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Supplementary Methods from Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Supplementary Figures 1-4 from Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6- to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both α and β isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38α and p38β, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer. Cancer Res; 71(3); 1041–9. ©2010 AACR.

International audience; BACKGROUND and AIMS. During balance rehabilitation, automatic visual-vestibular compensations occur to reduce the patients’ visual dependence due to the vestibular inhibition suppression. This study presents the positive therapeutic effects of interactive protocols based on immersive virtual reality (VR) that restore the reciprocal visual-vestibular inhibition on a short period of two months, and the use of an identification procedure to characterize the relationship between visual stimulation features and the adaptive equilibrium parameters associated to the balance enhancement. METHODS. Included in an 8 weeks clinical trial, nine unilateral vestibular patients (42-80 y.o) were immersed into structured large-field visual virtual flows, whose the dynamic constraints and complexity (scroll, radial and rotation visual pattern, stimulation speed, and gaze anchoring) increase throughout the therapeutic session. The analysis focus on the gaze behavior, feet center-of-pressure trajectory (CoPT) and disequilibrium indicators. RESULTS. The results show that the balance perturbations and the associated compensatory postural strategies are intensified (increasing of the CoPT and ID values) related to the complexity of the virtual pattern and speed, but progressively decrease significantly throughout the sessions, for all the stimulation conditions and scenarios. The methodical repetition of the virtual scenarios, associated to the consistent practice through sessions, strengthened the adaptive balance improvement. Data indicates the balance recovery and a patients’ self-confidence due to the reduction of the visual dependence boosted by the visual-vestibular reverse compensation. CONCLUSION. At a clinical level, our results demonstrate the real and rapid effectiveness of the large-field visual immersion on condition of controlled and repetitive virtual scenario. Despite the lack of long-term effects (reported by patients on a six months period) requiring periodic booster sessions, new rehabilitation strategies including virtual visual immersions have to be preferred comparing to standardized rehabilitation protocols (uncontrolled optokinetic stimulation). At a neuro-functional level, the visual-vestibular-motor adaptation despite the persistence of vestibular deficits indicates the relative reweighting of the visual-vestibular sensory inputs for a functional reciprocal inhibition restoration. New questions on the neural basis of the visual-vestibular plasticity for balance control will be addressed. Finally, our study corroborate the proof of concept of controlled VR-rehabilitation, with experimental, practicable and clinical validation.

Cet article s’interroge sur le développement simultané, au XVIIIe siècle, de la police de Paris, souvent associée à une « modernité » policière, et celui des relations domestiques de travail en son sein, à travers le cas des clercs et des commis au service des commissaires au Châtelet et des inspecteurs de police. L’efficacité prêtée à la police parisienne tient en partie à ces précieux auxiliaires, toujours présents et disponibles. Dans les dernières décades de l’Ancien Régime puis dans les premières années de la Révolution, les critiques contre ces agents donnent lieu à des mesures d’encadrement puis à certaines réformes, sans pouvoir empêcher le retour de ces pratiques à partir de 1793-1794. Domestic working relations in the police of Paris during the eighteenth century. How can we explain the simultaneous development, in the eighteenth century, of the police of Paris, often synonymous with the idea of a «modern» police force, and of domestic working relations. Exploring the case of clerks and «commis» employed by commissaires au Châtelet (police commissioners) and police inspectors, this article demonstrates that the police of Paris was efficient partly thanks to these precious auxiliaries, who were always present and available. In the last decades before 1789, then during the first years of the Revolution, the critics against those agents were followed by some measures of regulation, then police reforms, but eventually did not prevent the return to such practices from 1793-1794 and onwards.

