Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

Particle representations for stochastic partial differential equations with boundary conditions

In this article, we study weighted particle representations for a class of stochastic partial differential equations (SPDE) with Dirichlet boundary conditions. The locations and weights of the particles satisfy an infinite system of stochastic differential equations. The locations are given by independent, stationary reflecting diffusions in a bounded domain, and the weights evolve according to an infinite system of stochastic differential equations driven by a common Gaussian white noise W which is the stochastic input for the SPDE. The weights interact through V, the associated weighted empirical measure, which gives the solution of the SPDE. When a particle hits the boundary its weight jumps to a value given by a function of the location of the particle on the boundary. This function determines the boundary condition for the SPDE. We show existence and uniqueness of a solution of the infinite system of stochastic differential equations giving the locations and weights of the particles and derive two weak forms for the corresponding SPDE depending on the choice of test functions. The weighted empirical measure V is the unique solution for each of the nonlinear stochastic par- tial differential equations. The work is motivated by and applied to the stochastic Allen-Cahn equation and extends the earlier of work of Kurtz and Xiong in [14, 15

Optimal-order exit point bounds in exponential last-passage percolation via the coupling technique

We develop a new probabilistic method for deriving deviation estimates in directed planar polymer and percolation models. The key estimates are for exit points of geodesics as they cross transversal down-right boundaries. These bounds are of optimal cubic-exponential order. We derive them in the context of last-passage percolation with exponential weights with near-stationary boundary conditions. As a result, the probabilistic coupling method is empowered to treat a variety of problems optimally, which could previously be achieved only via inputs from integrable probability. As applications in the bulk setting, we obtain upper bounds of cubic-exponential order for transversal fluctuations of geodesics, and cube-root upper bounds with a logarithmic correction for distributional Busemann limits and competition interface limits. Several other applications are already in the literature.Comment: Accepted version. Two main corrections: Added to Prop. 3.6 a missing assumption that was used in its proof. (The z-parameter must be close to zeta). Also added a related assumption to Thm. 4.4(b) (previously Prop. C.1), which relies on Prop. 3.6. Some further minor corrections and edits. Slightly improved Thm. 3.4 and Prop. B.6. Significantly revised introduction. New reference