Insulin-like growth factor binding protein-3 has dual effects on gastrointestinal stromal tumor cell viability and sensitivity to the anti-tumor effects of imatinib mesylate in vitro

<p>Abstract</p> <p>Background</p> <p>Imatinib mesylate has significantly improved survival and quality of life of patients with gastrointestinal stromal tumors (GISTs). However, the molecular mechanism through which imatinib exerts its anti-tumor effects is not clear. Previously, we found up-regulation of insulin-like growth factor binding protein-3 (IGFBP3) expression in imatinib-responsive GIST cells and tumor samples. Because IGFBP3 regulates cell proliferation and survival and mediates the anti-tumor effects of a number of anti-cancer agents through both IGF-dependent and IGF-independent mechanisms, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 levels in two imatinib-responsive GIST cell lines and observed cell viability after drug treatment.</p> <p>Results</p> <p>In the GIST882 cell line, imatinib treatment induced endogenous IGFBP3 expression, and IGFBP3 down-modulation by neutralization or RNA interference resulted in partial resistance to imatinib. In contrast, IGFBP3 overexpression in GIST-T1, which had no detectable endogenous IGFBP3 expression after imatinib, had no effect on imatinib-induced loss of viability. Furthermore, both the loss of IGFBP3 in GIST882 cells and the overexpression of IGFBP3 in GIST-T1 cells was cytotoxic, demonstrating that IGFBP3 has opposing effects on GIST cell viability.</p> <p>Conclusion</p> <p>This data demonstrates that IGFBP3 has dual, opposing roles in modulating GIST cell viability and response to imatinib <it>in vitro</it>. These preliminary findings suggest that there may be some clinical benefits to IGFBP3 therapy in GIST patients, but further studies are needed to better characterize the functions of IGFBP3 in GIST.</p

FORESAIL-1 cubesat mission to measure radiation belt losses and demonstrate de-orbiting

Abstract Today, the near-Earth space is facing a paradigm change as the number of new spacecraft is literally sky-rocketing. Increasing numbers of small satellites threaten the sustainable use of space, as without removal, space debris will eventually make certain critical orbits unusable. A central factor affecting small spacecraft health and leading to debris is the radiation environment, which is unpredictable due to an incomplete understanding of the near-Earth radiation environment itself and its variability driven by the solar wind and outer magnetosphere. This paper presents the FORESAIL-1 nanosatellite mission, having two scientific and one technological objectives. The first scientific objective is to measure the energy and flux of energetic particle loss to the atmosphere with a representative energy and pitch angle resolution over a wide range of magnetic local times. To pave the way to novel model - in situ data comparisons, we also show preliminary results on precipitating electron fluxes obtained with the new global hybrid-Vlasov simulation Vlasiator. The second scientific objective of the FORESAIL-1 mission is to measure energetic neutral atoms (ENAs) of solar origin. The solar ENA flux has the potential to contribute importantly to the knowledge of solar eruption energy budget estimations. The technological objective is to demonstrate a satellite de-orbiting technology, and for the first time, make an orbit manoeuvre with a propellantless nanosatellite. FORESAIL-1 will demonstrate the potential for nanosatellites to make important scientific contributions as well as promote the sustainable utilisation of space by using a cost-efficient de-orbiting technology.Peer reviewe

Roles of insulin-like growth factor binding protein-3 in gastrointestinal stromal tumors

