Purpose: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates.Experimental Design: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates.

No abstract

In this paper we study the effect of constant-yield predator harvesting on the dynamics of a Leslie-Gower type predator-prey model. It is shown that the model has a Bogdanov-Takens singularity (cusp case) of codimension 3 or a weak focus of multiplicity two for some parameter values, respectively. Saddle-node bifurcation, repelling and attracting Bogdanov-Takens bifurcations, supercritical and subcritical Hopf bifurcations, and degenerate Hopf bifurcation are shown as the values of parameters vary. Hence, there are different parameter values for which the model has a homoclinic loop or two limit cycles. It is also proven that there exists a critical harvesting value such that the predator specie goes extinct for all admissible initial densities of both species when the harvest rate is greater than the critical value. These results indicate that the dynamical behavior of the model is very sensitive to the constant-yield predator harvesting and the initial densities of both species and it requires careful management in the applied conservation and renewable resource contexts. Numerical simulations, including the repelling and attracting Bogdanov-Takens bifurcation diagrams and corresponding phase portraits, two limit cycles, the coexistence of a stable homoclinic loop and an unstable limit cycle, and a stable limit cycle enclosing an unstable multiple focus with multiplicity one, are presented which not only support the theoretical analysis but also indicate the existence of Bogdanov-Takens bifurcation (cusp case) of codimension 3. These results reveal far richer and much more complex dynamics compared to the model without harvesting or with only constant-yield prey harvesting.

In this paper, we study a susceptible-infectious-recovered (SIRS) epidemic model with a generalized nonmonotone and saturated incidence rate kI 2 S 1+βI +αI 2 , in which the infection function first increases to a maximum when a new infectious disease emerges, then decreases due to psychological effect, and eventually tends to a saturation level due to crowding effect. It is shown that there are a weak focus of multiplicity at most two and a cusp of codimension at most two for various parameter values, and the model undergoes saddle-node bifurcation, Bogdanov-Takens bifurcation of codimension two, Hopf bifurcation, and degenerate Hopf bifurcation of codimension two as the parameters vary. It is shown that there exists a critical value α = α 0 for the psychological effect, and two critical values k = k 0 , k 1 (k 0 < k 1 ) for the infection rate such that: (i) when α > α 0 , or α ≤ α 0 and k ≤ k 0 , the disease will die out for all positive initial populations; (ii) when α = α 0 and k 0 < k ≤ k 1 , the disease will die out for almost all positive initial populations; (iii) when α = α 0 and k > k 1 , the disease will persist in the form of a positive coexistent steady state for some positive initial populations; and (iv) when α < α 0 and k > k 0 , the disease will persist in the form of multiple positive periodic coexistent oscillations and coexistent steady states for some positive initial populations. Numerical simulations, including the existence of one or two limit cycles and data-fitting of the influenza data in Mainland China, are presented to illustrate the theoretical results.

In this paper the dynamical behaviors of a predator-prey system with Holling Type-IV functional response are investigated in detail by using the analyses of qualitative method, bifurcation theory, and numerical simulation. The qualitative analyses and numerical simulation for the model indicate that it has a unique stable limit cycle. The bifurcation analyses of the system exhibit static and dynamical bifurcations including saddlenode bifurcation, Hopf bifurcation, homoclinic bifurcation and bifurcation of cusp-type with codimension two (ie, the Bogdanov-Takens bifurcation), and we show the existence of codimension three degenerated equilibrium and the existence of homoclinic orbit by using numerical simulation.