Predictive Modeling of Drug Response in Non-Hodgkin's Lymphoma.

We combine mathematical modeling with experiments in living mice to quantify the relative roles of intrinsic cellular vs. tissue-scale physiological contributors to chemotherapy drug resistance, which are difficult to understand solely through experimentation. Experiments in cell culture and in mice with drug-sensitive (Eµ-myc/Arf-/-) and drug-resistant (Eµ-myc/p53-/-) lymphoma cell lines were conducted to calibrate and validate a mechanistic mathematical model. Inputs to inform the model include tumor drug transport characteristics, such as blood volume fraction, average geometric mean blood vessel radius, drug diffusion penetration distance, and drug response in cell culture. Model results show that the drug response in mice, represented by the fraction of dead tumor volume, can be reliably predicted from these inputs. Hence, a proof-of-principle for predictive quantification of lymphoma drug therapy was established based on both cellular and tissue-scale physiological contributions. We further demonstrate that, if the in vitro cytotoxic response of a specific cancer cell line under chemotherapy is known, the model is then able to predict the treatment efficacy in vivo. Lastly, tissue blood volume fraction was determined to be the most sensitive model parameter and a primary contributor to drug resistance

Regression of Inflammation in Atherosclerosis by the LXR Agonist R211945 A Noninvasive Assessment and Comparison With Atorvastatin

OBJECTIVES The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945. BACKGROUND R211945 induces reversal cholesterol transport and modulates inflammation in atherosclerotic plaques. We aimed to characterize with F-18-fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography (CT) and dynamic contrast-enhanced cardiac magnetic resonance (DCE-CMR) inflammation and neovascularization, respectively, in atherosclerotic plaques with R211945 treatment compared with atorvastatin treatment and a control. METHODS Twenty-one atherosclerotic New Zealand white rabbits were divided into 3 groups (control, R211945 [3 mg/kg orally], and atorvastatin [3 mg/kg orally] groups). All groups underwent F-18-FDG-PET/CT and DCE-CMR at baseline and at 1 and 3 months after treatment initiation. Concomitantly, serum metabolic parameters and histology were assessed. For statistical analysis, continuous DCE-CMR and PET/CT outcomes were modeled as linear functions of time by using a linear mixed model, whereas the histological data, animal characteristics data, and nonlinear regression imaging data were analyzed with a 2-tailed Student t test. RESULTS F-18-FDG-PET/CT detected a decrease in mean and maximum standard uptake values (SUV) over time in the R211945 group (both p = 0.001), indicating inflammation regression. The atorvastatin group displayed no significant change (p = 0.371 and p = 0.600, respectively), indicating no progression or regression. The control group demonstrated an increase in SUV (p = 0.01 and p = 0.04, respectively), indicating progression. There was a significant interaction between time and group for mean and maximum SUV (p = 0.0003 and p = 0.0016, respectively). DCE-CMR detected a trend toward difference (p = 0.06) in the area under the curve in the atorvastatin group, suggesting a decrease in neovascularization. There was no significant interaction between time and group (p = 0.6350 and p = 0.8011, respectively). Macrophage and apolipoprotein B immunoreactivity decreased in the R211945 and atorvastatin groups (p <0.0001 and p = 0.0004, respectively), and R211945 decreased oxidized phospholipid immunoreactivity (p = 0.02). CONCLUSIONS Noninvasive imaging with F-18-FDG-PET/CT and DCE-CMR and histological analysis demonstrated significant anti-inflammatory effects of the LXR agonist R211945 compared with atorvastatin. The results suggest a possible role for LXR agonists in the treatment of atherosclerosis. (J Am Coll Cardiol Img 2012; 5: 819-28) (C) 2012 by the American College of Cardiology Foundatio

Regression of Inflammation in Atherosclerosis by the LXR Agonist R211945 A Noninvasive Assessment and Comparison With Atorvastatin

