Serum-Nutrient Starvation Induces Cell Death Mediated by Bax and Puma That Is Counteracted by p21 and Unmasked by Bcl-xL Inhibition

The cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) is a multifunctional protein known to promote cell cycle arrest and survival in response to p53-dependent and p53 independent stimuli. We herein investigated whether and how it might contribute to the survival of cancer cells that are in low-nutrient conditions during tumour growth, by culturing isogenic human colorectal cancer cell lines (HCT116) and breast cancer cell lines in a medium deprived in amino acids and serum. We show that such starvation enhances, independently from p53, the expression of p21 and that of the pro-apoptotic BH3-only protein Puma. Under these conditions, p21 prevents Puma and its downstream effector Bax from triggering the mitochondrial apoptotic pathway. This anti-apoptotic effect is exerted from the cytosol but it is unrelated to the ability of p21 to interfere with the effector caspase 3. The survival function of p21 is, however, overcome by RNA interference mediated Bcl-xL depletion, or by the pharmacological inhibitor ABT-737. Thus, an insufficient supply in nutrients may not have an overt effect on cancer cell viability due to p21 induction, but it primes these cells to die, and sensitizes them to the deleterious effects of Bcl-xL inhibitors regardless of their p53 status

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Amélioration des propriétés mécaniques transverses de matériaux composites polymérisés sous rayonnement ionisant (étude des facteurs influents)

La polymérisation sous rayonnement ionisant (électrons, rayons X) est une technologie prometteuse pour la fabrication de matériaux composites. Cependant, ces matériaux présentent des propriétés mécaniques transverses insuffisantes pour des applications hautes performances, propriétés que ce travail vise à améliorer. Les matériaux considérés sont des matrices acrylates, et des fibres de carbones. Le mouillage des fibres par la matrice, le retrait volumique de la matrice lors de la polymérisation et la chimie à l interface fibre / matrice sont les principaux phénomènes qui contrôlent l adhésion fibre/matrice. L'influence de ces trois aspects a été étudiée et des solutions ont été proposées, à l'échelle du laboratoire puis au niveau du matériau composite. Une amélioration significative a été obtenue par une voie consistant à optimiser les liaisons chimiques entre la fibre et la matrice. Par ailleurs, une étude de la morphologie de réseaux diacrylates polymérisés sous UV et sous faisceau d'électrons a été réalisée.Electron-beam curing is a promising technology for manufacturing fiber-reinforced composite materials. These materials generally present insufficient transverse mechanical properties for high performances applications. This work was aimed at improving the properties of carbon fiber-reinforced composites based on epoxy acrylate matrices. Various aspects as fibers wetting, matrix shrinkage on curing, and chemistry occurring at the fiber-matrix interface were studied separately in some details. Solutions were proposed and evaluated at the lab scale and implemented on the composite materials. Significant improvements were obtained by inducing covalent bonding between fibers and matrix. In addition, a study of the morphology of UV- and EB-cured diacrylate networks was carried out to address the issue of matrix heterogeneity.LILLE1-BU (590092102) / SudocSudocFranceF

A Smart Analytical and Numerical Interpretation of Injection Tests in Unsaturated, Fractured and Karstified Carbonate Reservoirs

International audienc

Caractérisation d'une population cellulaire stromale associée au glioblastome (GASC) en vue d'un ciblage thèrapeutique

National audienc

Escape from p21-mediated Oncogene-induced Senescence Leads to Cell Dedifferentiation and Dependence on Anti-apoptotic Bcl-xL and MCL1 Proteins

International audienceOncogene-induced senescence (OIS) is a tumor suppressor response that induces permanent cell cycle arrest in response to oncogenic signaling. Through the combined activation of the p53-p21 and p16-Rb suppressor pathways, OIS leads to the transcriptional repression of proliferative genes. Although this protective mechanism has been essentially described in primary cells, we surprisingly observed in this study that the OIS program is conserved in established colorectal cell lines. In response to the RAS oncogene and despite the inactivation of p53 and p16INK4, HT29 cells enter senescence, up-regulate p21WAF1, and induce senescence-associated heterochromatin foci formation. The same effect was observed in response to B-RAFv600E in LS174T cells. We also observed that p21WAF1 prevents the expression of the CDC25A and PLK1 genes to induce cell cycle arrest. Using ChIP and luciferase experiments, we have observed that p21WAF1 binds to the PLK1 promoter to induce its down-regulation during OIS induction. Following 4–5 weeks, several clones were able to resume proliferation and escape this tumor suppressor pathway. Tumor progression was associated with p21WAF1 down-regulation and CDC25A and PLK1 reexpression. In addition, OIS and p21WAF1 escape was associated with an increase in DNA damage, an induction of the epithelial-mesenchymal transition program, and an increase in the proportion of cells expressing the CD24low/CD44high phenotype. Results also indicate that malignant cells having escaped OIS rely on survival pathways induced by Bcl-xL/MCL1 signaling. In light of these observations, it appears that the transcriptional functions of p21WAF1 are active during OIS and that the inactivation of this protein is associated with cell dedifferentiation and enhanced survival.</p

