Accurate prediction of tumor growth is critical in modeling the effects of anti-tumor agents. Popular models of tumor growth inhibition (TGI) generally offer empirical description of tumor growth. We ...propose a lifespan-based tumor growth inhibition (LS TGI) model that describes tumor growth in a xenograft mouse model, on the basis of cellular lifespan T. At the end of the lifespan, cells divide, and to account for tumor burden on growth, we introduce a cell division efficiency function that is negatively affected by tumor size. The LS TGI model capability to describe dynamic growth characteristics is similar to many empirical TGI models. Our model describes anti-cancer drug effect as a dose-dependent shift of proliferating tumor cells into a non-proliferating population that die after an altered lifespan TA. Sensitivity analysis indicated that all model parameters are identifiable. The model was validated through case studies of xenograft mouse tumor growth. Data from paclitaxel mediated tumor inhibition was well described by the LS TGI model, and model parameters were estimated with high precision. A study involving a protein casein kinase 2 inhibitor, AZ968, contained tumor growth data that only exhibited linear growth kinetics. The LS TGI model accurately described the linear growth data and estimated the potency of AZ968 that was very similar to the estimate from an established TGI model. In the case study of AZD1208, a pan-Pim inhibitor, the doubling time was not estimable from the control data. By fixing the parameter to the reported in vitro value of the tumor cell doubling time, the model was still able to fit the data well and estimated the remaining parameters with high precision. We have developed a mechanistic model that describes tumor growth based on cell division and has the flexibility to describe tumor data with diverse growth kinetics.
Age‐related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The ...complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease‐modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.
Accurate prediction of tumor growth is critical in modeling the effects of anti-tumor agents. Popular models of tumor growth inhibition (TGI) generally offer empirical description of tumor growth. We ...propose a lifespan-based tumor growth inhibition (LS TGI) model that describes tumor growth in a xenograft mouse model, on the basis of cellular lifespan T. At the end of the lifespan, cells divide, and to account for tumor burden on growth, we introduce a cell division efficiency function that is negatively affected by tumor size. The LS TGI model capability to describe dynamic growth characteristics is similar to many empirical TGI models. Our model describes anti-cancer drug effect as a dose-dependent shift of proliferating tumor cells into a non-proliferating population that die after an altered lifespan TA. Sensitivity analysis indicated that all model parameters are identifiable. The model was validated through case studies of xenograft mouse tumor growth. Data from paclitaxel mediated tumor inhibition was well described by the LS TGI model, and model parameters were estimated with high precision. A study involving a protein casein kinase 2 inhibitor, AZ968, contained tumor growth data that only exhibited linear growth kinetics. The LS TGI model accurately described the linear growth data and estimated the potency of AZ968 that was very similar to the estimate from an established TGI model. In the case study of AZD1208, a pan-Pim inhibitor, the doubling time was not estimable from the control data. By fixing the parameter to the reported in vitro value of the tumor cell doubling time, the model was still able to fit the data well and estimated the remaining parameters with high precision. We have developed a mechanistic model that describes tumor growth based on cell division and has the flexibility to describe tumor data with diverse growth kinetics.
Thesis (Ph.D.)--Boston University
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The action of progesterone and estrogen on uterine mast cells of the ovariectomized rat was studied. A single injection of estradiol-17B (0.25 μg) produced a highly significant (P < O.OO1) reduction in both mesometrial and antimesometrial mast cell populations. The mean ± S.E. number of mesometrial and antimesometrial mast cells in the control animals was 19.2 ± 1.3 and 6.3 ± 0.7 respectively, while in the estrogen treated animals the respective values at 15 hours post treatment were 4.1 ± 0.5 and 2.9 ± 0.4. Estrogen treatment also resulted in considerable degranulation of the mast cells. In comparison, progesterone, when administered as a single injection (5 mg) did not produce a drastic reduction of the mast cells. Fifteen hours after its administration, progesterone had produced only a moderate reduction of the mast cell population; however, the decline was significantly smaller than those values obtained at the same time interval following estrogen treatment.;
Since it is known that progesterone treatment for at least 48 hours, followed by estrogen constitute the basic hormonal sequence for decidualizationin the rat, experiments were designed to study possible relationship between mast cell population and deciduoma development. Results obtained from these experiments demonstrate quite clearly that maximal decidual response was possible only among animals treated over a 48 hour period with progesterone (5 mg/ 24 hours) followed by a small (0.25 μg) injection of estradiol-17B and then traumatized 15 hours later (at a time when mast cell population was reduced to the lowest level). Thus, the hormonal treatment which resulted in the lowest level of mast cell numbers also permitted the largest deciduoma development.;
Shelesnyak (1957) proposed that histamine play a vital role in decidualization in the rat. On the other hand, it has been shown that mast cell degranulation with the accompanying loss of metachromasia is related to histamine release (Thon, 1967). In order to evaluate the role of estrogen as opposed to that of histamine in decidualization, animals were treated with estrogen and progesterone in addition to an estrogen antagonist -CN-55,945-27. The data from these experiments indicated only a moderate decidual response among the treated animals. In addition, the mast cell population in the uterine wall of these animals, at the time of traumatization, was considerably reduced and degranulated. Thus, uninterrupted estrogen action seems to be necessary for the establishment of sensitivity for maximal deciduoma development.;
In another set of investigations, uterine mast cells were depleted by administration of compound 48/80. Animals depleted of their mast cells and then treated with progesterone, estrogen, followed by trauma developed only small to moderate deciduomata. However, when rats were allowed to recover for seven days (at which time over 50% of the mast cells had reappeared) and then given the treatment as the preceding group, massive full length deciduoma were produced.;
The evidence suggests that maximal uterine sensitivity to decidualization is possible only after adequate hormonal treatment, and only in uteri not depleted of mast cells.
2031-01-01
A two-dimensional stochastic model for the dynamics of microtubules in gliding-assay experiments is presented here, which includes the viscous drag acting on the moving fiber and the interaction with ...the kinesins. For this purpose, we model kinesin as a spring, and explicitly use parameter values to characterize the model from experimental data. We numerically compute the mean attachment lifetimes of all motors, the total force exerted on the microtubules at all times, the effects of a distribution in the motor speeds, and also the mean velocity of a microtubule in a gliding assay. We find quantitative agreement with the results of J. Howard, A. J. Hudspeth, and R. D. Vale,
Nature. 342:154–158. We perform additional numerical analysis of the individual motors, and show how cancellation of the forces exerted by the many motors creates a resultant longitudinal force much smaller than the maximum force that could be exerted by a single motor. We also examine the effects of inhomogeneities in the motor-speeds. Finally, we present a simple theoretical model for microtubules dynamics in gliding assays. We show that the model can be analytically solved in the limit of few motors attached to the microtubule and in the opposite limit of high motor density. We find that the speed of the microtubule goes like the mean speed of the motors in good quantitative agreement with the experimental and numerical results.
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