OBJECTIVES: The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945. BACKGROUND: R211945 induces reversal cholesterol transport and modulates inflammation in atherosclerotic plaques. We aimed to characterize with (18)F-fluorodeoxyglucose (FDG)–positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced cardiac magnetic resonance (DCE-CMR) inflammation and neovascularization, respectively, in atherosclerotic plaques with R211945 treatment compared with atorvastatin treatment and a control. METHODS: Twenty-one atherosclerotic New Zealand white rabbits were divided into 3 groups (control, R211945 [3 mg/kg orally], and atorvastatin [3 mg/kg orally] groups). All groups underwent (18)F-FDG–PET/CT and DCE-CMR at baseline and at 1 and 3 months after treatment initiation. Concomitantly, serum metabolic parameters and histology were assessed. For statistical analysis, continuous DCE-CMR and PET/CT outcomes were modeled as linear functions of time by using a linear mixed model, whereas the histological data, animal characteristics data, and nonlinear regression imaging data were analyzed with a 2-tailed Student t test. RESULTS: (18)F-FDG–PET/CT detected a decrease in mean and maximum standard uptake values (SUV) over time in the R211945 group (both p = 0.001), indicating inflammation regression. The atorvastatin group displayed no significant change (p = 0.371 and p = 0.600, respectively), indicating no progression or regression. The control group demonstrated an increase in SUV (p = 0.01 and p = 0.04, respectively), indicating progression. There was a significant interaction between time and group for mean and maximum SUV (p = 0.0003 and p = 0.0016, respectively). DCE-CMR detected a trend toward difference (p = 0.06) in the area under the curve in the atorvastatin group, suggesting a decrease in neovascularization. There was no significant interaction between time and group (p = 0.6350 and p = 0.8011, respectively). Macrophage and apolipoprotein B immunoreactivity decreased in the R211945 and atorvastatin groups (p < 0.0001 and p = 0.0004, respectively), and R211945 decreased oxidized phospholipid immunoreactivity (p = 0.02). CONCLUSIONS: Noninvasive imaging with (18)F-FDG–PET/CT and DCE-CMR and histological analysis demonstrated significant anti-inflammatory effects of the LXR agonist R211945 compared with atorvastatin. The results suggest a possible role for LXR agonists in the treatment of atherosclerosis

Mathematical model predicts lymphoma tumor death due to chemotherapy drug treatment.

<p>Comparison of histopathology measurements with mathematical model predictions (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129433#pone.0129433.e003" target="_blank">Eq 2</a>, solid lines) based on estimates of two parameters <i>r</i>_<i>b</i> / <i>L</i> and <math><mrow><msubsup><mi>f</mi><mrow>kill</mrow>M</msubsup></mrow></math>. Data points for drug-resistant cells (blue) were scaled by 3.5 (see <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129433#pone.0129433.g002" target="_blank">Fig 2A</a></b>) to be comparable with data for drug-sensitive cells (green). Obtained <i>R</i>² = 0.86; estimated <math><mrow><msubsup><mi>f</mi><mrow>kill</mrow>M</msubsup></mrow></math> = 0.25, and <i>r</i>_<i>b</i> / <i>L</i> = 0.068. Diffusion distance of drug from the vessels (40 ± 20 μm) was assumed in the best case not to exceed half that of O₂. Each point represents measurements from one tumor Set; 5 data points for the drug-sensitive cell line (green) and 6 data points for the drug-resistant cell line (blue).</p

Average of tumor measurements from IHC used for model calibration.

<p>Average of tumor measurements from IHC used for model calibration.</p

Necrotic cell fraction in murine lymphoma tumors after treatment with Dox.

<p>Data are shown for tumor slices S1 through S5. Most of the necrosis is a result of the drug treatment since necrosis measured in untreated tumors was negligible (<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129433#pone.0129433.t002" target="_blank">Table 2</a></b>). Note that the drug-sensitive tumors shrank in size after treatment and thus had one less histological slice than the drug-resistant tumors (to account for this, two slices of the drug-resistant tumor are included in the central region S3, i.e., five total slices for <i>Eμ-myc/Arf-/-</i> and six for <i>Eμ-myc/p53-/-</i>). All error bars represent standard deviation from at least n = 3 measurements in each section. Asterisks show level of statistical significance determined by student’s <i>t</i>-test with α = 0.05 (asterisk, <i>P</i> < 0.05).</p

Whole-tumor measurement of lymphoma characteristics.

<p>Measurements from the IHC data after treatment with Dox shows cell fractions for: (<b>A</b>) apoptosis, (<b>B</b>) endothelium, (<b>C</b>) hypoxia, (<b>D</b>) proliferation. Note that the drug-sensitive tumors shrank in size after treatment and thus had one less histological slice than the drug-resistant tumors in the middle Set (S3). Error bars represent standard deviation (n = 3 regions of interest per slice).</p

Sensitivity analysis results.

<p>Plots of absolute values of sensitivity coefficients for the three parameters for <b>(A)</b> the drug-sensitive cell line, <i>Eμ-myc/Arf-/-</i> and <b>(B)</b> the drug-resistant cell line, <i>Eμ-myc/p53-/-</i>. The range of variation for each parameter is listed in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129433#pone.0129433.s001" target="_blank">S1 Table</a></b>. <i>S</i> represents sensitivity coefficient.</p