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Previous work done by our laboratory described the use of an immunocompetent spontaneous melanoma-prone mouse model, TGS (TG-3/SKH-1), to evaluate treatment outcomes using inhibitors of glutamatergic signaling and immune checkpoint for 18 weeks. We showed a significant therapeutic efficacy with a notable sex-biased response in male mice. In this follow-up 18-week study, the dose of the glutamatergic signaling inhibitor was increased (from 1.7 mg/kg to 25 mg/kg), which resulted in improved responses in female mice but not male mice. The greatest reduction in tumor progression was observed in male mice treated with single-agent troriluzole and anti-PD-1. Furthermore, a randomly selected group of mice was removed from treatment after 18 weeks and maintained for up to an additional 48 weeks demonstrating the utility of the TGS mouse model to perform a ≥1-year preclinical therapeutic study in a physiologically relevant tumor-host environment. Digital spatial imaging analyses were performed in tumors and tumor microenvironments across treatment modalities using antibody panels for immune cell types and immune cell activation. The results suggest that immune cell populations and cytotoxic activities of T cells play critical roles in treatment responses in these mice. Examination of a group of molecular protein markers based on the proposed mechanisms of action of inhibitors of glutamatergic signaling and immune checkpoint showed that alterations in expression levels of xCT, γ-H2AX, EAAT2, PD-L1, and PD-1 are likely associated with the loss of treatment responses. These results suggest the importance of tracking changes in molecular markers associated with the mechanism of action of therapeutics over the course of a longitudinal preclinical therapeutic study in spatial and temporal manners., (© 2024 The Authors.)

As climate change alters the global environment, it is critical to understand the relationship between shifting climate suitability and species distributions. Key questions include whether observed changes in population abundance are aligned with the velocity and direction of shifts predicted by climate suitability models and if the responses are consistent among species with similar ecological traits. We examined the direction and velocity of the observed abundance-based distribution centroids compared with the model-predicted bioclimatic distribution centroids of 250 bird species across the United States from 1969 to 2011. We hypothesized that there is a significant positive correlation in both direction and velocity between the observed and the modeled shifts. We then tested five additional hypotheses that predicted differential shifting velocity based on ecological adaptability and climate change exposure. Contrary to our hypotheses, we found large differences between the observed and modeled shifts among all studied bird species and within specific ecological guilds. However, temperate migrants and habitat generalist species tended to have higher velocity of observed shifts than other species. Neotropical migratory and wetland birds also had significantly different observed velocities than their counterparts, which may be due to their climate change exposure. The velocity based on modeled bioclimatic suitability did not exhibit significant differences among most guilds. Boreal forest birds were the only guild with significantly faster modeled-shifts than the other groups, suggesting an elevated conservation risk for high latitude and altitude species. The highly idiosyncratic species responses to climate and the mismatch between shifts in modeled and observed distribution centroids highlight the challenge of predicting species distribution change based solely on climate suitability and the importance of non-climatic factors traits in shaping species distributions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)