Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas

Platinum drug-resistance in ovarian cancers is a major factor contributing to chemotherapeutic resistance of recurrent disease. Members of the Bcl-2 family such as the anti-apoptotic protein Bcl-XL have been shown to play a role in this resistance. Consequently, concurrent inhibition of Bcl-XL in combination with standard chemotherapy may improve treatment outcomes for ovarian cancer patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-XL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo\ud experimental data, wherein tumor xenografts were established in mice and treated with ABT-737 and carboplatin on a fixed periodic schedule, alone or in combination, and tumor sizes recorded regularly. We show that the validated model can be used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the time of infusion of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin administered each week combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. We also investigate the potential of ABT-737 co-therapy with carboplatin to prevent or delay the onset of carboplatin-resistance under two scenarios. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, the model is used to identify drug delivery schedules that induce tumor remission with even low doses of combination therapy. When resistance is intrinsic, due to a pre-existing cohort of resistant cells, tumor remission is no longer feasible, but our model can be used to identify dosing strategies that extend disease-free survival periods. These results underscore the potential of our model to accelerate the development of novel therapeutics such as ABT-737, by predicting optimal treatment strategies when these drugs are given in combination with currently approved cancer medications

Carbon Monitoring System Flux Estimation and Attribution: Impact of ACOS-GOSAT X(CO2) Sampling on the Inference of Terrestrial Biospheric Sources and Sinks

Using an Observing System Simulation Experiment (OSSE), we investigate the impact of JAXA Greenhouse gases Observing SATellite 'IBUKI' (GOSAT) sampling on the estimation of terrestrial biospheric flux with the NASA Carbon Monitoring System Flux (CMS-Flux) estimation and attribution strategy. The simulated observations in the OSSE use the actual column carbon dioxide (X(CO2)) b2.9 retrieval sensitivity and quality control for the year 2010 processed through the Atmospheric CO2 Observations from Space algorithm. CMS-Flux is a variational inversion system that uses the GEOS-Chem forward and adjoint model forced by a suite of observationally constrained fluxes from ocean, land and anthropogenic models. We investigate the impact of GOSAT sampling on flux estimation in two aspects: 1) random error uncertainty reduction and 2) the global and regional bias in posterior flux resulted from the spatiotemporally biased GOSAT sampling. Based on Monte Carlo calculations, we find that global average flux uncertainty reduction ranges from 25% in September to 60% in July. When aggregated to the 11 land regions designated by the phase 3 of the Atmospheric Tracer Transport Model Intercomparison Project, the annual mean uncertainty reduction ranges from 10% over North American boreal to 38% over South American temperate, which is driven by observational coverage and the magnitude of prior flux uncertainty. The uncertainty reduction over the South American tropical region is 30%, even with sparse observation coverage. We show that this reduction results from the large prior flux uncertainty and the impact of non-local observations. Given the assumed prior error statistics, the degree of freedom for signal is approx.1132 for 1-yr of the 74 055 GOSAT X(CO2) observations, which indicates that GOSAT provides approx.1132 independent pieces of information about surface fluxes. We quantify the impact of GOSAT's spatiotemporally sampling on the posterior flux, and find that a 0.7 gigatons of carbon bias in the global annual posterior flux resulted from the seasonally and diurnally biased sampling when using a diagonal prior flux error covariance

Development and application of 2D and 3D transient electromagnetic inverse solutions based on adjoint Green functions: A feasibility study for the spatial reconstruction of conductivity distributions by means of sensitivities

