TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth.

The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings confirm TWIST1 as promising therapeutic target in NB

Oxytocin promotes prosocial behavior and related neural responses in infantmacaques at-risk for compromised social development

© 2021 The Authors. Published by Elsevier. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1016/j.dcn.2021.100950Although positive effects of oxytocin (OT) on social functioning are well-demonstrated, little is known about the mechanisms through which OT may drive early social development, or its therapeutic efficacy in infancy. To address these critical issues, we investigated the effects of exogenous OT on neural (EEG) and behavioral responses during observation of live facial gestures in infant macaques with limited social exposure (i.e. nursery-reared). Three key findings were revealed. First, OT increased alpha suppression over posterior scalp regions during observation of facial gestures but not non-biological movement, suggesting that OT targets self-other matching and attentional cortical networks involved in social perception from very early infancy. Second, OT increased infant production of matching facial gestures and attention towards the most socially-relevant facial stimuli, both behaviors typically silenced by early social deprivation. Third, infants with higher cortisol levels appeared to benefit the most from OT, displaying greater improvements in prosocial behaviors after OT administration. Altogether, these findings suggest that OT promotes prosocial behaviors and associated neural responses likely impacted by early social adversity, and demonstrate the potential of OT administration to ameliorate social difficulties in the context of neurodevelopmental and early-emerging psychiatric disorders, at a developmental stage when brain plasticity is greatest.This work was supported by the National Institutes of Health (NICHD Grant P01HD064653 to P.F.F.) and the NICHD Division of Intramural Research. This work was performed within the framework of the LABEX CORTEX (ANR-11-LABX-0042) of Université de Lyon operated by the French National Research Agency (ANR)

Amélioration du comportement en cyclage thermique d'un dépôt plasma métallique par compression isostatique à chaud

Afin d'améliorer les performances de revêtements métalliques FeCrAlY projetés par plasma sous pression réduite sur des substrats de type FeCrAl et compte-tenu des résultats intéressants déjà obtenus par application d'un post-traitement par compression isostatique à chaud, nous avons cherché à optimiser les conditions d'application de la CIC. Trois types de traitement ont ainsi été testés. Les différentes évolutions des depôts obtenus dans chacun des cas ont été caractérisés par diffraction des RX, microscopie, microanalyse et microdureté. Les comportements des différents échantillons ont ensuite été comparés au cours d'essais de cyclage thermique ainsi que l'évolution respective de leurs microstructures.A HIP post-treatment applied on LPPS FeCrAIY coatings improved resistance under thermal cycling (high coating densification, strong adherence to the substrate). Observation of the oxide scale using SEM, enabled us to explain such an improvement of the behaviour of post-hipped coatings when submitted to both oxidation and thermal stresses

Critical effect of local pressure on jump frequencies in intermetallics

International audienceThrough an extensive atomic-scale investigation of NiAl3, a cementite-like structure, we show that only a proper account of saddle- point pressures leads to unambiguous jump attempt frequency spectra. We also demonstrate that attempt frequencies can spread over ranges exceeding five orders of magnitude and therefore cannot be realistically described by simplified few-valued schemes, as commonly assumed. These issues cast doubt on generally admitted assumptions in kinetic simulations, which may have critical consequences on their accuracy

Diffusion in complex ordered alloys: atomic scale investigation of NiAl3

International audienceAlthough involved in most solid-state processes, ordered compounds are often characterized by complex crystallographies and chemical properties, which drastically restricts the range of experimental investigations, and urges more realistic simulation frameworks. Considering the case of NiAl3 and the unknown diffusion properties of its practically important cementite-type structure, we use embedded-atom-method-based atomicscale simulations to perform a detailed analysis of its kinetic parameters controlling jump rates, including migration profiles, saddle points and attempt frequencies. The global approach proposed here is made necessary by the intricate coupling between these quantities, which rules out more usual schemes relying on selected transitions. It provides the required material for atomistic simulations of diffusion in low-symmetry ordered phases

Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

BACKGROUND: Histone deacetylase inhibitors (HDACi) are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB) is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. RESULTS: We show here that the HDACi Sodium Butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA) strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. CONCLUSION: HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells

Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma.

BACKGROUND: The successful targeting of neuroblastoma (NB) by associating tumor-initiating cells (TICs) is a major challenge in the development of new therapeutic strategies. The subfamily of aldehyde dehydrogenases 1 (ALDH1) isoenzymes, which comprises ALDH1A1, ALDH1A2, and ALDH1A3, is involved in the synthesis of retinoic acid, and has been identified as functional stem cell markers in diverse cancers. By combining serial neurosphere passages with gene expression profiling, we have previously identified ALDH1A2 and ALDH1A3 as potential NB TICs markers in patient-derived xenograft tumors. In this study, we explored the involvement of ALDH1 isoenzymes and the related ALDH activity in NB aggressive properties. METHODS: ALDH activity and ALDH1A1/A2/A3 expression levels were measured using the ALDEFLUOR? kit, and by real-time PCR, respectively. ALDH activity was inhibited using the specific ALDH inhibitor diethylaminobenzaldehyde (DEAB), and ALDH1A3 gene knock-out was generated through the CRISPR/Cas9 technology. RESULTS: We first confirmed the enrichment of ALDH1A2 and ALDH1A3 mRNA expression in NB cell lines and patient-derived xenograft tumors during neurosphere passages. We found that high ALDH1A1 expression was associated with less aggressive NB tumors and cell lines, and correlated with favorable prognostic factors. In contrast, we observed that ALDH1A3 was more widely expressed in NB cell lines and was associated with poor survival and high-risk prognostic factors. We also identified an important ALDH activity in various NB cell lines and patient-derived xenograft tumors. Specific inhibition of ALDH activity with diethylaminobenzaldehyde (DEAB) resulted in a strong reduction of NB cell clonogenicity, and TIC self-renewal potential, and partially enhanced NB cells sensitivity to 4-hydroxycyclophosphamide. Finally, the specific knock-out of ALDH1A3 via CRISPR/Cas9 gene editing reduced NB cell clonogenicity, and mediated a cell type-dependent inhibition of TIC self-renewal properties. CONCLUSIONS: Together our data uncover the participation of ALDH enzymatic activity in the aggressive properties and 4-hydroxycyclophosphamide resistance of NB, and show that the specific ALDH1A3 isoenzyme increases the aggressive capacities of a subset of NB cells