A model for the intrinsic limit of cancer therapy: duality of treatment-induced cell death and treatment-induced stemness

Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a "stem-like state" that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from "maximal tolerated dose," which may promote therapy induced-stemness, to repeated "minimally effective doses" (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression.

Behavior of Polyelectrolyte Gels in Concentrated Solutions of Highly Soluble Salts

ABSTRACTIonic hydrogels are an abundant class of materials with applications ranging from drug delivery devices to high performance concrete to baby diapers. A more thorough understanding of interactions between polyelectrolyte networks and ionic solutes is critical as these materials are further tailored for performance applications in highly targeted ionic environments. In this work, we seek to develop structure-property relationships between polyelectrolyte gels and environments containing high concentrations of multivalent ions. Specifically, this work seeks to elucidate the causes behind differences in hydrogel response to divalent ions of main group metals versus transition metals. PANa-co-PAM hydrogels containing low and high fractions of ionic groups are investigated in solutions of DI water, NaCl, CaCl2, and CuSO4 at concentrations ranging from 5 to 100 mM in order to understand 1) the transient or permanent nature of crosslinks produced in these networks by divalent counter-ions, 2) the role of polymer ionic content in these interactions, and 3) how these interactions scale with salt concentration. Gravimetric swelling and mechanical compression testing are employed to characterize water and salt-swollen hydrogels in order to develop guiding principles to control and manipulate material properties through polymer-counter-ion interactions. The work presented here confirms the formation of permanent crosslinks by transition metal ions, offers explanation for the behavioral discrepancy observed between ionic hydrogels and main group versus transition metal ions, and illustrates how such hydrogel properties scale with counter-ion concentration.

Succession versus Transition

Although the current regime has attempted to install a viable successor to the Castro brothers, the future of the island nation’s political structure can take a number of different paths. Since so much of U.S. approach toward diplomatic normalization with Cuba has hinged on regime change, the possibilities of political succession and transition are of paramount importance. This chapter addresses theories of political transition and succession to discuss the Cuban case. Using democratic transitions around the world, and among Cuba’s neighbors, as a point of departure this chapter addresses the key players and strategies that are most likely to be invoked over the next few decades both over the short, medium, and long term.