Videofluoroscopic Swallow studies (VFSS) are useful radiological examinations to explore swallowing disorders but which require ionizing radiation. The aim of our study was to evaluate the comparability of pediatric VFSS at 15 frames per second (fps) with 30 fps. Fifty-five loops including 190 swallowings of VFSS at 30 fps performed on 32 consecutive pediatric patients in a University Hospital Center were retrospectively modified by a software to delete one image out of two to obtain secondary loops with a frame rate of 15 fps. An otorhinolaryngologist-phonatrician and a radiologist reviewed all swallowings blindly and randomly using the penetration and aspiration scale (PAS). In case of discordance, they concluded a consensual interpretation. Fifteen girls and seventeen boys were included. The median age was 4 years and 8 months (range = 4 months-16 yr.). 144 swallowings were normal. Swallowing disorder was confirmed in 46 swallowings, (23 supraglottic penetrations and 23 aspirations). Considering each swallowing at 15 fps, sensitivity and specificity were, respectively, 93% (CI 0.82-0.98) and 98% (CI 0.94-0.99). The Cohen'Kappa coefficient between each interpretation at 15 and 30 fps was "almost perfect" (κ = 0.95; CI 0.88-0.99). Considering each loop, conclusion was identical. Reducing frame rate at 15 fps during pediatric VFSS seemed to be acceptable with comparable diagnostic performances without clinical impact compared to 30 fps, while being an efficient way to reduce the ionizing radiation exposition in children. We would suggest reconsidering the possibility of using VFSS with a 15 fps in a pediatric population.

The Laser Megajoule facility, developed by the CEA is based on 176 Nd:glass laser beams focused on a micro -target positioned inside a 10-meter diameter spherical chamber. The facility will deliver a total energy of 1.4MJ of UV light at 0.35 μm and a maximum power of 400 TW. A specific petawatt beam, PETAL, offers a combination of a very high intensity beam, synchronized with the nanosecond beams of the LMJ. This combination allows expanding the LMJ experimental field in the High Energy Density Physics (HEDP) domain. Since October 2019, 56 beams are fully operational (7 bundle of 8 beams). The installation and the commissioning of new laser bundles and new plasma diagnostics around the target chamber are continuing, simultaneously to the realization of plasma experiments. A major project milestone has been achieved at the end of 2019, with the first experiment in the facility involving neutron production, through D-D reaction in a D2 capsule inside a gold rugby cavity. The next major milestones for LMJ will take place at the end of 2021 with the commissioning of the half LMJ (10 heating bundles of 8 beams and a specific bundle for plasma diagnostics purpose). The full presentation will describe the software environment used for the laser operation, the first results on the laser damages using our 3w optical components inspection system, the laser damages analysis software, the system of spot blocking, and the last performances obtained with the PETAL beam.

Cet article présente un travail de description phonotactique du russe basé sur une analyse de 15 000 lemmes transcrits phonologiquement et syllabés. Un ensemble de données quantitatives relatives aux structures syllabiques a été examiné dans une perspective typologique. À partir d’une analyse distributionnelle des segments consonantiques ±PAL, des probabilités phonotactiques ont été estimées. Les résultats montrent que le russe suit globalement les tendances générales observées dans les langues de la base de données G-ULSID (Vallée, Rousset & Rossato, 2009) et mettent en évidence des asymétries de distribution des consonnes ±PAL à l’intérieur de la syllabe. Le fait que le système consonantique du russe présente une distinctivité ±PAL étendue à tous les lieux d’articulation, semble contraindre les coccurrences entre consonne et voyelle d’une même syllabe prédites par la théorie Frame/Content (MacNeilage, 1998) et trouvées dans de nombreuses langues.

Au cours du xviiie siecle, particulierement entre 1750 et 1800, les hommes des Lumieres sont confrontes a un soudain afflux d’informations qu’ils cherchent a maitriser grâce a l’invention de nouvelles technologies de papier. Cet article se penche sur la genese de ces nouveaux instruments pour centraliser, classer et extraire les informations, qui ont ete developpes simultanement dans les administrations et les milieux savants. Malgre l’apparition des premieres fiches, on observe une relative inertie des pratiques qui s’explique par un attachement non dementi au registre relie comme principal support des inscriptions

The Laser MegaJoule (LMJ) is a 176-beam laser facility, located at the CEA CESTA near Bordeaux (France). It is designed to deliver about 1.4 MJ of energy to targets, for high energy density physics experiments, including fusion experiments. A computational system, PARC has been developed and is under deployment to automate the laser setup process, and accurately predict laser energy, spatial and temporal shapes. PARC is based on MIRO computer simulation code. For each shot on LMJ, PARC determines the characteristics of the injection laser system required to achieve the desired main laser output and supplies post-shot data analysis and reporting. The presentation compares all characteristics (energy, spatial and temporal shapes, spot size, synchronism, wavefront correction and alignment on target) after amplification and after frequency conversion with predicted results or results computed with PARC.

