Model-Informed Dose Selection for Xentuzumab, a Dual Insulin-Like Growth Factor-I/II-Neutralizing Antibody.

Over the past decade, the insulin-like growth factor (IGF)-signaling pathway has gained substantial interest as potential therapeutic target in oncology. Xentuzumab, a humanized IgG1 monoclonal antibody, binds to IGF-I and IGF-II thereby inhibiting the downstream signaling essential for survival and tumor growth. This pathway is further regulated by circulating IGF binding proteins (IGFBPs). In this work, a mechanistic model characterizing the dynamics and interactions of IGFs, IGFBPs, and Xentuzumab has been developed to guide dose selection. Therefore, in vitro and in vivo literature information was combined with temporal IGF-I, IGF-II, and IGFBP-3 total plasma concentrations from two phase I studies. Based on the established quantitative framework, the time-course of free IGFs as ultimate drug targets not measured in clinics was predicted. Finally, a dose of 1000 mg/week-predicted to reduce free IGF-I and free IGF-II at steady-state by at least 90% and 64%, respectively-was suggested for phase II.

Optimal dynamic control approach in a multi-objective therapeutic scenario: Application to drug delivery in the treatment of prostate cancer.

Numerous problems encountered in computational biology can be formulated as optimization problems. In this context, optimization of drug release characteristics or dosing schedules for anticancer agents has become a prominent area not only for the development of new drugs, but also for established drugs. However, in complex systems, optimization of drug exposure is not a trivial task and cannot be efficiently addressed through trial-error simulation exercises. Finding a solution to those problems is a challenging task which requires more advanced strategies like optimal control theory. In this work, we perform an optimal control analysis on a previously developed computational model for the testosterone effects of triptorelin in prostate cancer patients with the goal of finding optimal drug-release characteristics. We demonstrate how numerical control optimization of non-linear models can be used to find better therapeutic approaches in order to improve the final outcome of the patients.

Clogging transition of many-particle systems flowing through bottlenecks.

When a large set of discrete bodies passes through a bottleneck, the flow may become intermittent due to the development of clogs that obstruct the constriction. Clogging is observed, for instance, in colloidal suspensions, granular materials and crowd swarming, where consequences may be dramatic. Despite its ubiquity, a general framework embracing research in such a wide variety of scenarios is still lacking. We show that in systems of very different nature and scale -including sheep herds, pedestrian crowds, assemblies of grains, and colloids- the probability distribution of time lapses between the passages of consecutive bodies exhibits a power-law tail with an exponent that depends on the system condition. Consequently, we identify the transition to clogging in terms of the divergence of the average time lapse. Such a unified description allows us to put forward a qualitative clogging state diagram whose most conspicuous feature is the presence of a length scale qualitatively related to the presence of a finite size orifice. This approach helps to understand paradoxical phenomena, such as the faster-is-slower effect predicted for pedestrians evacuating a room and might become a starting point for researchers working in a wide variety of situations where clogging represents a hindrance.

Pharmacological profiles of acute myeloid leukemia treatments in patient samples by automated flow cytometry: a bridge to individualized medicine.

BACKGROUND: We have evaluated the ex vivo pharmacology of single drugs and drug combinations in malignant cells of bone marrow samples from 125 patients with acute myeloid leukemia using a novel automated flow cytometry-based platform (ExviTech). We have improved previous ex vivo drug testing with 4 innovations: identifying individual leukemic cells, using intact whole blood during the incubation, using an automated platform that escalates reliably data, and performing analyses pharmacodynamic population models. PATIENTS AND METHODS: Samples were sent from 24 hospitals to a central laboratory and incubated for 48 hours in whole blood, after which drug activity was measured in terms of depletion of leukemic cells. RESULTS: The sensitivity of single drugs is assessed for standard efficacy (EMAX) and potency (EC50) variables, ranked as percentiles within the population. The sensitivity of drug-combination treatments is assessed for the synergism achieved in each patient sample. We found a large variability among patient samples in the dose-response curves to a single drug or combination treatment. CONCLUSION: We hypothesize that the use of the individual patient ex vivo pharmacological profiles may help to guide a personalized treatment selection.

Target-mediated disposition model describing the dynamics of IL12 and IFNγ after administration of a mifepristone-inducible adenoviral vector for IL-12 expression in mice.