S100A4 Is a Biomarker of Tumorigenesis, EMT, Invasion, and Colonization of Host Organs in Experimental Malignant Mesothelioma

International audienceRecent findings suggest that S100A4, a protein involved in communication between stromal cells and cancer cells, could be more involved than previously expected in cancer invasiveness. To investigate its cumulative value in the multistep process of the pathogenesis of malignant mesothelioma (MM), SWATH-MS (sequential window acquisition of all theoretical fragmentation spectra), an advanced and robust technique of quantitative proteomics, was used to analyze a collection of 26 preneoplastic and neoplastic rat mesothelial cell lines and models of MM with increasing invasiveness. Secondly, proteomic and histological analyses were conducted on formalin-fixed paraffin-embedded sections of liver metastases vs. primary tumor, and spleen from tumor-bearing rats vs. controls in the most invasive MM model. We found that S100A4, along with 12 other biomarkers, differentiated neoplastic from preneoplastic mesothelial cell lines, and invasive vs. non-invasive tumor cells in vitro, and MM tumors in vivo. Additionally, S100A4 was the only protein differentiating preneoplastic mesothelial cell lines with sarcomatoid vs. epithelioid morphology in relation to EMT (epithelial-to-mesenchymal transition). Finally, S100A4 was the most significantly increased biomarker in liver metastases vs. primary tumor, and in the spleen colonized by MM cells. Overall, we showed that S100A4 was the only protein that showed increased abundance in all situations, highlighting its crucial role in all stages of MM pathogenesis

c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1

International audienceBackground Anti-apoptotic signals induced downstream of HER2 are known to contribute to the resistance to current treatments of breast cancer cells that overexpress this member of the EGFR family. Whether or not some of these signals are also involved in tumor maintenance by counteracting constitutive death signals is much less understood. To address this, we investigated what role anti- and pro-apoptotic Bcl-2 family members, key regulators of cancer cell survival, might play in the viability of HER2 overexpressing breast cancer cells. Methods We used cell lines as an in vitro model of HER2-overexpressing cells in order to evaluate how anti-apoptotic Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic Puma and Bim impact on their survival, and to investigate how the constitutive expression of these proteins is regulated. Expression of the proteins of interest was confirmed using lysates from HER2-overexpressing tumors and through analysis of publicly available RNA expression data. Results We show that the depletion of Mcl-1 is sufficient to induce apoptosis in HER2-overexpressing breast cancer cells. This Mcl-1 dependence is due to Bim expression and it directly results from oncogenic signaling, as depletion of the oncoprotein c-Myc, which occupies regions of the Bim promoter as evaluated in ChIP assays, decreases Bim levels and mitigates Mcl-1 dependence. Consistently, a reduction of c-Myc expression by inhibition of mTORC1 activity abrogates occupancy of the Bim promoter by c-Myc, decreases Bim expression and promotes tolerance to Mcl-1 depletion. Western blot analysis confirms that naïve HER2-overexpressing tumors constitutively express detectable levels of Mcl-1 and Bim, while expression data hint on enrichment for Mcl-1 transcripts in these tumors. Conclusions This work establishes that, in HER2-overexpressing tumors, it is necessary, and maybe sufficient, to therapeutically impact on the Mcl-1/Bim balance for efficient induction of cancer cell death.</p

L’aqueduc antique de Reims (Durocortorum)

