Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model.

EGFR-targeted therapies are efficacious, but toxicity is common and can be severe. Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are only emerging, so neither their efficacy nor toxicity is fully established. Recombinant eBAT was created by combining cytokines EGF and uPA on the same single-chain molecule with truncated toxin.

Steady-state, therapeutic, and helminth-induced IL-4 compromise protective CD8 T cell bystander activation.

Memory CD8 T cells (T) can be activated into innate-like killers by cytokines like IL-12, IL-15, and/or IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are not fully resolved. We found strain-intrinsic deficiencies in bystander activation using specific pathogen-free mice, whereby basal IL-4 signals antagonize IL-18 sensing. We show that therapeutic and helminth-induced IL-4 impairs protective bystander-mediated responses against pathogens.

Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8 T cells.

Interleukin-7 (IL-7) is considered a critical regulator of memory CD8 T cell homeostasis, but this is primarily based on analysis of circulating and not tissue-resident memory (T) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion, we found that loss had only a modest effect on persistence of circulating memory and T subsets and that IL-7Rα was primarily required for normal basal proliferation.

Increased risk of cancer in dogs and humans: a consequence of recent extension of lifespan beyond evolutionarily-determined limitations?

Cancer is among the most common causes of death for dogs (and cats) and humans in the developed world, even though it is uncommon in wildlife and other domestic animals. We provide a rationale for this observation based on recent advances in our understanding of the evolutionary basis of cancer. Over the course of evolutionary time, species have acquired and fine-tuned adaptive cancer protective mechanisms that are intrinsically related to their energy demands, reproductive strategies, and expected lifespan.