Imatinib mesylate, a selective inhibitor of KIT, PDGFR, and Abl kinases, has shown significant success as a therapy for patients with advanced gastrointestinal stromal tumors (GISTs). However, the underlying mechanisms of imatinib-induced cytotoxicity are not well understood. Using gene expression profiling and real-time PCR for target validation, we identified insulin-like growth factor binding protein-3 (IGFBP3) to be to be up-regulated after imatinib treatment in imatinib-sensitive GISTs. IGFBP3 is a multifunctional protein that regulates cell proliferation and survival and mediates the effects of a variety of anti-cancer agents through IGF-dependent and IGF-independent mechanisms. Therefore, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 protein levels in two KIT mutant, imatinib-sensitive GIST cell lines and assessed the resultant changes in cell viability, survival, and imatinib sensitivity. In GIST882 cells, endogenous IGFBP3 was required for cell viability. However, inhibiting imatinib-induced IGFBP3 up-regulation by RNA interference or neutralization resulted in reduced drug sensitivity, suggesting that IGFBP3 sensitizes GIST882 cells to imatinib. GIST-T1 cells, on the other hand, had no detectable levels of endogenous IGFBP3, nor did imatinib induce IGFBP3 up-regulation, in contrast to our previous findings. IGFBP3 overexpression in GIST-T1 cells reduced viability but did not induce cell death; rather, the cells became polyploid through a mechanism that may involve attenuated Cdc20 expression and securin degradation. Moreover, IGFBP3 overexpression resulted in a loss of KIT activation and decreased levels of mature KIT. Consistent with this, GIST-T1 cells overexpressing IGFBP3 were less sensitive to imatinib. Furthermore, as neither GIST882 cells nor GIST-T1 cells expressed detectable levels of IGF-1R, IGFBP3 is likely not exerting its effects by modulating IGF signaling through IGF-1R or IR/IGF-1R hybrid receptors in these cell lines. Collectively, these findings demonstrate that IGFBP3 has cell-dependent effects and would, therefore, not be an ideal marker for identifying imatinib response in GISTs. Nevertheless, our results provide preliminary evidence that IGFBP3 may have some therapeutic benefits in GISTs

Étude du mécanisme de piégeage dans un eutectique lamellaire

In this paper we calculate, in the London approximation, the magnetic structure of a vortex in a material the superconducting parameters of which are varying along a particular direction. This leads to the determination of an intrinsic pinning force due to the inhomogeneity of the material. Then the authors make use of their result to calculate the critical current in a lamellar eutectic Pb-Sn.Les auteurs ont calculé, dans l'approximation de London, la répartition du champ magnétique d'un vortex situé dans un milieu où les paramètres supraconducteurs sont variables suivant une direction. On peut ainsi calculer une force de piégeage intrinsèque liée à l'inhomogénéité du matériau. Ce calcul est ensuite appliqué à la détermination du courant critique dans un eutectique lamellaire Pb-Sn

Mécanismes de piégeage et effets de proximité dans des échantillons monograins d'alliages eutectiques lamellaires orientés

Magnetization measurements, carried out on monograined bulk samples of a lamellar Pb-Sn eutectic alloy for lamellar spacings aE in the range 1.5 μm to 5 μm, have shown that the Sn lamellae remain diamagnetic up to 7 K, which proves the existence of a very strong proximity effect. The magnetization curves can be explained assuming a preponderant pinning at the numerous Sn/Pb interfaces. The Ic(H) curves obtained on Pb-Sn or ln2Bi-In 20 μm thick films having a perfect lamellar structure (1.5 μm < aE < 10 μm ; I // lamellae ; H // lamellae and I) exhibit a peculiar behaviour in the small-field range : Ic remains constant for fields increasing up to a certain value H1 (∼ 50 Oe at 4.2 K). This behaviour can be related to the successive potential barriers, due to the interfaces, for the vortices. The major role of these interfaces is confirmed by the study of the bulk pinning force Fp(b) ∝ b½(1 - b), b = H/Hc2 ; this peculiar b dependence is indeed typical of pinning at N/S boundaries.Des mesures d'aimantation réalisées sur des échantillons massifs monograins de l'eutectique lamellaire Pb-Sn, de périodes eutectiques aE comprises entre 1,5 μm et 5 μm, montrent que les lamelles Sn restent diamagnétiques jusqu'à 7 K, (Tc (Sn massif) = 3,7 K), donc qu'il existe un très fort effet de proximité. L'allure générale des courbes d'aimantation peut s'expliquer en supposant que le principal mécanisme de piégeage est relié aux interfaces Sn/Pb. Les courbes Ic(H) obtenues pour les systèmes Pb-Sn et In2Bi-In sur des films minces à structure parfaite (épaisseur 20 μm; 1,5 μm < aE < 10 μm ; I // lamelles, H // lamelles et I) présentent un comportement particulier aux champs faibles : Ic reste constant pour H compris entre 0 et une certaine valeur H1 (∼ 50 Oe à 4,2 K). Ce comportement peut être relié à l'existence des barrières de potentiel induites par les interfaces que les lignes de flux ont à franchir successivement. Le rôle prépondérant joué par ces interfaces est confirmé par l'étude de la force volumique de piégeage Fp(b) ∝ b½(1- b) avec b = H/Hc2 ; cette dépendance particulière en b est en effet caractéristique du piégeage par des interfaces N/S

