Analytical Models of Intra- and Extratumoral Cell Interactions at Avascular Stage of Growth in the Presence of Targeted Chemotherapy.

In this study, we propose a set of nonlinear differential equations to model the dynamic growth of avascular stage tumors, considering nutrient supply from underlying tissue, innate immune response, contact inhibition of cell migration, and interactions with a chemotherapeutic agent. The model has been validated against available experimental data from the literature for tumor growth. We assume that the size of the modeled tumor is already detectable, and it represents all clinically observed existent cell populations; initial conditions are selected accordingly. Numerical results indicate that the tumor size and regression significantly depend on the strength of the host immune system. The effect of chemotherapy is investigated, not only within the malignancy, but also in terms of the responding immune cells and healthy tissue in the vicinity of a tumor.

Sampling with poling-based flux balance analysis: optimal versus sub-optimal flux space analysis of Actinobacillus succinogenes.

BACKGROUND: Flux balance analysis is traditionally implemented to identify the maximum theoretical flux for some specified reaction and a single distribution of flux values for all the reactions present which achieve this maximum value. However it is well known that the uncertainty in reaction networks due to branches, cycles and experimental errors results in a large number of combinations of internal reaction fluxes which can achieve the same optimal flux value. RESULTS: In this work, we have modified the applied linear objective of flux balance analysis to include a poling penalty function, which pushes each new set of reaction fluxes away from previous solutions generated. Repeated poling-based flux balance analysis generates a sample of different solutions (a characteristic set), which represents all the possible functionality of the reaction network. Compared to existing sampling methods, for the purpose of generating a relatively "small" characteristic set, our new method is shown to obtain a higher coverage than competing methods under most conditions. The influence of the linear objective function on the sampling (the linear bias) constrains optimisation results to a subspace of optimal solutions all producing the same maximal fluxes. Visualisation of reaction fluxes plotted against each other in 2 dimensions with and without the linear bias indicates the existence of correlations between fluxes. This method of sampling is applied to the organism Actinobacillus succinogenes for the production of succinic acid from glycerol. CONCLUSIONS: A new method of sampling for the generation of different flux distributions (sets of individual fluxes satisfying constraints on the steady-state mass balances of intermediates) has been developed using a relatively simple modification of flux balance analysis to include a poling penalty function inside the resulting optimisation objective function. This new methodology can achieve a high coverage of the possible flux space and can be used with and without linear bias to show optimal versus sub-optimal solution spaces. Basic analysis of the Actinobacillus succinogenes system using sampling shows that in order to achieve the maximal succinic acid production CO2 must be taken into the system. Solutions involving release of CO2 all give sub-optimal succinic acid production.

Modeling flexible pharmacophores with distance geometry, scoring, and bound stretching.

The study of pharmacophores, i.e., of common features between different ligands, is important for the quantitative identification of "compatible" enzymes and binding species. A pharmacophore-based technique is developed that combines multiple conformations with a distance geometry method to create flexible pharmacophore representations. It uses a set of low-energy conformations combined with a new process we call bound stretching to create sets of distance bounds, which contain all or most of the low-energy conformations. The bounds can be obtained using the exact distances between pairs of atoms from the different low-energy conformations. To avoid missing conformations, we can take advantage of the triangle distance inequality between sets of three points to logically expand a set of upper and lower distance bounds (bound stretching). The flexible pharmacophore can be found using a 3-D maximal common subgraph method, which uses the overlap of distance bounds to determine the overlapping structure. A scoring routine is implemented to select the substructures with the largest overlap because there will typically be many overlaps with the maximum number of overlapping bounds. A case study is presented in which 3-D flexible pharmacophores are generated and used to eliminate potential binding species identified by a 2-D pharmacophore method. A second case study creates flexible pharmacophores from a set of thrombin ligands. These are used to compare the new method with existing pharmacophore identification software.

Operating characteristics of full count and binomial sampling plans for green peach aphid (Hemiptera: Aphididae) in potato.

Counts of green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae), in potato, Solanum tuberosum L., fields were used to evaluate the performance of the sampling plan from a pest management company. The counts were further used to develop a binomial sampling method, and both full count and binomial plans were evaluated using operating characteristic curves. Taylor's power law provided a good fit of the data (r2 = 0.95), with the relationship between the variance (s2) and mean (m) as ln(s2) = 1.81(+/- 0.02) + 1.55(+/- 0.01) ln(m). A binomial sampling method was developed using the empirical model ln(m) = c + dln(-ln(1 - P(T))), to which the data fit well for tally numbers (T) of 0, 1, 3, 5, 7, and 10. Although T = 3 was considered the most reasonable given its operating characteristics and presumed ease of classification above or below critical densities (i.e., action thresholds) of one and 10 M. persicae per leaf, the full count method is shown to be superior. The mean number of sample sites per field visit by the pest management company was 42 +/- 19, with more than one-half (54%) of the field visits involving sampling 31-50 sample sites, which was acceptable in the context of operating characteristic curves for a critical density of 10 M. persicae per leaf. Based on operating characteristics, actual sample sizes used by the pest management company can be reduced by at least 50%, on average, for a critical density of 10 M. persicae per leaf. For a critical density of one M. persicae per leaf used to avert the spread of potato leaf roll virus, sample sizes from 50 to 100 were considered more suitable.