11 research outputs found

    C6 tumour growth is slowed by MLN0518 treatment.

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    <p>The growth rate of tumours in mice treated with 20 mg/kg MLN0518 was significantly slower than tumours in vehicle treated mice over 10 days. Tumour doubling times were calculated on an individual tumour basis (n = 15 per treatment group). Mean ±1s.e.m.</p

    Summary of the quantitative MRI biomarkers acquired from intrinsic susceptibility MRI of C6 xenografts in mice treated with vehicle or 20 mg/kg MLN0518 for 10 days.

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    <p>Mean of median R<sub>2</sub>* and ΔR<sub>2</sub>* values from each tumour ± 1s.e.m. (n≥5 per treatment group). The proportion of voxels in which R<sub>2</sub>* changed significantly, either negatively (ΔR<sub>2</sub>* <0) or positively (ΔR<sub>2</sub>* >0), with carbogen breathing are also shown.</p

    Dynamic contrast-enhanced MRI is sensitive to the response of C6 tumours to MLN0518.

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    <p>Representative parametric maps and quantification of initial area under the gadolinium concentration curve (IAUGC) demonstrate a reduction in tumour blood vessel permeability/flow in mice treated with 20 mg/kg MLN0518 for 3 days compared to controls. Mean parameter values from each tumour ± 1s.e.m. (n≥6 per treatment group), * p<0.05.</p

    Histological assessment of tumour response to MLN0518.

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    <p><b>A.</b> Tumour sections stained for the perfusion marker Hoechst 33342 (blue), endothelial marker CD31 (red) and pimonidazole adduct formation, a marker of hypoxia (green) demonstrate that the hypoxic area was lower in tumours treated with 20 mg/kg MLN0518 for 10 days than vehicle treated controls. The percentage of the total vessels perfused and the overall perfused vessel area was also lower in treated versus control tumours. Representative composite images are shown. <b>B.</b> Alpha smooth muscle actin (α-SMA) immunohistochemistry demonstrates a significant reduction in α-SMA positive blood vessels in MLN0518 treated tumours compared to controls. Magnification ×200.</p

    Diffusion-weighted and susceptibility contrast MRI of C6 tumours treated with MLN0518.

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    <p>Parametric maps of apparent diffusion coefficient (ADC, top panel), fractional blood volume (fBV, middle panel) and vessel size index (R<sub>v</sub>, bottom panel) from C6 xenografts in mice treated with vehicle or 20 mg/kg MLN0518 for 10 days show no clear differences between vehicle and treated tumours. Representative maps are shown.</p

    A representation of the fate of hyperpolarized [1-<sup>13</sup>C]pyruvate (P) that is injected into a system with input function <i>P<sub>in</sub></i>(<i>t</i>).

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    <p>Observable <sup>13</sup>C signals originating from [1-<sup>13</sup>C]pyruvate are indicated in red. The schematic shows the transport of pyruvate into a cell, facilitated by MCT1 transporters, and its conversion to other metabolites. Solid lines correspond to the cell membrane and dashed lines to the mitochondrial membrane. is the effective relaxation rate of the hyperpolarized signal for metabolite <i>i</i>. Conversion to metabolites [1-<sup>13</sup>C]lactate (L), [1-<sup>13</sup>C]alanine (A), and [1-<sup>13</sup>C]bicarbonate (B) occur with reaction rates (<i>k</i>), and enzymes that catalyze reactions are shown. <i>k<sub>EL</sub></i> and <i>k<sub>LE</sub></i> are the rates of lactate transport into and out of the cell, governed by the MCT4 transporters. Entry of pyruvate into the TCA cycle results in conversion of the 1-<sup>13</sup>C label to CO<sub>2</sub> and then to bicarbonate. Acetyl-CoA is not seen owing to the [1-<sup>13</sup>C] label of pyruvate being utilized in the formation of CO<sub>2</sub>. The grey box indicates the terms that need to be considered for the AUC ratio analysis method when the reaction of interest is pyruvate-lactate conversion, whereas kinetic modeling requires fitting of all terms depicted here, except for acetyl-CoA.</p

    Representative dynamic spectra from a WM266.4 melanoma cell suspension.

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    <p>Kinetic modeling was performed using a 2-site (left) and 3-site (right) model. Total (T), intracellular (I) and extracellular (E) [1-<sup>13</sup>C]lactate fits, derived from the 3-site kinetic model are shown. Residuals between the data and the model are shown (central row). The concentration curves (bottom) were generated by correcting data for hyperpolarized relaxation.</p

    <i>In vitro</i> AUC ratios plotted against forward rate constant (<i>k<sub>PL</sub></i>), derived from the 2-site model.

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    <p>Data is normalized to initial pyruvate concentration and cell number. An excellent correlation is observed between AUC ratio and <i>k<sub>PL</sub></i> across a range of cell lines. Clustering between cell types can also be seen, and spread between data points of the same cell type tends to be in the direction of the best-fit line.</p
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