237 research outputs found
RÎle du microenvironnement dans le maintien et la résistance des cellules souches leucémiques de la Leucémie Myéloïde Chronique. voie BMP et contraintes mécaniques
One of the main causes of treatment failure in cancers is the development of drug resistance by cancer cells. The persistence of cancer stem cells (CSCs) might explain cancer relapses as they could allow reactivation of cancer cells proliferation following therapy, leading to disease persistence and ultimately to patientsâ death. Clinically, it is crucial to develop therapeutic strategies able to target resistant CSCs in order to cure the patients. CSCs are controlled by a variety of biochemical and biomechanical signals from the leukemic niche. My project aims to determine the involvement of the tumor microenvironment (BMP signaling pathway and mechanical stress) in the maintenance and resistance of Leukemic Stem Cells (LSCs) in Chronic Myelogenous Leukemia (CML). For this, we combined functional and molecular assays to the analysis of tumor microenvironment on more than 200 CML patientsâ samples. We demonstrated that alterations of intracellular BMP signaling pathway in CP-CML primary samples corrupt and amplify the response to exogenous BMP2 and BMP4, which are abnormally abundant in the tumor microenvironment. These results, recently published in Blood led us to evaluate the role of the BMP pathway in LSC maintenance under TKI treatment. Atomic force microscopy allowed us to demonstrate that BCR-ABL expression alone is sufficient to increases the rigidity of immature CML cells compared to healthy ones. Finally, using a unique cell confining system, we were able to demonstrate that mechanical stress controls the proliferation of immature leukemic cells by regulating the expression of mechano-sensitive genes such as Twist-1. These results could explain how LSCs can benefit from a mechanical stress exerted by their microenvironment to acquire a proliferative advantage over normal cells. Ultimately, we hope that this transdisciplinary approach will help to identify key molecules in the transduction of mechanical signals potentially involved in maintenance and resistance of CSCs and thus offer new targets to counter these effects.Une des principales causes dâĂ©chec dans le traitement des cancers est le dĂ©veloppement de rĂ©sistances aux drogues par les cellules tumorales. Les cellules souches cancĂ©reuses (CSC) sont suspectĂ©es dâĂȘtre responsables de ces rechutes, conduisant Ă la rĂ©currence de la maladie et bien souvent au dĂ©cĂšs des patients. En clinique, il est donc nĂ©cessaire de dĂ©velopper des stratĂ©gies thĂ©rapeutiques capables de cibler ces CSC rĂ©sistantes et aboutir Ă la guĂ©rison des patients. Les CSC sont rĂ©gulĂ©es par un ensemble de signaux aussi bien biologiques que physiques au sein de la niche tumorale. Mon projet a pour objectif de dĂ©terminer lâimplication du microenvironnement tumoral (voie de signalisation BMP et contraintes mĂ©caniques) dans le maintien et la rĂ©sistance des cellules souches leucĂ©miques (CSLs) de la leucĂ©mie myĂ©loĂŻde chronique (LMC). Pour cela, nous avons combinĂ© tests fonctionnels et molĂ©culaires ainsi que lâanalyse de la niche tumorale sur plus de 200 Ă©chantillons de patients atteints de LMC. Nous avons ainsi dĂ©montrĂ© que lâaltĂ©ration de la voie BMP intrinsĂšque aux cellules immatures de la LMC corrompt et amplifie la rĂ©ponse Ă BMP2 et BMP4, prĂ©sents en quantitĂ©s anormalement abondantes au sein de la niche tumorale. Ces rĂ©sultats rĂ©cemment publiĂ©s dans Blood nous ont amenĂ©s Ă Ă©valuer le rĂŽle de la voie BMP dans le maintien des CSLs sous traitement par les ITK. La microscopie Ă force atomique nous a permis de dĂ©montrer que lâexpression de BCR-ABL est suffisante pour induire une augmentation de la rigiditĂ© des cellules immatures de LMC par rapport Ă des cellules saines. Enfin, lâutilisation dâun systĂšme de confinement cellulaire nous a permis de dĂ©montrer que le stress mĂ©canique contrĂŽle la prolifĂ©ration des cellules leucĂ©miques immatures en rĂ©gulant lâexpression de gĂšnes mĂ©cano-sensibles comme Twist-1. Ces rĂ©sultats pourraient expliquer comment des CSLs tirent profit des contraintes mĂ©caniques issues de leur microenvironnement afin dâacquĂ©rir un avantage prolifĂ©ratif par rapport aux cellules saines. Ultimement, nous espĂ©rons que cette approche transdisciplinaire permettra dâidentifier les molĂ©cules clĂ©s de la transduction de signaux mĂ©caniques potentiellement impliquĂ©s dans le maintien et la rĂ©sistance des CSC et ainsi proposer de nouvelles cibles pour contrer ces effets
Incidence of Apoptosis in the Lymphoid Organs of Normal or Malaria Infected Mice is Decreased in CD18 and Urokinase - Receptor (UPAR, CD87) Deficient Mice
Incidence of apoptosis was investigated in the spleen and lymph nodes of +/+, CD18 -/- and
urokinase receptor (uPAR, CD87) -/- mice, untreated or Plasmodium Berghei Anka (PbA)
infected. In non infected mice, incidence of apoptosis was lower in the lymph nodes of CD18
-/- and uPAR -/- than in +/+ mice, as seen by FACS analysis to count the number of hypodiploid