International audienceDer Aqueduc von Reims, erstmalig um 1831 erwähnt, wurde mehrmals im 19. Jahrhundert untersucht bevor er durch die Ereignisse des erstenWeltkriegs in Vergessenheit geriet. Erst am Anfang der 80iger Jahre vollzog die G.E.A.C.A. (Groupe d’Etude Archéologique de ChampagneArdenne) eine neue Untersuchung des Gebäudes, vor allem anhand von Prospektionen und Sondagen. Ab 2005, wurden im südöstlichenRandgebiet Reims mehrere Rettungsforschungen größeren Ausmaßes realisiert. Diese neueren Untersuchungen trugen maßgeblich zurBereicherung der architektonischen Kenntnisse des hydraulischen Bauwerks bei, ebenso konnte der Verlauf des Aqueducs 40 km langnachvollzogen werden. Entsprechend der Keramikstudien und den Radiokarbondatierungen, kann von der Erbauung des Aqueducs in derzweiten Hälfte der Regierungszeit des Augustus, also im ersten Viertel des ersten Jahrhunderts nach Christus ausgegangen werden. Abgesehenvon einer Auflassungsphase welche es noch zu definieren gilt, erlaubt die Korrelation der archäologischen Daten und mit denen der antikenUmbauphasen der Stadt jene Auflassungsphase auf das Ende des 4. oder Anfang des 5. Jahrhunderts zu begrenzen.Die ersten Plünderungen der Baumaterialien des Aqueducs fanden bereits vor der Merowingerzeit statt. Die an den Aqueduc angrenzendenBaureste zeigen, dass die Zerstörung der Anlagen durch eine organisierte Baustelle größeren Ausmaßes durchgeführt wurde. MehrerePlünderungsphasen und der Wiederverwendung den Materialen fanden bis ins 19. Jahrhundert statt.In der vorliegenden Arbeit soll die Zusammenfassung der archäologischen Untersuchungen und der Wiederentdeckung des Bauwerkes seit 1830bis heute präsentiert werden. (Traduction de K. Zipper, Inrap)Mentionné pour la première fois en 1831, l’aqueduc antique de Reims a fait l’objet de plusieurs observations pendant le XIXesiècle avant qu’il ne soit effacé des mémoires avec la première Guerre Mondiale.Il fallu attendre le début des années 80 pour que le G.E.A.C.A. entreprenne une nouvelle étude de l’édifice, au moyen decampagnes de prospections, appuyées par des sondages. Dès 2005, des opérations archéologiques préventives de plusgrande envergure ont été réalisées en périphérie sud-est de Reims. Ces recherches récentes ont permis de progresser surles connaissances architecturales de l’ouvrage hydraulique et sur la précision de son tracé de près de 40 km. Il a été possiblede répondre à des questions encore mal connues jusque là, comme la chronologie ou les méthodes de récupération desmatériaux. D’après les résultats des études céramiques et des datations par radiocarbone, il est désormais acquis que laconstruction de l’ouvrage se situe durant la seconde partie du règne d’Auguste, dans le premier quart du Ier siècle de notreère.Malgré une phase d’abandon à définir encore plus précisément, la corrélation des éléments archéologiques et des donnéesapportés par les aménagements hydrauliques antiques dans la ville, semblent situer celle-ci à la fin du IVe siècle ou au débutdu Ve siècle.La première récupération des matériaux de l’aqueduc est antérieure à la période mérovingienne. Les vestiges environnantsl’ouvrage indiquent que la démolition des installations a nécessité un chantier important et bien organisé. D’autres phasesde récupération se succèdent ensuite jusqu’au XIXe siècle.C’est la synthèse de l’ensemble des travaux archéologiques menés de la redécouverte du monument, depuis les années 1830à nos jours qui est présentée dans cet ouvrage.Mentionado por primera vez en 1831, el aqueducto antiguo de Reims a sido observado varias veces durante el siglo XIX antes de estar borradode las memorias con la primera guerra mundial.Se ha necesitado esperar el inicio de los años 80 para que el G.E.A.C.A. empieze de nuevo a estudiar el edificio, con el medio de campañas deprospección y el apoyo de excavaciones arqueológicas. Desde 2005, algunas excavaciónes de mas grande amplitud han sido realisadas en laperiferia sur-este de Reims. Estas investigaciones han permitido ciertos progresos en los conocimientos arquitectónicos de la construcciónhidráulica, dando indicaciones precisas de su ubicación en una distancia que se acerca de los 40 kilometros. Ha sido posible de responder aalgunas preguntas mal conocidas hasta ahora, como la cronología o les medios de recuperación de material. Segun los resultados de los estudiosde la ceramica y las fechas conseguidas por datación por carbono radiactivo, es