Sorption of nalidixic acid onto micrometric and nanometric magnetites: experimental study and modeling

International audienceThe sorption of nalidixic acid (NA) was studied onto three kinds of magnetite characterized by different particle sizes (from micrometric to nanometric) and surface properties. Experiments were performed under static batch and dynamic flow conditions. Obtained results indicate that kinetics and extent of sorption was strongly affected by the particle size of tested magnetites. Ionic strength effect was less significant suggesting that aggregation state of the magnetite particles did not affect the sorption. During kinetic sorption experiments, apparent rate constant normalized to solid mass was faster for nanosized magnetite while an opposite trend was observed for the surface area-normalized rate constants. Infrared data suggested the possibility of similar surface interactions on both microsized and nanosized magnetites. Transport of NA in magnetite-packed column was found associated to the instantaneous sorption without any significant effect of kinetic limitation. Breakthrough curves (BC) and sorption extent in columns were calculated by using Thomas, Yan and Yoon-Nelson models. Sorption capacities predicted by Thomas or Yan model were in good agreement with that determined by integrating total area above BC. However, Thomas model failed particularly to predict an accurate concentration at lower and higher time points of the BC. These findings have strong implications in relation to the transport and removal of environmental pollutants in natural and engineered systems

The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients

The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system. Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o.) in BCR-ABL expressing SCLtTAxBCR-ABL double transgenic (dtg) mice. Dasatinib robustly antagonized the CML phenotype in vivo in our transgenic mouse model, and this effect included both mature and immature cell populations. However, similar to patients with CML, the fraction of Lin(neg)Sca-1(+)KIT(+)CD48(neg)CD150(+) hematopoietic stem cells was not reduced by dasatinib treatment, suggesting that these cells are not oncogene-addicted. Moreover, we observed differential effects of dasatinib in these animals as compared to wild-type (wt) animals: while granulocytes were significantly reduced in dtg animals, they were increased in wt mice. And Ter119(+) erythrocytic and B220(+) B cells were increased in dtg mice but decreased in wt mice. Finally, while dasatinib induced a shift from CD49b/NK1.1 positive NK cells from the bone marrow to the spleen in wt animals, there was no change in dtg mice. In conclusion, the present mouse model provides a useful tool to study mechanisms of TKI resistance and dasatinib-associated beneficial effects and adverse events.Peer reviewe

Therapeutic inhibition of FcgammaRIIb signaling targets leukemic stem cells in chronic myeloid leukemia

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcgammaRIIb, CD32b) for being critical in LSC resistance and show that targeting FcgammaRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcgammaRIIb upregulation in primary CML stem cells. FcgammaRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcgammaRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcgammaRIIb-BTK axis in primary CML CD34(+) cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition

Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.</p

Kinasen der Src-Familie vermitteln die zytoplasmatische Retention von aktiviertem STAT5A in BCR-ABL positiven Leukämiezellen

The transcription factor STAT5 belongs to the family of Signal Transducer and Activator of Transcription and subdivides into STAT5A and STAT5B which share 96% sequence homology on the amino acid level. STAT5A is involved in hematopoiesis, immunity and mammary differentiation. The phosphorylation of a conserved tyrosine is essential for the activation of STAT transcription factors leading to the dimerization of two STAT proteins through reciprocal SH2 domain-phosphotyrosine interactions. The phosphorylated STAT dimers accumulate in the nucleus where they bind to specific promoter sequences and finally induce target gene expression. Persistent activation of STAT5 was detected amongst others in breast, prostate, ovarian and head and neck cancer. In addition, its important role in the development of myeloid neoplasms was demonstrated. The constitutively active kinase BCR-ABL is the result of a characteristic chromosomal translocation and leads to the development of chronic myeloid leukemia (CML). STAT5A is persistently phosphorylated at tyrosine 694 in BCR-ABL positive cells and therefore activated. Activation of STAT5 is essential for the initiation and maintenance of CML in murine models of the disease. Interestingly, activated STAT5A is localized predominantly in the cytoplasm of BCR-ABL positive leukemic cells, although phosphorylation at its main tyrosine typically causes nuclear accumulation of the transcription factor. The underlying mechanism was topic of the following investigation. Fluorescent STAT5A fusion proteins were cloned for confocal laser scanning microscopy. After cytokine stimulation the fusion proteins were phosphorylated at Y694, translocate into the nucleus and subsequently induce gene expression of a reporter gene. This verifies fluorescently labeled STAT5A as a functional transcription factor. Cytoplasmic localization of activated STAT5A was validated in CD34+ progenitor cells from a CML patient in chronic phase and in a CML cell line (K562). However, ectopic expression of BCR-ABL in non-myeloid cells leads to the accumulation of activated STAT5A. The Src family kinases (SFKs) Hck and v-Src phosphorylated STAT5A at Y694 but prevented BCR-ABL induced nuclear accumulation of the fluorescently labeled transcription factor. It turned out that the cytoplasmic retention depends on the kinase activity of SFKs. Inhibition of the kinase activity in K562 cells led to the nuclear accumulation of STAT5A and enhanced target gene expression. Furthermore, an intact SH2 domain is essential for the cytoplasmic retention of STAT5A and the robust interaction with the SFKs. FLT3-ITD, a constitutively active receptor tyrosine kinase found in acute myeloid leukemia, induced nuclear accumulation of STAT5A even if Hck is coexpressed. Thus, SFK-induced cytoplasmic retention of STAT5A is not universally valid and depends on the STAT5A activating oncogene

Tensions interfaciales liquide-liquide. II. Ordre chimique local. III. Comparaison avec les résultats expérimentaux

A l'aide d'un modèle d'interface en deux couches, nous étudions l'influence sur la tension interfaciale a entre deux liquides métalliques binaires, d'un ordre chimique local. Nous montrons que cet effet n'est sensible qu'à l'approche de la température critique.Les valeurs calculées de la tension interfaciale et de ses variations avec la température (systèmes binaires) et la concentration (systèmes ternaires) sont comparées aux résultats expérimentaux

Estimation du travail d’adhesion et des angles de contact dans les systemes non reactifs metal-oxyde ionocovalent

Nous exposons brièvement les modèles proposés antérieurement pour évaluer le travail d’adhésion dans les systèmes non réactifs métal-oxyde. Nous rappelons un travail théorique que nous avons présenté récemment, permettant le calcul du travail d’adhésion des couples métal/alumine à l’aide d’un modèle à deux paramètres. Nous proposons ensuite une modification de ce modèle permettant de supprimer un des deux paramètres et nous discutons de sa validité pour d’autres systèmes du type métal-oxyde ionocovalent

Wetting of Decagonal Al13Co4 and Cubic AlCo Thin Films by Liquid Pb

International audienceWetting of ìm-sized Pb droplets on thin polycrystalline films of decagonal Al13Co4 and cubic crystalline AlCo phases is reported. The sample preparation is crucial to have Pb droplets lying on a clean surface. Decagonal and cubic films were prepared under high vacuum conditions, by sequential deposition and annealing of specific stackings of Al and Co layers of nanometric thicknesses. A 300nm-thick Pb slab was then deposited on the top of the films. Dewetting experiments were performed in situ in a scanning Auger microprobe where the surface chemistry can be monitored: the Pb slab dewetts into droplets. The wetting of Pb on both substrates was found to be similar with contact angles around 45°