and Annexin-V binding cells. Infection of mice with PbA resulted in a marked increase
in the size of spleen and lymph nodes 7â8 days after infection, which was slightly higher in
uPAR -/- and CD18 -/- than in +/+ mice. PbA infection increased about 7 fold the incidence of
apoptosis in the lymphoid organs of +/+, especially in the white pulp and germinal centers of
the spleen and lymph nodes, while in contrast it was unchanged in PbA infected CD18 -/- or
uPAR -/- mice. Serum IgG levels, and number of circulating leukocytes were significantly
higher in both uPAR and CD18 -/- than in +/+ mice. These results indicate that the CD18 and
uPAR surface molecules, which are known to be associated in the cell membrane, have an
important influence upon the incidence of cell survival in both normal or stimulated lymphoid
organs
Cavitation Erosion Prediction on Francis Turbines Part 3 : Methodologies of Prediction
In the frame of a joint research program between EDF, Hydro Québec and IMHEF, different methods are investigated to predict cavitation erosion on Francis turbines from model. They are based on measurement of pitting, pressure fluctuations and acceleration. The measurement techniques have been detailed in Part I and Part 2. The present article describes essentially the theoretical and practical aspects of the methods and discusses the results obtained until now from the mode! and prototype tests. The first analysis shows that the methods proposed are suitable to measure cavitation aggressiveness on mode! and on prototype, and that the level on the mode! is several orders of magnitude smaller than on the prototype. To adjust transposition laws, a more complete set of data is needed
Direct transfection of clonal organoids in matrigel microbeads : a promising approach toward organoid-based genetic screens
Organoid cultures in 3D matrices are relevant models to mimic the complex in vivo environment that supports cell physiological and pathological behaviors. For instance, 3D epithelial organoids recapitulate numerous features of glandular tissues including the development of fully differentiated acini that maintain apico-basal polarity with hollow lumen. Effective genetic engineering in organoids would bring new insights in organogenesis and carcinogenesis. However, direct 3D transfection on already formed organoids remains challenging. One limitation is that organoids are embedded in extracellular matrix and grow into compact structures that hinder transfection using traditional techniques. To address this issue, we developed an innovative approach for transgene expression in 3D organoids by combining single-cell encapsulation in Matrigel microbeads using a microfluidic device and electroporation. We demonstrate that direct electroporation of encapsulated organoids reaches up to 80% of transfection efficiency. Using this technique and a morphological read-out that recapitulate the different stages of tumor development, we further validate the role of p63 and PTEN as key genes in acinar development in breast and prostate tissues. We believe that the combination of controlled organoid generation and efficient 3D transfection developed here opens new perspectives for flow-based high-throughput genetic screening and functional genomic applications
Highly integrated multi-material fibers for soft robotics
Soft robots are envisioned as the next generation of safe biomedical devices in minimally invasive procedures. Yet, the difficulty of processing soft materials currently limits the size, aspect-ratio, manufacturing throughput, as well as, the design complexity and hence capabilities of soft robots. Multi-material thermal drawing is introduced as a material and processing platform to create soft robotic fibers imparted with multiple actuations and sensing modalities. Several thermoplastic and elastomeric material options for the fibers are presented, which all exhibit the rheological processing attributes for thermal drawing but varying mechanical properties, resulting in adaptable actuation performance. Moreover, numerous different fiber designs with intricate internal architectures, outer diameters of 700 ”m, aspect ratios of 103, and a fabrication at a scale of 10s of meters of length are demonstrated. A modular tendon-driven mechanism enables 3-dimensional (3D) motion, and embedded optical guides, electrical wires, and microfluidic channels give rise to multifunctionality. The fibers can perceive and autonomously adapt to their environments, as well as, probe electrical properties, and deliver fluids and mechanical tools to spatially distributed targets
Cavitation Erosion Prediction on Francis Turbines Part 2 : Model Tests and Flow Analysis
Different measurement techniques have been used to detect cavitation on a Francis turbine model. The results are compared to those obtained on the prototype and presented in the first of this series of articles. The runner mode! used for that study is built on the basis of a geometrical recovery of one of most eroded blade of the prototype. The results of the different measurements are presented and commented by comparison with prototype measurements. This comparison leads to a proposal of the physics which should be involved in transposition laws for the prediction of prototype erosion from cavitation mode! tests. The consequences of such scaling laws, as well as their application to the prototype and mode! results, are part of the third facet of this work
