Disease Progression Modeling Analysis of the Change of Bone Mineral Density by Postoperative Hormone Therapies in Postmenopausal Patients With Early Breast Cancer.

The osteoporosis incidence in postmenopausal patients on aromatase inhibitors (AI) is much higher than in those on tamoxifen, and adverse effects other than musculoskeletal disorders are less on AI than on tamoxifen. In this study we performed disease-progression modeling in postmenopausal patients with early breast cancer who had received 5 years of postoperative hormone therapy. Clinical data from postmenopausal patients who had received postoperative hormonal therapy and met the predefined selection criteria were retrospectively collected in an anonymized way. Disease-progression modeling and simulations were performed using NONMEM version 7.42. A first-order deterioration model with a combination of a symptomatic model (when a drug effect provides a transient bad effect by offsetting the severity of the disease) and a disease-modifying model (when a drug affects the disease progression rate) was used. Vitamin D supplementation was found to have a disease-modifying effect in osteoporosis, whereas AI decreased the bone mineral density by a t score of -0.21. However, after stopping the AI, the estrogen level reverted to normal, thereby reexercising protective effects against bone loss. In the simulation the probability of osteoporosis increased by 10% in the AI group compared with the other groups (tamoxifen, no-treatment group) during the medication period. Tamoxifen showed no significant effects in the final model.

The effects of interleukin-2 on immune response regulation.

The immune system has many adaptive and dynamic components that are regulated to ensure appropriate, precise and rapid response to a foreign pathogen. A delayed or inadequate immune response can lead to prolonged disease, while an excessive or under-regulated response can lead to autoimmunity. The cytokine, interleukin-2 (IL-2) and its receptor IL-2R play an important role in maintaining this balance.The IL-2 receptor transduces pSTAT5 signal through both the intermediate and high affinity receptors, which differ from each other by the presence of CD25 chain in IL-2 receptor. We present experimental data on the kinetics of pSTAT5 signalling through both of the receptors and develop a model that captures this kinetics. We then use this model to parameterize key aspects of two additional models in which we propose and study two different mechanisms by which IL-2 receptor can transduce distinct signals leading to either an activated or a non-activated cell state. We speculate that this initial state differentiation, perhaps enhanced by downstream feedbacks, may eventually lead to differential cell fates.Our result shows that non-linear dynamical models can suggest resolution of a puzzling array of seemingly contradictory experimental results on IL-2 effect on proliferation and differentiation of T-cells.