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.

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.

We report experimental results for pipe flow of granular materials discharged through vertical narrow tubes by means of a conveyor belt placed at the bottom. When the diameter of the tube is not much larger than the particle size, the system clogs due to the development of hanging arches that are able to support the weight of the grains above them. We find that the time it takes to develop a stable clog decays exponentially, which is compatible with a clogging probability that remains constant during the discharge. From this, and making an analogy with the discharge of silos, we introduce the avalanche size, measured in terms of the number of discharged tubes before the system clogs. The mean avalanche size is found to increase as the tube diameter is enlarged, the velocity of the conveyor belt grows, and the tube tilt deviates from the vertical. © 2015, Springer-Verlag Berlin Heidelberg.

Los medios granulados ¿materia inerte compuesta por sólidos divididos¿ al pasar por una abertura que sea sólo un poco mayor al tamaño de las partículas se pueden atascar. Se ha estudiado como disminuye la probabilidad de que este sistema se atasque gracias a la colocación de un obstáculo delante de la salida. El resultado obtenido demuestra que se disminuye la probabilidad de atasco dependiendo dónde esté colocado el obstáculo, siendo una posición óptima donde la distancia entre el obstáculo y la salida es similar al tamaño de la abertura. Estos resultados pueden ser interesantes para el diseño óptimo de una salida de evacuación.

nterleukin-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-gamma (IFN gamma). 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 IFN gamma on inducible systems. The aim of this work is to develop a semi-mechanistic model to characterize the relationship between IL12 and IFN gamma in wild-type and knock-out mice for the IFN gamma 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 IFN gamma, respectively). The final model included: (1) IFN gamma 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 IFN gamma receptor, and (5) synthesis of IFN gamma controlled by the relative increments in the bound IL12. In conclusion, a model simultaneously describing the kinetics of IL12 and IFN gamma 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.

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.

"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.

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.

Transport of material through pipes or channels in mines or gravel quarries seems to be a simple and economic form of conveying blasted ore between different levels. Despite the apparent advantages of moving the material by means of the gravity force, there exists an important problem that makes the applicability of this method more difficult: the election of the pipe diameter to prevent clogging of the stones. It was R. Kvapil in the sixties who extended the ideas of granular flows in silos to underground mining. Nevertheless, after his pioneering works there are only a few manuscripts focused on this topic, and many questions remain unsolved. In this work, we present experimental results about the flow of particles (gravel) driven by gravity through tilted tubes. The amount of material discharged between clogs shows that the probability of clogging can be estimated by the same procedures introduced for silos. Finally, by changing the ratio between the tube diameter and the typical particle size, we discuss about the existence or not of a critical size beyond which clogging is not possible.

We present an experimental study of the effect that an obstacle above the outlet of a silo has on the clogging probability. Both, the size of the orice and the obstacle position are varied for a chosen obstacle size and shape. If the position of the obstacle is properly selected the clogging probability can be importantly reduced. Indeed, as the outlet size is increased ¿ and we approach the critical size above which there is not clogging ¿ the obstacle effect is enhanced. For the largest outlet size studied, the clogging probability is reduced by a factor of more than one hundred. We will show, using numerical simulations, that the physical parameter behind the reduction of the silo clogging seems to be the decrease of the vertical pressure at the outlet proximities.

The role of density and velocity profiles in the flow of particles through apertures has been recently put on evidence in a two-dimensional experiment (Phys. Rev. Lett. 108, 248001). For the whole range of apertures studied, both velocity and density profiles are selfsimilar and the obtained scaling functions allow to derive the relevant scales of the problem. Indeed, by means of the functionality obtained for these profiles, an exact expression for the mass flow rate was proposed. Such expression showed a perfect agreement with the experiential data. In this work, we generalize this study to the three dimensional case.We perform numerical simulations of a 3D silo in which the velocity and volume fraction profiles are determined. Both profiles shows that the scaling obtained for 2D can be generalized to the 3D case. Finally, the scaling of the mass flow rate with the outlet radius is discussed.