SO2 addition to alkenes: a new formation mechanism of organosulfates in the atmosphere

SSCI-VIDE+CARE+MPI:SPR:CGOInternational audienceSecondary organic aerosol (SOA) formation and composition have received increasing attention in the last years due to their impact on climate, air quality and human health. Organosulfates have been increasingly and widely detected in tropospheric particles and has been suggested to arise as side products from SOA production (Tolocka, 2012). Therefore, they have also been identified as SOA tracers (Zhang, 2012). Originally, the production of organosulfates was explained by the esterification reaction of alcohols, but this reaction in atmosphere is kinetically negligible. Other formation pathways have been suggested such as hydrolysis of peroxides and reaction of organic matter with sulfite and sulfate radical anions (SO3-", SO4-") (Nozière, 2010), but it remains unclear if these can completely explain atmospheric organo-sulfur aerosol loading.Figure 1. A possible formation pathway of organosulfates in atmosphere.We have investigated a new formation pathway of organo-sulfur compounds: the addition of SO2 to alkenes (Figure 1). The sulphur dioxide addition to double bond can occur with different mechanisms (photoreaction, ene-reaction, cycloaddition) (Jones, 1974; Vogel, 2007; Lan, 2011). Differently to ozone, sulphur dioxide is a 1,3-dipole with a strong zwitterion character and the most favourable cycloaddition to double bond is a 2+2 addition. On the other hand, O3 adds to alkenes by a well-known 3+2 cycloaddition (Lan, 2011). In order to better understand this reaction and its environmental impact we have studied the reactivity of SO2 with respect to different alkenes (cis/trans, terminal/internal alkenes). The experiments were carried out at the solid (or liquid)-gas interface. A custom built coated-wall flow tube reactor was developed to control relativity humidity, SO2 concentration, temperature and gas flow rate. The uptake coefficients of SO2 on organic films were calculated and resulting products were identified using liquid chromatography coupled with an orbitrap mass spectrometer (LC-HR-MS).The results show that surprisingly SO2 reacts efficiently with alkenes to form organulfates. For examples, the experiments carried out on 1-dodecene highlighted a rapid SO2 uptake and the efficient formation of C12H24O4S, which could be a cyclic organosulfate (Figure 1). Moreover, we have observed that the reaction is acid-catalysed, a faster uptake of SO2 is observed in presence of an acid function. Indeed, it was observed that unsaturated acids (oleic acid) are very sensitive to SO2 addition. These preliminary results tend to elucidate the role of organo-sulfates interfacial chemistry, as a significant pathway for understanding of atmospheric SOA formation

Reactions of SIV species with organic compounds: formation mechanisms of organo-sulfur derivatives in atmospheric aerosols