Restauration morpho-dynamique et redynamisation de la section court-circuitée du Rhin en aval du barrage de Kembs (projet INTERREG / EDF)
National audienceThe Upper Rhine River has been heavily impacted by channelization for flood protection and navigation, and then by damming for hydropower generation. In normal non flooding conditions, most of the flows are diverted in a canalized section whereas the regulated âold Rhineâ bypassed reach runs a minimum flow. Between Huningue and Neuf-Brisach, engineering works induced simplification and stabilization of the channel pattern from a formerly braiding sector to a single incised channel, hydrological modifications, bottom armouring due to bedload decrease, and thus ecological alterations. Two complementary and interdisciplinary projects have been initiated to restore alluvial morphodynamics: i) the international âINTERREG IV - Redynamisation of the old Rhineâ project (2009-2012) coordinated by the Alsace region, France; ii) the left bank âcontrolled erosionâ project launched by ElectricitĂ© de France (EDF) within Kembs hydroelectric station relicensing process since 2003-2004. The purpose of these projects is to evaluate the feasibility of an important hydro-morphological and ecological restoration plan on a 45 km long reach, through both field testing of bank erosion techniques at favourable locations, and artificial sediments input from right bank excavations. This will help define possible long term prospective scenarios, in order to restore sustainable sediment transport, morphodynamics variability and associated ecological functions. The study will involve historical analysis, hydro-morphological / hydraulic physical and numerical modelling, physical and ecological monitoring, and sociological aspectsLe Rhin alsacien-allemand a enregistrĂ© de profondes modifications morphologiques et hydrologiques Ă la suite de sa correction et de sa rĂ©gularisation pour la protection contre les crues et la navigation, puis aprĂšs la construction de barrages hydro-Ă©lectriques. Les amĂ©nagements rĂ©alisĂ©s entre Huningue et Neuf-Brisach ont engendrĂ© une simplification et une stabilisation du style fluvial. Un fleuve en tresses a cĂ©dĂ© la place Ă un chenal unique incisĂ©. Le fond de chenal est devenu pavĂ© Ă cause dâune diminution des apports de charge de fond et des altĂ©rations Ă©cologiques ont Ă©tĂ© observĂ©es (simplification des habitats aquatiques et riverains). Deux projets complĂ©mentaires et interdisciplinaires ont Ă©tĂ© engagĂ©s afin de restaurer une dynamique des formes alluviales : i) le projet international INTERREG IV â Redynamisation du Vieux Rhin (2009-2012) sous lâimpulsion de la rĂ©gion Alsace ; ii) le projet dâĂ©rosion maitrisĂ©e des berges de la rive gauche conduit par ElectricitĂ© de France (EDF) dans le cadre du renouvellement de la concession de lâamĂ©nagement de Kembs. Lâobjectif des deux projets est de dĂ©finir un plan de restauration hydro-morphologique et Ă©cologique conduisant Ă la redynamisation dâun tronçon de 45 km. LâĂ©tude repose sur une analyse historique, lâexploitation de modĂšles Ă la fois physiques et numĂ©riques, et les suivis morphologiques in situ dâune recharge artificielle en sĂ©diments et dâĂ©rosions de berge contrĂŽlĂ©es. Ces Ă©tudes de faisabilitĂ© sont complĂ©tĂ©es par des analyses Ă©cologique et sociologique pour apprĂ©cier lâimpact socio-environnemental de ces projets
Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis
Myeloid leukaemias share the common characteristics of being stem cell-derived clonal diseases, characterised by excessive proliferation of one or more myeloid lineage. Chronic myeloid leukaemia (CML) arises from a genetic alteration in a normal haemopoietic stem cell (HSC) giving rise to a leukaemic stem cell (LSC) within the bone marrow (BM) ânicheâ. CML is characterised by the presence of the oncogenic tyrosine kinase fusion protein breakpoint cluster region-abelson murine leukaemia viral oncogene homolog 1 (BCR-ABL), which is responsible for driving the disease through activation of downstream signal transduction pathways. Recent evidence from our group and others indicates that important regulatory networks involved in establishing primitive and definitive haemopoiesis during development are reactivated in myeloid leukaemia, giving rise to an LSC population with altered self-renewal and differentiation properties. In this review, we explore the role the bone morphogenic protein (BMP) signalling plays in stem cell pluripotency, developmental haemopoiesis, HSC maintenance and the implication of altered BMP signalling on LSC persistence in the BM niche. Overall, we emphasise how the BMP and Wnt pathways converge to alter the CdxâHox axis and the implications of this in the pathogenesis of myeloid malignancies
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