Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

To identify mechanisms underlying oxaliplatin resistance, a subline of the human gastric adenocarcinoma TSGH cell line, S3, was made resistant to oxaliplatin by continuous selection against increasing drug concentrations. Compared with the parental TSGH cells, the S3 subline showed 58-fold resistance to oxaliplatin; it also displayed 11-, 2-, and 4.7-fold resistance to cis-diammine-dichloroplatinum (II) (CDDP), copper sulphate, and arsenic trioxide, respectively. Interestingly, S3 cells were fourfold more susceptible to 5-fluorouracil-induced cytotoxicity due to downregulation of thymidylate synthase. Despite elevated glutathione levels in S3 cells, there was no alteration of resistant phenotype to oxaliplatin or CDDP when cells were co-treated with glutathione-depleting agent, l-buthionine-(S,R)-sulphoximine. Cellular CDDP and oxaliplatin accumulation was decreased in S3 cells. In addition, amounts of oxaliplatin- and CDDP–DNA adducts in S3 cells were about 15 and 40% of those seen with TSGH cells, respectively. Western blot analysis showed increased the expression level of copper transporter ATP7A in S3 cells compared with TSGH cells. Partial reversal of the resistance of S3 cells to oxaliplatin and CDDP was observed by treating cell with ATP7A-targeted siRNA oligonucleotides or P-type ATPase-inhibitor sodium orthovanadate. Besides, host reactivation assay revealed enhanced repair of oxaliplatin- or CDDP-damaged DNA in S3 cells compared with TSGH cells. Together, our results show that the mechanism responsible for oxaliplatin and CDDP resistance in S3 cells is the combination of increased DNA repair and overexpression of ATP7A. Downregulation of thymidylate synthase in S3 cells renders them more susceptible to 5-fluorouracil-induced cytotoxicity. These findings could pave ways for future efforts to overcome oxaliplatin resistance

Segmented flow generator for serial crystallography at the European X-ray free electron laser

Serial femtosecond crystallography (SFX) with X-ray free electron lasers (XFELs) allows structure determination of membrane proteins and time-resolved crystallography. Common liquid sample delivery continuously jets the protein crystal suspension into the path of the XFEL, wasting a vast amount of sample due to the pulsed nature of all current XFEL sources. The European XFEL (EuXFEL) delivers femtosecond (fs) X-ray pulses in trains spaced 100 ms apart whereas pulses within trains are currently separated by 889 ns. Therefore, continuous sample delivery via fast jets wastes >99% of sample. Here, we introduce a microfluidic device delivering crystal laden droplets segmented with an immiscible oil reducing sample waste and demonstrate droplet injection at the EuXFEL compatible with high pressure liquid delivery of an SFX experiment. While achieving ~60% reduction in sample waste, we determine the structure of the enzyme 3-deoxy-D-manno-octulosonate-8-phosphate synthase from microcrystals delivered in droplets revealing distinct structural features not previously reported

The impact of Populist Radical Right Parties on socio-economic policies

Because they are now members of most Western European parliaments, Populist Radical Right Parties (PRRPs) have the potential to influence the formulation of socio-economic policies. However, scholarly attention so far has nearly exclusively focussed on the impact of PRRPs on what is considered their core issue', that is migration policy. In this paper, we provide the first mixed methods comparative study of the impact of PRRPs on redistributive and (de-)regulative economic policies. Combining quantitative data with qualitative case studies, our results show that the participation of PRRPs in right-wing governments has noteworthy implications for socio-economic policies. Due to the heterogeneous constituencies of PRRPs, these parties not only refrain from welfare state retrenchment but are also less inclined to engage in deregulation compared with right-wing governments without PRRP participation

DOSAGE NÉPHÉLO-COLORIMÉTRIQUE DU LACTOSE

International audienc

A Flow Adsorption Microcalorimetry-Logistic Modeling Approach for Assessing Heterogeneity of Brønsted-Type Surfaces: Application to Pyrogenic Organic Materials

Biogeochemical functioning of oxides and pyrogenic organic matter (<i>py</i>OM) are greatly influenced by surface and deprotonation characteristics. We present an energetics-based, logistic modeling approach for quantifying surface homogeneity (ϕ_surf) and surface acidity (<i>p</i>K_{<i>a</i>, surf}) for Brønsted-type surfaces. The ϕ_<i>surf</i>, <i>p</i>K_{<i>a</i>, surf} and associated deprotonation behavior of <i>py</i>OM were quantified across feedstock (honey mesquite, HM; pine, PI; cord grass, CG) and heat-treatment-temperatures (HTT; 200–650 °C). At HTT200, lower ϕ_surf [HM (0.86) > PI (0.61) > CG (0.42)] and higher <i>p</i>K_{<i>a</i>, surf} [CG (4.4) > PI (4.2) > HM (4.1)] for CG indicated higher heterogeneity and lower acidity for Brønsted-type surface moieties on grass versus wood <i>py</i>OM. Surface acidity of CG increased at HTT550/650 °C with no effect on ϕ_surf; while the surface heterogeneity of both wood <i>py</i>OMs increased, the acidity of HM increased and that of PI decreased. Despite different HTT-induced ϕ_surf and <i>p</i>K_{<i>a</i>, surf} trajectories, the deprotonation range for all <i>py</i>OM was pH = pKa,surf±2ϕsurf. Therefore, higher heterogeneity <i>py</i>OMs deprotonate more readily at lower pH, over a wider range and (for similar <i>p</i>K_{<i>a</i>,surf} and cation exchange capacity) are better cation/metal binding surfaces at pH<<i>p</i>K_{<i>a</i>,surf}. The approach also facilitates the evaluation of surface and deprotonation characteristics for mixtures and more complex surfaces

In vitro selective cytotoxicities of rebeccamycin analogues toward various tumor cell lines: influence of the substituents

Poste