[V. Denis, V. Milliot et C. Lucrezio Monticelli (dir.), Special section on policing and urban crisis, Urban History, volume 43, issue 2, May 2016, p. 200-305. En savoir plus https://www.cambridge.org/core/journals/urban-history/issue/4BF2E88B7804439C0E4F27CD68107F47 (consulté le 10/10/2016)]; The articles gathered here aim at outlining a complex view of the relationship between cities in a state of ‘crisis’ and changes to policing systems, in a period marked by rapid urbanization and industrialization. They explore the connections between the rhythms of urban change and the changes in the institutions responsible for policing the city. This introduction defines ‘urban crisis’ as a brief paroxysm and a way of describing rapid urban change that is considered problematic especially in terms of social control. It examines three sets of issues to highlight the relationships between policing powers and urban dynamics: first, how the police managed to handle unforeseen, traumatic events in emergency situations; second, how the police forces tried to legitimize their status through their understanding and control of urban dynamics; and third, how the police used the discourse of urban crisis they helped to produce, as a tool for their own ends.

La numérotation des maisons est considérée comme une technique innovante et moderne introduite par l’administration militaire et les autorités urbaines dans les années 1760 en France, pour faciliter l’orientation et la circulation des étrangers, ainsi qu’un contrôle plus serré de l’espace urbain. Cet article analyse l’impact de la numérotation des maisons et son usage par les habitants de Paris, de 1780 à 1807, et comment elle a pu changer la manière dont ils expriment leur localisation, physique et sociale, dans la cité. Il est fondé sur le dépouillement des déclarations d’adresse dans les archives de police. Il montre que les Parisiens ont finalement adopté rapidement et massivement le système de numérotage révolutionnaire, inventé pour d’autres fins que permettre aux citadins de se repérer dans la ville. La Révolution a coïncidé avec une transformation majeure dans la manière dont les individus définissent leur position dans l’espace parisien. House numbering has been considered as a distinctive, innovative feature introduced by military administration and urban authorities by the 1760s in France to make circulation easier for foreigners and enhance a stricter control on urban space. This article tries to assess the use of house numbering by the people of Paris from 1780 to 1807 and how it changed the way they expressed their location, physical and social, in the city. It is based on the declaration of address in police records. The people of Paris quickly and largely adopted the numbering system of the Revolution, although it was never designed to help the city dwellers orient themselves in the capital. The Revolution coincided with a major transformation in the way people defined their position in Paris and their perception of the city.

BACKGROUND: Cetuximab, a monoclonal antibody against EGFR used for the treatment of colorectal cancer (CRC), is ineffective in many patients. The aim of this study was to identify the signalling pathways activated by cetuximab in CRC cells and define new biomarker of response. METHODS: We used in vitro, in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action. RESULTS: We show that cetuximab activates the MAPK p38. Specifically, p38 inhibition reduced cetuximab efficacy on cell growth and cell death. At the molecular level, cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation, leading to the upregulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, we found that high FOXO3a and p38 expression levels are associated with better response rate and improved outcome in cetuximab-treated patients with CRC harbouring WT KRAS. CONCLUSIONS: We identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells and define p38 as its activator in this context. Moreover, high FOXO3a and p38 expression could predict the response to cetuximab in patients with CRC harbouring WT KRAS.British Journal of Cancer advance online publication, 29 September 2016; doi:10.1038/bjc.2016.313 www.bjcancer.com.