@ CARE+MPI:JSH:YDU:SPR:CGOInternational audienceSecondary organic aerosol (SOA) have an important impact on climate, air quality and human health. However the chemical reactions involved in their formation and growth are not fully understood or well-constrained in climate models. It is well known that inorganic sulfur (mainly in oxidation states (+IV) and (+VI)) plays a key role in aerosol formation, for instance sulfuric acid is known to be a good nucleating gas. In addition, acid-catalyzed heterogeneous reactions of organic compounds has shown to produce new particles, with a clear enhancement in the presence of ozone (Iinuma 2013). Organosulfates have been detected in tropospheric particles and aqueous phases, which suggests they are products of secondary organic aerosol formation process (Tolocka 2012). Originally, the production of organosulfates was explained by the esterification reaction of alcohols, but this reaction in atmosphere is kinetically negligible. Other formation pathways have been suggested such as hydrolysis of peroxides and reaction of organic matter with sulfite and sulfate radical anions (SO3-•, SO4-•) (Nozière 2010), but it remains unclear if these can completely explain atmospheric organo-sulfur aerosol loading.To better understand the formation of organo-sulfur compounds, we started to investigate the reactivity of SIV species (SO2 and SO32-) with respect to specific functional groups (organic acids and double bonds) on atmospherically relevant carboxylic acids and alkenes. The experiments were carried out in the homogeneous aqueous phase and at the solid-gas interface. A custom built coated-wall flow tube reactor was developed to control relativity humidity, SO2 concentration, temperature and gas flow rate. Homogeneous and heterogeneous reaction kinetics were measured and resulting products were identified using liquid chromatography coupled with an orbitrap mass spectrometer (LC-HR-MS). The experiments were performed with and without the presence of ozone in order to evaluate any impact on the SIV oxidation and product formation. Preliminary results reveal that oxidation of SIV species can occur under a variety of atmospherically relevant conditions. Furthermore, LC-HR-MS analysis confirms the formation of organo-sulfur compounds that could derive from sulfate and/or the sulfite radical anion. These results elucidate the role of organo-sulfates aqueous and interfacial chemistry, important for our scientific understanding of atmospheric SOA formation

SDW VECTOR AND AMPLITUDE IN (TMTTF)2 SbF6 AND (TMTST)2 ClO4 BY NMR AND ANISOTROPY BY EPR

By NMR, the nesting vector Q and amplitude d of the SDW state in the organic conductors with sulfur (TMTTF)2 SbF6 and selenium (TMTST)2 ClO4 are respectively Q = -0.05b* and 0.12b* and d = 0.18 and 0.12 µB. By EPR the, up to this date, unknown orientation of easy axis has been determined toward crystal axis a in agreement with the theory of anisotropy

reactions of siv species with organic compounds: formation mechanisms of organo-sulfur derivatives in atmospheric aerosols

SSCI-VIDE+CARE+MPI:SPR:SRS:CGONational audienceSecondary organic aerosol (SOA) have an important impact on climate, air quality and human health. However the chemical reactions involved in their formation and growth are not fully understood or well-constrained in climate models. It is well known that inorganic sulfur (mainly in oxidation states (+IV) and (+VI)) plays a key role in aerosol formation, for instance sulfuric acid is known to be a good nucleating gas. In addition, acid-catalyzed heterogeneous reactions of organic compounds has shown to produce new particles, with a clear enhancement in the presence of ozone (Iinuma 2013). Organosulfates have been detected in tropospheric particles and aqueous phases, which suggests they are products of secondary organic aerosol formation process (Tolocka 2012). Originally, the production of organosulfates was explained by the esterification reaction of alcohols, but this reaction in atmosphere is kinetically negligible. Other formation pathways have been suggested such as hydrolysis of peroxides and reaction of organic matter with sulfite and sulfate radical anions (SO3-â¢, SO4-â¢) (Nozière 2010), but it remains unclear if these can completely explain atmospheric organo-sulfur aerosol loading.To better understand the formation of organo-sulfur compounds, we started to investigate the reactivity of SIV species (SO2 and SO32-) with respect to specific functional groups (organic acids and double bonds) on atmospherically relevant carboxylic acids and alkenes. The experiments were carried out in the homogeneous aqueous phase and at the solid-gas interface. A custom built coated-wall flow tube reactor was developed to control relativity humidity, SO2 concentration, temperature and gas flow rate. Homogeneous and heterogeneous reaction kinetics were measured and resulting products were identified using liquid chromatography coupled with an orbitrap mass spectrometer (LC-HR-MS). The experiments were performed with and without the presence of ozone in order to evaluate any impact on the SIV oxidation and product formation. Preliminary results reveal that oxidation of SIV species can occur under a variety of atmospherically relevant conditions. Furthermore, LC-HR-MS analysis confirms the formation of organo-sulfur compounds that could derive from sulfate and/or the sulfite radical anion. These results elucidate the role of organo-sulfates aqueous and interfacial chemistry, important for our scientific understanding of atmospheric SOA formation