20, 40, 60% p/p), temperatura del jarabe (20, 40, 60ºC), tiempo (rango: 0-240 min), con relación fruta:jarabe constante de 1:10 sin agitación; SPR: temperatura (20, 40, 60ºC), tiempo de SPR (0-240 min), vacío constante de 40 mmHg. En primer lugar se evaluó el proceso individual de DO mediante la metodología de superficie de respuesta a fin de establecer las mejores condiciones para obtener la máxima pérdida de agua (WL) con una moderada incorporación de sólidos solubles (SG). El análisis de optimización de respuestas múltiple permitió establecer que tanto en solución de sacarosa como en glucosa a una concentración de 60% p/p a 20ºC es posible obtener una WL máxima de 40.2% y una SG de 17.3% en un tiempo de proceso de 221.7 minutos. En el mismo sentido, se determinaron las condiciones óptimas para el tratamiento individual de SPR que resultaron 60|C a un tiempo. En el estudio de los procesos combinados, se evaluó el efecto de un pre-tratamiento por DO en condiciones óptimas de proceso (sacarosa, 20% p/p, 20 ºC) sobre el SPR. El proceso combinado (DO+SPR) redujo los tiempos de tratamiento del tratamiento individual por SPR para alcanzar un determinado contenido de humedad final. Por otro lado, basándose en un modelo difusional fueron calculadas las difusividades efectivas de humedad para las diferentes temperaturas de SPR de las frutas frescas y pre-deshidratadas por ósmosis, observándose que los coeficientes de difusión del agua fueron mayores para las muestras DO+SPR: 1,0523×10⁻⁹ m²/s (20ºC); 2,1553×10⁻⁹ m²/s (40ºC) y 6,8613×10⁻⁹ m²/s (60ºC) frente a los siguientes valores de difusividad para el SPR: 4,1330×10⁻¹² m²/s (20°C); 3,5427×10⁻¹¹ m²/s (40°C) y 1,3503×10⁻¹⁰ m²/s (60°C). Sobre la base de estos resultados, mediante una ecuación tipo Arrhenius se determinó la energía de activación para la deshidratación de las naranjas predeshidratadas por ósmosis.Centro de Investigación y Desarrollo en Criotecnología de Alimento

miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia

MicroRNA (miRNA)-126 is a known regulator of hematopoietic stem cell quiescence. We engineered murine hematopoiesis to express miRNA-126 across all differentiation stages. Thirty percent of mice developed monoclonal B cell leukemia, which was prevented or regressed when a tetracycline-repressible miRNA-126 cassette was switched off. Regression was accompanied by upregulation of cell-cycle regulators and B cell differentiation genes, and downregulation of oncogenic signaling pathways. Expression of dominant-negative p53 delayed blast clearance upon miRNA-126 switch-off, highlighting the relevance of p53 inhibition in miRNA-126 addiction. Forced miRNA-126 expression in mouse and human progenitors reduced p53 transcriptional activity through regulation of multiple p53-related targets. miRNA-126 is highly expressed in a subset of human B-ALL, and antagonizing miRNA-126 in ALL xenograft models triggered apoptosis and reduced disease burden

The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1.

In non-small cell lung cancer (NSCLC), receptor tyrosine kinases (RTKs) stand out among causal dominant oncogenes, and the ablation of RTK signaling has emerged as a novel tailored therapeutic strategy. Nonetheless, long-term RTK inhibition leads invariably to acquired resistance, tumor recurrence and metastatic dissemination. In ALK+ cell lines, inhibition of ALK signaling was associated with coactivation of several RTKs, whose pharmacological suppression reverted the partial resistance to ALK blockade. Remarkably, ERBB2 signaling synergized with ALK and contributed to the neoplastic phenotype. Moreover, the engagement of wild-type epidermal growth factor receptor or MET receptors could sustain cell viability through early growth response 1 (EGR1) and/or Erk1/2; Akt activation and EGR1 overexpression prevented cell death induced by combined ALK/RTK inhibition. Membrane expression of ERBB2 in a subset of primary naive ALK+ NSCLC could be relevant in the clinical arena. Our data demonstrate that the neoplastic phenotype of ALK-driven NSCLC relays ‘ab initio' on the concomitant activation of multiple RTK signals via autocrine/paracrine regulatory loops. These findings suggest that molecular and functional signatures are required in de novo lung cancer patients for the design of efficacious and multi-targeted ‘patient-specific' therapies

Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes

Anaplastic large cell lymphomas (ALCLs) represent a subset of lymphomas in which the anaplastic lymphoma kinase (ALK) gene is frequently fused to the nucleophosmin (NPM) gene. We previously demonstrated that the constitutive phosphorylation of ALK chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo and that ALK activity is strictly required for the survival of ALK-positive ALCL cells. To elucidate the signaling pathways required for ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of multiple ALK-positive ALCL cell lines, abrogating their ALK-mediated signaling by inducible ALK RNA interference (RNAi) or with potent and cell-permeable ALK inhibitors. Transcripts derived from the gene expression profiling (GEP) analysis uncovered a reproducible signature, which included a novel group of ALK-regulated genes. Functional RNAi screening on a set of these ALK transcriptional targets revealed that the transcription factor C/EBP\u3b2 and the antiapoptotic protein BCL2A1 are absolutely necessary to induce cell transformation and/or to sustain the growth and survival of ALK-positive ALCL cells. Thus, we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions

Impact of chronic obstructive pulmonary disease on short-term outcome in patients with ST-elevation myocardial infarction during COVID-19 pandemic: insights from the international multicenter ISACS-STEMI registry

Background: Chronic obstructive pulmonary disease (COPD) is projected to become the third cause of mortality worldwide. COPD shares several pathophysiological mechanisms with cardiovascular disease, especially atherosclerosis. However, no definite answers are available on the prognostic role of COPD in the setting of ST elevation myocardial infarction (STEMI), especially during COVID-19 pandemic, among patients undergoing primary angioplasty, that is therefore the aim of the current study. Methods: In the ISACS-STEMI COVID-19 registry we included retrospectively patients with STEMI treated with primary percutaneous coronary intervention (PCI) between March and June of 2019 and 2020 from 109 high-volume primary PCI centers in 4 continents. Results: A total of 15,686 patients were included in this analysis. Of them, 810 (5.2%) subjects had a COPD diagnosis. They were more often elderly and with a more pronounced cardiovascular risk profile. No preminent procedural dissimilarities were noticed except for a lower proportion of dual antiplatelet therapy at discharge among COPD patients (98.9% vs. 98.1%, P = 0.038). With regards to short-term fatal outcomes, both in-hospital and 30-days mortality occurred more frequently among COPD patients, similarly in pre-COVID-19 and COVID-19 era. However, after adjustment for main baseline differences, COPD did not result as independent predictor for in-hospital death (adjusted OR [95% CI] = 0.913[0.658–1.266], P = 0.585) nor for 30-days mortality (adjusted OR [95% CI] = 0.850 [0.620–1.164], P = 0.310). No significant differences were detected in terms of SARS-CoV-2 positivity between the two groups. Conclusion: This is one of the largest studies investigating characteristics and outcome of COPD patients with STEMI undergoing primary angioplasty, especially during COVID pandemic. COPD was associated with significantly higher rates of in-hospital and 30-days mortality. However, this association disappeared after adjustment for baseline characteristics. Furthermore, COPD did not significantly affect SARS-CoV-2 positivity. Trial registration number: NCT 04412655 (2nd June 2020)

Gender Difference in the Effects of COVID-19 Pandemic on Mechanical Reperfusion and 30-Day Mortality for STEMI: Results of the ISACS-STEMI COVID-19 Registry

Background. Several reports have demonstrated the impact of the COVID-19 pandemic on the management and outcome of patients with ST-segment elevation myocardial infarction (STEMI). The aim of the current analysis is to investigate the potential gender difference in the effects of the COVID-19 pandemic on mechanical reperfusion and 30-day mortality for STEMI patients within the ISACS-STEMI COVID-19 Registry. Methods. This retrospective multicenter registry was performed in high-volume primary percutaneous coronary intervention (PPCI) centers on four continents and included STEMI patients undergoing PPCIs in March–June 2019 and 2020. Patients were divided according to gender. The main outcomes were the incidence and timing of the PPCI, (ischemia time ≥ 12 h and door-to-balloon ≥ 30 min) and in-hospital or 30-day mortality. Results. We included 16683 STEMI patients undergoing PPCIs in 109 centers. In 2020 during the pandemic, there was a significant reduction in PPCIs compared to 2019 (IRR 0.843 (95% CI: 0.825–0.861, p < 0.0001). We did not find a significant gender difference in the effects of the COVID-19 pandemic on the numbers of STEMI patients, which were similarly reduced from 2019 to 2020 in both groups, or in the mortality rates. Compared to prepandemia, 30-day mortality was significantly higher during the pandemic period among female (12.1% vs. 8.7%; adjusted HR [95% CI] = 1.66 [1.31–2.11], p < 0.001) but not male patients (5.8% vs. 6.7%; adjusted HR [95% CI] = 1.14 [0.96–1.34], p = 0.12). Conclusions. The COVID-19 pandemic had a significant impact on the treatment of patients with STEMI, with a 16% reduction in PPCI procedures similarly observed in both genders. Furthermore, we observed significantly increased in-hospital and 30-day mortality rates during the pandemic only among females. Trial registration number: NCT 04412655