Dexamethasone is a glucocorticoid steroid with anti-inflammatory properties used to treat many diseases, including cancer, in which it helps manage various side effects of chemo-, radio-, and immunotherapies. Here, we investigate the tumor microenvironment (TME)-normalizing effects of dexamethasone in metastatic murine breast cancer (BC). Dexamethasone normalizes vessels and the extracellular matrix, thereby reducing interstitial fluid pressure, tissue stiffness, and solid stress. In turn, the penetration of 13 and 32 nm dextrans, which represent nanocarriers (NCs), is increased. A mechanistic model of fluid and macromolecule transport in tumors predicts that dexamethasone increases NC penetration by increasing interstitial hydraulic conductivity without significantly reducing the effective pore diameter of the vessel wall. Also, dexamethasone increases the tumor accumulation and efficacy of ∼30 nm polymeric micelles containing cisplatin (CDDP/m) against murine models of primary BC and spontaneous BC lung metastasis, which also feature a TME with abnormal mechanical properties. These results suggest that pretreatment with dexamethasone before NC administration could increase efficacy against primary tumors and metastases.

Honey bee queens are exceptionally promiscuous. Early in life, queens perform one to five nuptial flights, mating with up to 44 drones. Many studies have documented potential benefits of multiple mating. In contrast, potential costs of polyandry and the sensitivity of queens to such costs have largely been ignored because they are difficult to address experimentally. To consider one aspect of mating costs to queens, the difficulty of flight, we compared flight behavior and success among a group of control queens and two experimental groups of queens that carried lead weights of two different sizes. For each queen, we assessed the number and duration of all flights and, after egg‐laying commenced, the amount of stored sperm and the number of mates in terms of the offspring’s patrilineal genetic diversity. Added weights quantitatively decreased the number of flights, the mean duration of flights and consequently the total time spent flying. Mating success in terms of sperm quantity and patrilines detected among the queens’ offspring was also negatively impacted by the experimental manipulation. Thus, it can be concluded that the flight effort of honey bee queens during their mating period is adjusted in response to an experimentally increased cost of flying with multiple consequences for their mating success. Our results suggest that queen behavior is flexible and mating costs deserve more attention to explain the extreme polyandry in honey bees.

Definition S1.1 (Convex and Concave Relaxations [6]) Given a convex set Z ⊂ R n and a function w

We present a deterministic global optimization method for nonlinear programming formulations constrained by stiff systems of ordinary differential equation (ODE) initial value problems (IVPs). The examples arise from dynamic optimization problems exhibiting both fast and slow transient phenomena commonly encountered in model-based systems engineering applications. The proposed approach utilizes unconditionally stable implicit integration methods to reformulate the ODEconstrained problem into a nonconvex nonlinear program (NLP) with implicit functions embedded. This problem is then solved to global optimality in finite time using a spatial branch-and-bound framework utilizing convex/concave relaxations of implicit functions constructed by a method which fully exploits problem sparsity. The algorithms were implemented in the Julia programming language within the EAGO.jl package and demonstrated on five illustrative examples with varying complexity relevant in process systems engineering. The developed methods enable the guaranteed global solution of dynamic optimization problems with stiff ODE-IVPs embedded. K E Y W O R D S dynamic simulation, global optimization, implicit functions, stiff systems

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