No abstract

A new molecular dynamics method for calculating free energy profiles for rare events is presented. The new method is based on the creation of an adiabatic separation between a reaction coordinate subspace and the remaining degrees of freedom within a molecular dynamics run. This is achieved by associating with the reaction coordinate(s) a high temperature and large mass, thereby allowing the activated process to occur while permitting the remaining degrees of freedom to respond adiabatically. In this limit, by applying a formal multiple time scale Liouville operator factorization, it can be rigorously shown that the free energy profile is obtained directly from the probability distribution of the reaction coordinate subspace and, therefore, no unbiasing of the configuration space or postprocessing of the output data is required. The new method is applied to a variety of model problems including a two-dimensional free energy surface and its performance tested against free energy calculations using the “blue moon ensemble” approach. The comparison shows that free energy profiles can be calculated with greater ease and efficiency using the new method.

The objective of this study was to establish the repeatability and reproducibility limits of several volume-related PET imagederived indices-namely tumor volume (TV), mean standardized uptake value, total glycolytic volume (TGV), and total proliferative volume (TPV)-relative to those of maximum standardized uptake value (SUV max ), commonly used in clinical practice. Methods: Fixed and adaptive thresholding, fuzzy C-means, and fuzzy locally adaptive Bayesian methodology were considered for TV delineation. Double-baseline 18 F-FDG (17 lesions, 14 esophageal cancer patients) and 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) (12 lesions, 9 breast cancer patients) PET scans, acquired at a mean interval of 4 d and before any treatment, were used for reproducibility evaluation. The repeatability of each method was evaluated for the same datasets and compared with manual delineation. Results: A negligible variability of less than 5% was measured for all segmentation approaches in comparison to manual delineation (5%-35%). SUV max reproducibility levels were similar to others previously reported, with a mean percentage difference of 1.8% 6 16.7% and 20.9% 6 14.9% for the 18 F-FDG and 18 F-FLT lesions, respectively. The best TV, TGV, and TPV reproducibility limits ranged from 221% to 31% and 230% to 37% for 18 F-FDG and 18 F-FLT images, respectively, whereas the worst reproducibility limits ranged from 290% to 73% and 268% to 52%, respectively. Conclusion: The reproducibility of estimating TV, mean standardized uptake value, and derived TGV and TPV was found to vary among segmentation algorithms. Some differences between 18 F-FDG and 18 F-FLT scans were observed, mainly because of differences in overall image quality. The smaller reproducibility limits for volumederived image indices were similar to those for SUV max , suggesting that the use of appropriate delineation tools should allow the determination of tumor functional volumes in PET images in a repeatable and reproducible fashion.

Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m 2 /d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 Mg/mL in human glioma tumors and from 1.8 to 3.7 Mg/mL in normal brain, with the total drug exposure, as indicated by the tissue/ plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules. [Cancer Res 2009;69(1):120-7]

Two fully hydrated pure-species phospholipids bilayers, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dioleoyl-sn-glycero-3-phosphorylcholine (DOPC), in the fluid phase and explicit solvent have been studied using molecular dynamics simulation. Atom interactions were modeled using recently developed force fields based on AMBER with full atomistic details. Several representative liquid phase properties for the structure and dynamics of lipids with different length of hydrocarbon chains and different level of saturation have been reproduced without artificially biasing the system in order to match experimental data. In particular, as the new GAFF (General Amber Force Field) has not been explicitly developed to reproduce lipid characteristics and is naturally compatible with standard AMBER nucleic acids and proteins parameters, it is here proven a promising tool to study mixed lipid-protein processes as protein activity dependence on membrane composition, permeation of solute across membranes, and other cellular processes.