seguro que la construcción de la obra se ubica durante la segundaparte del reinado de Augusto, en el primer cuarto du primer siglo de nuestra era.A pesar de una fase de abandono que se debe precisar aun, la correlación entre los elementos arqueológicos y las informaciónes dadas por lasconstrucciónes hidráulicas antiguas en la ciudad, parece situarla al fin del siglo quarto o al inicio del siglo quinto.La primera recuperación de los materiales del aqueducto es anterior a la epoca merovingia. Las obras alrededor del monumento indican que lademolición de las instalaciones ha necesidado un astillero importante y bien organizado. Otras fases de recuperación se succeden hasta el siglodiez y nueve. Es la synthesis de todos los trabajos arqueologicos conducidos para descubrir el monumento, desde los años 1830 hasta hoy, queesta presentada en este livro. (Traduction de Xavier Pinto, Inrap et Lucia Pinto)Mentioned for the first time in 1831, the ancient aqueduct of Reims has been the subject of various observations during the 19th century, beforeit’s been erased for memory with world war one.It was only at the beginning of the eighties that the G.E.A.C.A. (1) undertook a new study of the building by means of prospection campaigns,backed by borings. From 2005, preventive archaeological operations of wider scale have been achieved in the south-east periphery of Reims.These recent research allowed to improve the architectural knowledge of the hydraulic work and the precision of its layout of close to 25 miles. Itwas possible to answer questions largely unknown so far such as chronology or materials recovery methods. According to results from ceramicsanalysis and radiocarbon dating, it is now proven that the construction of the work took place in the second half of Augustus reign, in the firstquarter of the first century of our era.A higher accuracy would be required regarding when it was stopped to be used but the correlation of archaeological items and data establishedfrom the ancient hydraulic fitting-out inside the city seem to indicate the end of the 4th century or the beginning of the 5th century.The first salvage of materials from the aqueduct is prior to the Merovigien period. The remains surrounding the work show that the demolition ofthe fittings required an important and well organized means. Other materials salvage operations will follow one another until the 19th century.The synthesis of the whole archaeological work built up from the re-discovery of the monument, in the years of 1830, to nowadays is presentedin this book. (traduction : Fabrice Laporta)Menzionato per la prima volta nel 1831, l’acquedotto antico di Reims ha fatto l’oggetto di diverse osservazioni nel XIX secolo, prima che il suoricordo svanisca con la prima guerra mondiale.Bisognerà attendere l’inizio degli anni 80 per assistere ad una ripresa delle ricerche sull’edificio, promossa dal G.E.A.C.A. attraverso l’esecuzionedi una serie di campagne di prospezione di superficie e di sondaggi. A partire dal 2005, delle più consistenti operazioni d’archeologia preventivavengono realizzate alla periferia sud-est di Reims. Queste ricerche recenti sono all’origine di un’evoluzione delle conoscenze sull’architetturadell’opera idraulica e sullo sviluppo del suo tracciato su quasi 40 Km. Dei dati relativi ad alcune questioni, ancora poco chiare alcuni anni fa,quali la cronologia dell’opera ed i metodi di recupero dei materiali da costruzione, sono oggi disponibili. Gli studi della ceramica ed una serie diradiodatazioni permettono di fissare l’edificazione dell’acquedotto durante la seconda parte del regno d’Augusto, nel primo quarto del I sec. d.C.La data dell’abbandono funzionale della struttura non è ancora definita con precisione ma, in base allo studio congiunto degli elementiarchéologici e delle informazioni sulle opere idrauliche urbane, essa potrebbe essere situata fra la fine del IV e l’inzio del V sec. d.C.I primi recuperi del materiale costruttivo sono anteriori all’epoca dei Merovingi. I resti archeologici nelle zone adiacenti all’acquedotto indicanola presenza di un cantiere di demolizione ben organizzato e di proporzioni notevoli. In seguito, delle ulteriori fasi di recupero si succederannofino al XIX secolo.Il presente lavoro sostituisce la sintesi degli studi archeologici realizzati su quest’opera architettonica, dal momento della sua riscoperta,nell’ottocento, ad oggi. (Traduction de A. Bandelli, Inrap