Interleukin-12 (IL12) is a cytokine with potential applications in the treatment of cancer given the potent immune response that it triggers, in part due to its ability to stimulate expression of interferon-γ (IFNγ). To avoid the toxicity associated with systemic exposure to IL12, a high-capacity adenoviral vector carrying a liver-specific, mifepristone-inducible IL12 expression system (HC-Ad/RUmIL12) has been developed. However, the maintenance of IL12 expression at therapeutic levels is compromised by the inhibitory effect of IFNγ on inducible systems. The aim of this work is to develop a semi-mechanistic model to characterize the relationship between IL12 and IFNγ in wild-type and knock-out mice for the IFNγ receptor treated with HC-Ad/RUmIL12 under different dosing regimens in order to better understand the key mechanisms controlling the system. Rapid binding was considered to account for target-mediated disposition exhibited by both cytokines (equilibrium dissociation constant were 18 and 2.28 pM for IL12 and IFNγ, respectively). The final model included: (1) IFNγ receptor turnover, (2) irreversible free cytokine elimination from the serum compartment, (3) internalization of the IL12 receptor complex, (4) IL12 expression upregulated by the co-administration of the adenoviral vector and mifepristone and downregulated by the IFNγ receptor, and (5) synthesis of IFNγ controlled by the relative increments in the bound IL12. In conclusion, a model simultaneously describing the kinetics of IL12 and IFNγ in the context of gene therapy was developed and validated with additional data. The model was applied to design an experimental dosing protocol intended to maintain sustained therapeutic IL12 levels.

Flow and clogging in a silo with an obstacle above the orifice.

In a recent paper [Zuriguel et al., Phys. Rev. Lett. 107, 278001 (2011)] it has been shown that the presence of an obstacle above the outlet can significatively reduce the clogging probability of granular matter pouring from a silo. The amount of this reduction strongly depends on the obstacle position. In this work, we present new measurements to analyze different outlet sizes, extending foregoing results and revealing that the effect of the obstacle is enhanced as the outlet size is increased. In addition, the effect of the obstacle position on the flow rate properties and in the geometrical features of arches is studied. These results reinforce previous evidence of the pressure reduction induced by the obstacle. In addition, it is shown how the mean avalanche size and the average flow rate are not necessarily linked. On the other hand, a close relationship is suggested between the mean avalanche size and the flow rate fluctuations.

Flow rate of particles through apertures obtained from self-similar density and velocity profiles.

"Beverloo's law" is considered as the standard expression to estimate the flow rate of particles through apertures. This relation was obtained by simple dimensional analysis and includes empirical parameters whose physical meaning is poorly justified. In this Letter, we study the density and velocity profiles in the flow of particles through an aperture. We find that, for the whole range of apertures studied, both profiles are self-similar. Hence, by means of the functionality obtained for them the mass flow rate is calculated. The comparison of this expression with the Beverloo's one reveals some differences which are crucial to understanding the mechanism that governs the flow of particles through orifices.

Fluctuations of grains inside a discharging two-dimensional silo.

We present experimental data corresponding to a two-dimensional dense granular flow, namely, the gravity-driven discharge of grains from a small opening in a silo. We study the local velocity field at the scale of single grains at different places with the help of particle-tracking techniques. From these data, the velocity profiles can be obtained and the validity of some long-standing approaches can be assessed. Moreover, the fluctuations of the velocities are taken into consideration to characterize the features of the advective motion (due to the gravity force) and the diffusive motion, which shows nontrivial behavior.

Silo clogging reduction by the presence of an obstacle.

We present experimental results on the effect that inserting an obstacle just above the outlet of a silo has on the clogging process. We find that, if the obstacle position is properly selected, the probability that the granular flow is arrested can be reduced by a factor of 100. This dramatic effect occurs without any remarkable modification of the flow rate or the packing fraction above the outlet, which are discarded as the cause of the change in the clogging probability. Hence, inspired by previous results of pedestrian crowd dynamics, we propose that the physical mechanism behind the clogging reduction is a pressure decrease in the region of arch formation.

Shape of jamming arches in two-dimensional deposits of granular materials.

We present experimental results on the shape of arches that block the outlet of a two-dimensional silo. For a range of outlet sizes, we measure some properties of the arches such as the number of particles involved, the span, the aspect ratio, and the angles between mutually stabilizing particles. These measurements shed light on the role of frictional tangential forces in arching. In addition, we find that arches tend to adopt an aspect ratio (the quotient between height and half the span) close to 1, suggesting an isotropic load. The comparison of the experimental results with data from numerical models of the arches formed in the bulk of a granular column reveals the similarities of both, as well as some limitations in the few existing models.