Equation of state at FAIR energies and the role of resonances

Two microscopic models, UrQMD and QGSM, are used to extract the effective equation of state (EOS) of locally equilibrated nuclear matter produced in heavy-ion collisions at energies from 11.6 AGeV to 160 AGeV. Analysis is performed for the fixed central cubic cell of volume V = 125 fm**3 and for the expanding cell that followed the growth of the central area with uniformly distributed energy. For all reactions the state of local equilibrium is nearly approached in both models after a certain relaxation period. The EOS has a simple linear dependence P/e = c_s**2 with 0.12 < c_s**2 < 0.145. Heavy resonances are shown to be responsible for deviations of the c_s**2(T) and c_s**2(mu_B) from linear behavior. In the T-mu_B and T-mu_S planes the EOS has also almost linear dependence and demonstrates kinks related not to the deconfinement phase transition but to inelastic freeze-out in the system.Comment: SQM2008 proceedings, 6 page

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

A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT

ObjectiveRecently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.MethodsIn the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.ResultsGenome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P&lt;10(-8)) with SNPs in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P&lt;10(-26)) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas.ConclusionThe previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations