What Role for Angiogenesis in Childhood Acute Lymphoblastic Leukaemia?

The role of angiogenesis in acute leukaemia has been discussed since the cloning of the gene of vascular endothelial growth factor (VEGF) from the acute myelogenous leukemia cell line (HL60) and, thereafter, when the first studies reported increased bone marrow vascularity and elevation of angiogenic cytokines in acute lymphoblastic leukaemia (ALL). VEGF and basic fibroblast growth factor (bFGF) are the major proangiogenic cytokines that have been studied, and evaluation of their prognostic impact in childhood ALL has been reported in several studies, though with controversial results. The antiangiogenic response, contributing to the angiogenic balance, has scarcely been reported. The origin of the factors, their prognostic value, and their relevance as good markers of what really happens in the bone marrow are discussed in this paper. The place of antiangiogenic drugs in ALL has to be defined in the global treatment strategy

User-friendly imaging algorithms for interferometry

OPTICON currently supports a Joint Research Activity (JRA) dedicated to providing easy to use image reconstruction algorithms for optical/IR interferometric data. This JRA aims to provide state-of-the-art image reconstruction methods with a common interface and comprehensive documentation to the community. These tools will provide the capability to compare the results of using different settings and algorithms in a consistent and unified way. The JRA is also providing tutorials and sample datasets to introduce the principles of image reconstruction and illustrate how to use the software products. We describe the design of the imaging tools, in particular the interface between the graphical user interface and the image reconstruction algorithms, and summarise the current status of their implementation.European Community’s Seventh Framework Programme (FP7/2013–2016) (Grant ID: 312430 (OPTICON))This is the author accepted manuscript. The final version is available from SPIE via http://dx.doi.org/10.1117/12.223338

Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

International audienceBackground: Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood.Methods: In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL). To look for an implication of hypoxia in chemoresistance, cell viability, total cell density and cell proliferation were analyzed. Survival and death signaling pathways were also screened by "reverse phase protein array" (RPPA) and western blotting experiments conducted on selected proteins to confirm the results.Results: We found that hypoxia promotes chemoresistance in both ALL cell lines. The induction of drug-resistance by hypoxia was not associated with an increase in total cell density nor an increase in cell proliferation. Using RPPA, we show that chemoresistance induced by hypoxia was mediated through an alteration of cell death signaling pathways. This protective effect of hypoxia seems to occur via a decrease in pro-apoptotic proteins and an increase in anti-apoptotic proteins. The results were confirmed by immunoblotting. Indeed, hypoxia is able to modulate the expression of anti-apoptotic proteins independently of chemotherapy while a pro-apoptotic signal induced by a chemotherapy is not modulated by hypoxia.Conclusions: Hypoxia is a factor in leukemia cell resistance and for two conventional chemotherapies modulates cell death signaling pathways without affecting total cell density or cell proliferation

AMBER/VLTI high spectral resolution observations of the Brγ\gamma emitting region in HD 98922. A compact disc wind launched from the inner disc region

We analyse the main physical parameters and the circumstellar environment of the young Herbig Be star HD 98922. We present AMBER/VLTI high spectral resolution (R =12000) interferometric observations across the Br$\gamma$ line, accompanied by UVES high-resolution spectroscopy and SINFONI-AO assisted near-infrared integral field spectroscopic data. To interpret our observations, we develop a magneto-centrifugally driven disc-wind model. Our analysis of the UVES spectrum shows that HD 98922 is a young (~5x10^5 yr) Herbig Be star (SpT=B9V), located at a distance of 440(+60-50) pc, with a mass accretion rate of ~9+/-3x10^(-7) M_sun yr^(-1). SINFONI K-band AO-assisted imaging shows a spatially resolved circumstellar disc-like region (~140 AU in diameter) with asymmetric brightness distribution. Our AMBER/VLTI UT observations indicate that the Br$\gamma$ emitting region (radius ~0.31+/-0.04 AU) is smaller than the continuum emitting region (inner dust radius ~0.7+/-0.2 AU), showing significant non-zero V-shaped differential phases (i.e. non S-shaped, as expected for a rotating disc). The value of the continuum-corrected pure Br$\gamma$ line visibility at the longest baseline (89 m) is ~0.8+/-0.1, i.e. the Br$\gamma$ emitting region is partially resolved. Our modelling suggests that the observed Br$\gamma$ line-emitting region mainly originates from a disc wind with a half opening angle of 30deg, and with a mass-loss rate of ~2x10(-7) M_sun yr^(-1). The observed V-shaped differential phases are reliably reproduced by combining a simple asymmetric continuum disc model with our Br$\gamma$ disc-wind model. The Br$\gamma$ emission of HD 98922 can be modelled with a disc wind that is able to approximately reproduce all interferometric observations if we assume that the intensity distribution of the dust continuum disc is asymmetric.Comment: Accepted for publication on Astronomy \& Astrophysics. High resolution figures published on the main journal (see Astronomy & Astrophysics: Forthcoming) or at www.researchgate.net/profile/Alessio_Caratti_o_Garatti/publication

Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model

Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anti-cancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac to carry the drug, a dose-effect ranging from 0.005 to 2.5mg of Fc-diOH per animal can be evidenced

Cytochemical techniques and energy-filtering transmission electron microscopy applied to the study of parasitic protozoa

The study of parasitic protozoa plays a major role in cell biology, biochemistry and molecular biology. Numerous cytochemical techniques have been developed in order to unequivocally identify the nature of subcellular compartments. Enzyme and immuno-cytochemistry allow the detection of, respectively, enzymatic activity products and antigens in particular sites within the cell. Energy-filtering transmission electron microscopy permits the detection of specific elements within such compartments. These approaches are particularly useful for studies employing antimicrobial agents where cellular compartments may be destroyed or remarkably altered and thus hardly identified by standard methods of observation. In this regard cytochemical and spectroscopic techniques provide valuable data allowing the determination of the mechanisms of action of such compounds

Quantitative and qualitative effect of gH625 on the nanoliposome-mediated delivery of mitoxantrone anticancer drug to HeLa cells

The present work investigates in vitro the delivery of the anticancer drug mitoxantrone (MTX) to HeLa cancer cells by means of liposomes functionalized with the novel cell penetrating peptide gH625. This hydrophobic peptide enhances the delivery of doxorubicin to the cytoplasm of cancer cells, while the mechanism of this enhancement has not yet been understood. Here, in order to get a better insight into the role of gH625 on the mechanism of liposome-mediated drug delivery, we treated HeLa cells with liposomes functionalized with gH625 and loaded with MTX; liposome were characterized in terms of their physico-chemical properties and drug release kinetics. To quantify the MTX uptake and to study the subcellular drug distribution and interaction, we took advantage of the intrinsic fluorescence of MTX and of the fluorescence-based techniques like fluorescence-activated cell sorting (FACS) and confocal spectral imaging (CSI). gH625 liposomes showed an enhanced staining of the internalized drug is observed mainly in hydrophobic regions of the cytoplasm, where the increased presence of an oxidative metabolite of the drug is observed. MTX delivery with gH625-decorated nanoliposomes enhances the quantity of both the intracellular drug and of its oxidative metabolite and contributes to higher anticancer efficacy of the drug