Gemcitabine and Arabinosylcytosin Pharmacogenomics: Genome-Wide Association and Drug Response Biomarkers

Cancer patients show large individual variation in their response to chemotherapeutic agents. Gemcitabine (dFdC) and AraC, two cytidine analogues, have shown significant activity against a variety of tumors. We previously used expression data from a lymphoblastoid cell line-based model system to identify genes that might be important for the two drug cytotoxicity. In the present study, we used that same model system to perform a genome-wide association (GWA) study to test the hypothesis that common genetic variation might influence both gene expression and response to the two drugs. Specifically, genome-wide single nucleotide polymorphisms (SNPs) and mRNA expression data were obtained using the Illumina 550K® HumanHap550 SNP Chip and Affymetrix U133 Plus 2.0 GeneChip, respectively, for 174 ethnically-defined “Human Variation Panel” lymphoblastoid cell lines. Gemcitabine and AraC cytotoxicity assays were performed to obtain IC50 values for the cell lines. We then performed GWA studies with SNPs, gene expression and IC50 of these two drugs. This approach identified SNPs that were associated with gemcitabine or AraC IC50 values and with the expression regulation for 29 genes or 30 genes, respectively. One SNP in IQGAP2 (rs3797418) was significantly associated with variation in both the expression of multiple genes and gemcitabine and AraC IC50. A second SNP in TGM3 (rs6082527) was also significantly associated with multiple gene expression and gemcitabine IC50. To confirm the association results, we performed siRNA knock down of selected genes with expression that was associated with rs3797418 and rs6082527 in tumor cell and the knock down altered gemcitabine or AraC sensitivity, confirming our association study results. These results suggest that the application of GWA approaches using cell-based model systems, when combined with complementary functional validation, can provide insights into mechanisms responsible for variation in cytidine analogue response

Thermo-kinetic analysis of Ni–Al intermetallic phase formation in powder system: a case of complex solid-solid reactions

Thermo-kinetic analysis was carried out to determine the kinetics of Ni–Al intermetallic phase formation from powder mixture of Ni and Al. The kinetic data were generated using dynamic temperature program at 5, 10, 15, 20 K min−1 in a differential scanning calorimeter. The phase formation was studied with the help of both qualitative and quantitative powder X-ray diffraction using Rietveld refinement. The activation energy for the reaction was calculated from model-free isoconversional technique employing both differential (Friedman’s method) and integral (Flynn–Wall–Ozawa and Kissinger–Akahira–Sunose method) methods. The result shows that formation of NiAl from elemental powders is multi-step in nature involving Ni2Al3Ni2Al3 as a major intermediate. The appropriate kinetic model for the reaction was evaluated by means of Málek’s method (model selection technique). Šesták Breggren (auto-catalytic model) was found to be in good agreement with the experimental data. The corresponding kinetic parameters and rate expression were determined for the reaction system involving solid–solid reaction between Ni and Al in the powder form.by Sanat Chandra Maiti and Chinmay Ghoro