Description: The fear (perceived predation risk) large carnivores inspire in mesocarnivores can affect ecosystem structure and function, and loss of the "landscape of fear" large carnivores create adds to concerns regarding the worldwide loss of large carnivores. Fear of humans has been proposed to act as a substitute, but new research identifies humans as a "super predator" globally far more lethal to mesocarnivores, and thus presumably far more frightening. Although much of the world now consists of human-dominated landscapes, there remains relatively little research regarding how behavioral responses to humans affect trophic networks, to the extent that no study has yet experimentally tested the relative fearfulness mesocarnivores demonstrate in reaction to humans versus nonhuman predators. Badgers ( Meles meles ) in Britain are a model mesocarnivore insofar as they no longer need fear native large carnivores (bears, Ursus arctos ; wolves, Canis lupus ) and now perhaps fear humans more. We tested the fearfulness badgers demonstrated to audio playbacks of extant (dog) and extinct (bear and wolf) large carnivores, and humans, by assaying the suppression of foraging behavior. Hearing humans affected latency to feed, vigilance, foraging time, number of feeding visits, and number of badgers feeding. Hearing dogs and bears had far lesser effects on latency to feed, and hearing wolves had no effects. Our results indicate fear of humans evidently cannot substitute for the fear large carnivores inspire in mesocarnivores because humans are perceived as far more frightening, which we discuss in light of the recovery of large carnivores in human-dominated landscapes.

Description: Purpose: Anticancer T-cell responses can control tumors, but immunosuppressive mechanisms in vivo prevent their function. The role of regulatory T cells (Tregs) in metastatic colorectal cancer is unclear. We have previously shown depletion of Tregs enhances colorectal cancer–specific effector T-cell responses. Low-dose cyclophosphamide targets Tregs in animal models and some human studies; however, the effect of cyclophosphamide in metastatic colorectal cancer is unknown. Experimental Design: Fifty-five patients with metastatic colorectal cancer were enrolled in a phase I/II trial and randomly assigned to receive 2-week-long courses of low-dose (50 mg twice a day) cyclophosphamide or not. The absolute number, phenotype, and antitumor function of peripheral blood–derived lymphocyte subsets were monitored throughout treatment, as well as during 18-month follow-up. Results: Initially, cyclophosphamide reduced proliferation in all lymphocyte subsets; however, a rapid mobilization of effector T cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell, and NK-cell numbers occurred. The expansion and subsequent activation of effector T cells was focused on tumor-specific T cells, producing both granzyme B and IFN. Cyclophosphamide-treated patients demonstrating the most enhanced IFN + tumor-specific T-cell responses exhibited a significant delay in tumor progression [HR = 0.29; 95% confidence interval (CI), 0.12–0.69; P = 0.0047), compared with nonresponders and no-treatment controls. Conclusions: Cyclophosphamide-induced Treg depletion is mirrored by a striking boost in antitumor immunity. This study provides the first direct evidence of the benefit of naturally primed T cells in patients with metastatic colorectal cancer. Our results also support the concept that nonmutated self-antigens may act as useful targets for immunotherapies. Clin Cancer Res; 23(22); 6771–80. ©2017 AACR .