To enhance interpretation capabilities of transient electromagnetic (TEM) methods, a multidimensional inverse solution is introduced, which allows for a explicit sensitivity calculation with reduced computational effort. The main conservation of computational load is obtained by solving Maxwell's equations directly in time domain. This is achieved by means of a high efficient Krylov-subspace technique that is particularly developed for the fast computation of EM fields in the diffusive regime. Traditional modeling procedures for Maxwell's equations yields solutions independently for every frequency or, in the time domain, at a given time through explicit time stepping. Because of this, frequency domain methods are rendered extremely time consuming for multi-frequency simulations. Likewise the stability conditions required by explicit time stepping techniques often result in highly inefficient calculations for large diffusion times and conductivity contrasts. The computation of sensitivities is carried out using the adjoint Green functions approach. For time domain applications, it is realized by convolution of the background electrical field information, originating from the primary signal, with the impulse response of the receiver acting as secondary source. In principle, the adjoint formulation may be extended allowing for a fast gradient calculation without calculating and storing the whole sensitivity matrix but just the gradient of the data residual. This technique, which is also known as migration, is widely used for seismic and, to some extend, for EM methods as well. However, the sensitivity matrix, which is not easily given by migration techniques, plays a central role in resolution analysis and would therefore be discarded. But, since it allows one to discriminate features in the a posteriori model which are data or regularization driven, it would therefore be very likely additional information to have. The additional cost of its storage and explicit computation is comparable low disbursement to the gain of a posteriori model resolution analysis. Inversion of TEM data arising from various types of sources is approached by two different methods. Both methods reconstruct the subsurface electrical conductivity properties directly in the time domain. A principal difference is given by the space dimensions of the inversion problems to be solved and the type of the optimization procedure. For two-dimensional (2D) models, the ill-posed and non-linear inverse problem is solved by means of a regularized Gauss-Newton type of optimization. For three-dimensional (3D) problems, due to the increase of complexity, a simpler, gradient based minimization scheme is presented. The 2D inversion is successfully applied to a long offset (LO)TEM survey conducted in the Arava basin (Jordan), where the joint interpretation of 168 transient soundings support the same subsurface conductivity structure as the one derived by inversion of a Magnetotelluric (MT) experiment. The 3D application to synthetic data demonstrates, that the spatial conductivity distribution can be reconstructed either by deep or shallow TEM sounding methods

Biomathematics of Chlamydia

Chlamydia trachomatis (C. trachomatis) related sexually transmitted infections are a major global public health concern. C. trachomatis afflict millions of men, women, and children worldwide and frequently result in serious medical diseases. In this thesis, mathematical modeling is applied in order to comprehend the dynamics of Chlamydia pathogens within host, their interactions with the immune systems, behavior in the presence of other pathogens, transmission dynamics in a human population, and the efficacy of control measures. The thesis begins with a brief introduction of the bacteria Chlamydia in Chapter 1. In Chapter 2, we give a brief detail of the mathematical modeling of infectious diseases, and its specific application to study the pathogen. In Chapter 3, a linear delay differential compartmental model is developed, and its special application is shown for a laboratory experiment conducted to study the intracellular development cycle of Chlamydia. The delay accounts for the time spent by bacteria in their various forms and for the time taken to go through the replication cycle. The mathematical model tracks the number of Chlamydia infected cells at each stage of the cell division cycle. Moreover, the formula for the final size of each compartment is derived. With initial conditions taken from the experiment, the model is fitted to results from the laboratory data. This simple linear model is capable of reflecting the outcomes of the laboratory experiment. In Chapter 4, at a population level, a novel mathematical model is introduced to study the dynamics of the co-infection between C. trachomatis, and herpes simplex virus (HSV). The concept of the model is based on the observation that in an individual simultaneously infected with both pathogens, the presence of HSV will make the Chlamydia persistent. In its persistent phase, Chlamydia is not replicating and is non-infectious. Important threshold parameters are obtained for the persistence of both infections. We prove global stability results for the disease-free and the boundary equilibria by applying the theory of asymptotically autonomous systems. Further, the model is calibrated to disease parameters to determine the population prevalence of both diseases and compare it with epidemiological findings. In Chapter 5, a compartmental maturity structured model is developed to investigate an optimal control problem for the treatment of chronic Chlamydia infection. The model takes into account the interaction of the pathogens with the immune system and its effects on the formation of persistent Chlamydia particles. As the system takes the form of a mixed ODE-PDE system, the results of the conventional form of Pontryagin’s maximal principle for ordinary differential equations are not suitable. For our purpose, we construct an optimal control problem for a general maturity compartmental model, and hence it consists of ordinary and partial differential equations, moreover, the boundary conditions are also nonlinear. For a fixed control, we verify the existence, uniqueness, and boundedness of the solutions. The system is numerically simulated for a variety of cost functions in order to calculate the optimal treatment for curing Chlamyida infection. We believe that since our findings were validated for a general model with maturity structure, they may be applied to any specific compartmental model that is compatible with the established system