Multivariate statistical analysis of the MR spectra.

<p>Scores plots (PC1 vs PC2) obtained by performing PCA on the MR spectra acquired on polar extracts (8 replicates per treatment condition) of (A) both PC3 and LNCaP cells, and individual (B) PC3 and (C) LNCaP prostate cancer cells following a 48-hrs treatment with DMSO (solvent control, black), LY294002 (green) and 17AAG (red).</p

Common metabolic changes in prostate and breast cancer cells following drug treatment.

<p>Quantification of selected metabolites (shown as percent of control, mean ± standard deviation) from MR spectra acquired on prostate (PC3 and LNCaP, N = 8) and breast (MCF-7, N = 3) cancer cell lines following 48 hours of treatment with (A) LY294002 or (B) 17AAG. *: p<0.05; **: p<0.005; ***: p<0.0005. Pcholine: phosphocholine.</p

Multivariate statistical analysis of the MR spectra.

<p>Loadings plots (on PC1) obtained by performing the PCA comparisons on the MR spectra of control and one treatment per analysis (as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026155#pone-0026155-g003" target="_blank">Fig. 3</a>) acquired on polar extracts of PC3 (black line) and LNCaP (red line) prostate cancer cells following 48 hours of treatment with (A) LY294002 or (B) 17AAG. Enlarged sections of the loadings plots represent the region of 1.9–4.1 ppm. Ala: alanine; Asn: asparagine; Cho: choline; Cit: citrate; Cre: creatine; Fum: fumarate; Glc: glucose; Gln: glutamine; Gly: glycine; GPcho: glycerophosphocholine; GSH: glutathione; His: histidine; Ile: isoleucine; Lac: lactate; Leu: leucine; m-Ino: myo-inositol; Pcho: phosphocholine; Pcre: phosphocreatine; Phe: phenylalanine; Tau: taurine; Tyr: tyrosine; Val: valine, UDPS: UDP sugars.</p

Accumulation of citrate following treatment with 17AAG in PC3 prostate cancer cells.

<p>Enlarged section (2.49 – 2.72 ppm) of the MR spectra acquired on polar extracts of PC3 cells following 48 hours of treatment with DMSO (solvent control, black), LY294002 (green) and 17AAG (red). Spectra were normalized according to the probabilistic quotient normalization method.</p

Inhibition of target signaling pathways in cancer cells following drug treatment.

<p>Schematic of signaling pathways targeted by LY294002 and 17AAG and Western blots showing modulation of p-4E-BP1 and c-Raf (β-actin as loading control) levels following administration of DMSO (solvent control; C), LY294002 (L) or 17AAG (A).</p

Multivariate statistical analysis of the MR spectra.

<p>Scores plots (PC1 vs PC2) obtained by performing PCA on the MR spectra acquired on polar extracts (8 replicates per treatment condition) of PC3 and LNCaP prostate cancer cells. Control samples were compared to samples treated for 48 hours with either LY294002 ((A) for PC3 and (C) for LNCaP cells) or 17AAG ((B) for PC3 and (D) for LNCaP cells).</p

Supplemental_Material_for_Three-dimensional_Co-culture_by_Lu_et_al – Supplemental material for Three-Dimensional Leukemia Co-Culture System for In Vitro High-Content Metabolomics Screening

Supplemental material, Supplemental_Material_for_Three-dimensional_Co-culture_by_Lu_et_al for Three-Dimensional Leukemia Co-Culture System for In Vitro High-Content Metabolomics Screening by Xiyuan Lu, Alessia Lodi, Marina Konopleva and Stefano Tiziani in SLAS Discovery</p

Additional file 1: of Serum metabolomic profiling predicts synovial gene expression in rheumatoid arthritis

Table S1. Baseline clinical characteristics of patients with rheumatoid arthritis. Table S2. Mean and standard deviation (SD) of synovial biomarker expression. Table S3. Mean and standard deviation (SD) of serum metabolites detected by 1H-NMR (ÎźM). Reference values are from the Human Metabolome Database (HMDB) and were collected via NMR, unless otherwise noted. 1GC/MS; 2HPLC; 3HPLC-fluoroescence; 4ion-exchange chromatography; 5DFI/MS/MS 6unknown. ND, no data available. Metabolites that were upregulated by at least 20% compared to reference values are in green. Metabolites that were downregulated by more than 20% compared to reference values are in red. (DOCX 26 kb

DataSheet_1_The Combined Treatment With the FLT3-Inhibitor AC220 and the Complex I Inhibitor IACS-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells.zip

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a high mortality rate and relapse risk. Although progress on the genetic and molecular understanding of this disease has been made, the standard of care has changed minimally for the past 40 years and the five-year survival rate remains poor, warranting new treatment strategies. Here, we applied a two-step screening platform consisting of a primary cell viability screening and a secondary metabolomics-based phenotypic screening to find synergistic drug combinations to treat AML. A novel synergy between the oxidative phosphorylation inhibitor IACS-010759 and the FMS-like tyrosine kinase 3 (FLT3) inhibitor AC220 (quizartinib) was discovered in AML and then validated by ATP bioluminescence and apoptosis assays. In-depth stable isotope tracer metabolic flux analysis revealed that IACS-010759 and AC220 synergistically reduced glucose and glutamine enrichment in glycolysis and the TCA cycle, leading to impaired energy production and de novo nucleotide biosynthesis. In summary, we identified a novel drug combination, AC220 and IACS-010759, which synergistically inhibits cell growth in AML cells due to a major disruption of cell metabolism, regardless of FLT3 mutation status.</p

Additional file 4: of Serum metabolomic profiling predicts synovial gene expression in rheumatoid arthritis

Figure S3. Correlation between serum metabolites and synovial CD19, CD79A, and IgGHC. (TIFF 14826 kb