Individual estimate of Q vs. baseline total bilirubin (with full phase I dataset).

<p>Regression analysis; Q = 11.21 * Bilirubin level+0.7422 (P<0.01).</p

Association of PGx, PK and bilirubin from the phase I dataset.

<p>Flavo-G PK parameter estimates from 27 patients were evaluated for relationships with PGx. Fewer TA repeats in the UGT1A1 promoter were weakly associated with lower flavo-G Cmax (Panel A) and AUC (Panel B). For SLCO1B1, the rs2306283 SNP correlated with flavo-G plasma concentrations (the total time flavo-G plasma concentrations were below 1.5 µM, p = .019; Panel C, one outlier removed). For ABCG2, the rs1564481 SNP was associated with flavo-G AUC (p = .050; Panel D) and the rs2231142 SNP was associated with flavopiridol AUC (p = 0.08, Panel E). The SLCO1B1 rs3829310 minor C allele was associated with higher baseline total bilirubin (p = .011; Panel F). For plots A and B, the x-axis indicates the number of promoter TA repeats for both gene copies (6.7 = 6 and 7 TA repeats; 7 = 7 TA repeats for each gene copy; 7.8 = 7 and 8 TA repeats; 8 = 8 TA repeats for each gene copy).</p

Significant covariate-parameter correlations after inclusion of single genetic covariates.

<p>Comparison of OFV was made between models with single genetic covariates and the base model, using the reduced dataset with deletion of subjects having missing values on each individual genetic covariate. Δ OFV, change in objective function value.</p

List of primers used for cloning, sequencing, and mutagenesis of SLCO1B1.

<p>List of primers used for cloning, sequencing, and mutagenesis of SLCO1B1.</p

Population estimates from final model and bootstrap analysis.

<p>Relative bias,i(%) = (Pbs,i−Pest,i)/Pest,I×100; Pbs,i: mean of parameter i estimate from bootstrap; Pest,i: final parameter i estimate.</p

Uptake of flavopiridol in nonsynonymous polymorphic variants of OATP1B1.

<p>The bar graph indicates means + SD for triplicate determinations of 10 µM flavopiridol uptake rates in MDCK-II cells transfected with empty control vector or vector cloned with the reference or polymorphic SLCO1B1 genes. All incubations were for 10 min. Variants are indicated with respect to their amino acid change; T155P = rs11045819, D130N = rs2306283, V174A = rs4149056. Transport rates were normalized to empty vector control. Differences in uptake rates were compared to the reference OATP1B1 transporter. * p<.05, ** p<0.01, Student's t-test.</p

Uptake of flavopiridol, flavo-G, SN-38 and lenalidomide in OATP1B1 transfected cells.

<p>The bar graph indicates means + SD for triplicate determinations of 10 µM flavopiridol, flavo-G, SN-38 and lenalidomide uptake rates in cell lines (HEK-293 or MDCK-II) transfected with empty control vector or vector cloned with the OATP1B1 gene (SCLO1B1). Incubations with flavo-G were for 30 min., and all other drugs were for 10 min. Transport rates are expressed as percentages normalized to empty vector control. * p<.05, ** p<0.001,Student's t-test.</p

Demographics and baseline labs of patients included in pharmacogenetic analyses (n = 35).

<p>Demographics and baseline labs of patients included in pharmacogenetic analyses (n = 35).</p

LY5 inhibits pSTAT3 in sarcoma cell lines.

<p>(A) The tumor cell lines RH30, EW8, and RD were treated with increasing concentrations of LY5 for 30 minutes. Cell lysates were collected for Western blotting of p-STAT3, total STAT3, and GAPDH. GAPDH was used as loading control. (B-C) The SJSA cell line was serum-starved overnight and then left untreated or treated with LY5 for two hours followed by stimulation with 50 ng/mL of OSM, IL-6, IFN-γ, IFN-α, or IL-4 for 30 minutes prior to collection of cell lysates for Western blotting of p-STAT3, total STAT3 p-STAT1, total STAT1, p-STAT2, p-STAT4, or p-STAT6. GAPDH was used as loading control.</p

Six significant covariate-parameter correlations after inclusion of single demographic or lab covariates.

<p>Comparison of OFV is made between model with single covariate and the base model. Δ OFV, change in objective function value.</p