Purpose A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic. Experimental Design A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC). Results A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively. Conclusions Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy.

Fish are capable of excellent vision and can be profoundly influenced by the visual properties of their environment. Ambient colours have been found to affect growth, survival, aggression and reproduction, but the effect of background darkness (i.e., the darkness vs. lightness of the background) on preference and aggression has not been evaluated systematically. One-hundred Coho salmon (Oncorhynchus kisutch), a species that is increasing in popularity in aquaculture, were randomly assigned to 10 tanks. Using a Latin-square design, every tank was bisected to allow fish in each tank to choose between all the following colour choices (8 choices in total): black vs. white, light grey, dark grey, and a mixed dark grey/black pattern, as well as industry-standard blue vs. white, light grey, dark grey, and black. Fish showed a strong preference for black backgrounds over all other options (p < 0.01). Across tests, preference strength increased with background darkness (p < 0.0001). Moreover, having darker backgrounds in the environment resulted in less aggressive behaviour throughout the tank (p < 0.0001). These results provide the first evidence that darker tanks are preferred by and decrease aggression in salmonids, which points to the welfare benefits of housing farmed salmon in enclosures containing dark backgrounds.

Curiosity—the motivation to seek out information—has been studied widely across the animal kingdom. To investigate curiosity in zebrafish we presented 30 novel objects to groups of zebrafish housed in semi-naturalistic tanks (6 tanks; 10 fish/tank; 10-min presentations). During the first 100 s and final 100 s of each object's 10-min presentation period, we recorded each group's: (i) latency to approach the object, (ii) attraction to the object, (iii) social dynamics: agonistic behavior and group cohesion and coordination, and (iv) diving behavior, a stress response in zebrafish. Comparing these behaviors to a 100 s baseline period when no object was present, we tested for neophobia (avoidance of novelty), neophilia (overall attraction to novelty), sustained interest (prolonged attraction to at least some presentations), discriminant interest (certain objects eliciting more attention than others), habituation (loss of interest over time), and alterations to social and stress behaviors. Zebrafish groups readily approached all objects (1 s median latency), were neophilic throughout all object presentations, and showed systematic sustained interest only for some object presentations at the beginning of the study (object presentations 1–10). Over the course of the study, zebrafish also showed signs of habituation such that by the final ten object presentations (21-30), there were no signs of overall sustained interest. During the beginning of the study (object presentations 1–10), we also found evidence for specific object-driven interest, with object ID accounting for 11% of the variability in interest scores (p &lt; 0.01), and object-driven interest corresponding to alterations in social behavior: decreased aggression (p &lt; 0.02), increased group cohesion (p &lt; 0.02), and increased group coordination (p &lt; 0.05). By explicitly investigating curiosity in fish, this work reveals that under certain conditions, zebrafish voluntarily engage in cognitive stimulation opportunities. More work is needed to clarify what types of information zebrafish find most rewarding and how long-term exposure to such opportunities may affect fish welfare.

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Aquaculture is a growing industry worldwide and Canadian finfish culture is dominated by marine salmonid farming. In part due to increasing public and stakeholder concerns around fish welfare protection, the first-ever Canadian Code of Practice for the Care and Handling of Farmed Salmonids was recently completed, following the National Farm Animal Care Council's (NFACC) rigorous Code development process. During this process, both the Scientific (responsible for reviewing existing literature and producing a peer-reviewed report that informs the Code) and Code Development (a diverse group of stakeholders including aquaculture producers, fish transporters, aquaculture veterinarians, animal welfare advocates, food retailers, government, and researchers) Committees identified research gaps in tandem, as they worked through the literature on salmonid physiology, health, husbandry, and welfare. When those lists are combined with the results of a public “top-of-mind” survey conducted by NFACC, they reveal several overlapping areas of scientific, stakeholder, and public concern where scientific evidence is currently lacking: (1) biodensity; (2) health monitoring and management, with a focus on sea lice infection prevention and management; (3) feed quality and management, particularly whether feed restriction or deprivation has consequences for welfare; (4) enclosure design, especially focused on environmental enrichment provision and lighting design; and (5) slaughter and euthanasia. For each of these five research areas, we provide a brief overview of current research on the topic and outline the specific research gaps present. The final section of this review identifies future research avenues that will help address these research gaps, including using existing paradigms developed by terrestrial animal welfare researchers, developing novel methods for assessing fish welfare, and the validation of new salmonid welfare indices. We conclude that there is no dearth of relevant research to be done in the realm of farmed salmonid welfare that can support crucial evidence-based fish welfare policy development.

The number of animals bred, raised, and slaughtered each year is on the rise, resulting in increasing impacts to welfare. Farmed animals are also becoming more diverse, ranging from pigs to bees. The diversity and number of species farmed invites questions about how best to allocate currently limited resources towards safeguarding and improving welfare. This is of the utmost concern to animal welfare funders and effective altruism advocates, who are responsible for targeting the areas most likely to cause harm. For example, is tail docking worse for pigs than beak trimming is for chickens in terms of their pain, suffering, and general experience? Or are the welfare impacts equal? Answering these questions requires making an interspecies welfare comparison; a judgment about how good or bad different species fare relative to one another. Here, we outline and discuss an empirically-based methodology that aims to improve our ability to make interspecies welfare comparisons by investigating welfare range, which refers to how good or bad animals can fare. We begin our proposal with a theory of welfare. We operationalize that theory of welfare by identifying metrics that are defensible proxies for measuring welfare, including cognitive, affective, behavioral, and neuro-biological measures. We assign differential weights to those proxies that reflect their evidential value for the determinants of welfare, such as the &ldquo;Delphi'' structured deliberation method with a panel of experts. Then we review the evidence and score its quality to ascertain whether a particular taxa may possess the proxies in question to construct a taxa-level welfare range profile. Finally, we use a Monte Carlo simulation to generate an overall estimate of comparative welfare range relative to our hypothetical index species - humans. Interspecies welfare comparisons will help facilitate empirically informed decision-making to streamline the allocation of resources and to ultimately better prioritize and improve animal welfare.

Billions of animals across many taxa are extensively farmed, with critical impacts on animal welfare. Societal efforts to reduce animal suffering lack rigorous and systematic approaches that facilitate maximising welfare improvements, such as informed funding allocation decisions. We present a multi-measure, cross-taxa framework for modelling differences in pain, suffering, and related cognition to assess whether certain animals have larger welfare ranges (how well or badly animals can fare). Measures include behavioural flexibility, cognitive sophistication, and general learning. We evaluated 90 empirically detectable proxies for cognition and welfare range (henceforth 'proxies') in pigs, chickens, carp, salmon, octopus, shrimp, crabs, crayfish, bees, and silkworms. We grouped a subset of proxies into: A) 10 ideal proxies and B) 10 less ideal proxies but with sufficient data for interspecies comparisons. We graded the strength of evidence per proxy across taxa, and constructed a cognition and welfare range profile, with overall judgement scores (ranging from likely no/low confidence to yes/very high confidence). We discuss the implications of comparisons and highlight key avenues for future research. This work is timely, given recent indications of significant political will towards reducing animal suffering, such as the inclusion of cephalopods and decapods in the Animal Welfare (Sentience) Bill following a UK government-commissioned research review. Given the novelty and robustness of our review, we believe it sets a new standard for investigating interspecies comparisons of cognition and welfare ranges and helps inform future research. This should help streamline funding allocations and improve the welfare of millions of farmed animals.

The number of animals bred, raised, and slaughtered each year is on the rise, resulting in increasing impacts to welfare. Farmed animals are also becoming more diverse, ranging from pigs to bees. The diversity and number of species farmed invite questions about how best to allocate currently limited resources towards safeguarding and improving welfare. This is of the utmost concern to animal welfare funders and effective altruism advocates, who are responsible for targeting the areas most likely to cause harm. For example, is tail docking worse for pigs than beak trimming is for chickens in terms of their pain, suffering, and general experience? Or are the welfare impacts equal? Answering these questions requires making an interspecies welfare comparison; a judgment about how good or bad different species fare relative to one another. Here, we outline and discuss an empirical methodology that aims to improve our ability to make interspecies welfare comparisons by investigating welfare range, which refers to how good or bad animals can fare. Beginning with a theory of welfare, we operationalize that theory by identifying metrics that are defensible proxies for measuring welfare, including cognitive, affective, behavioral, and neuro-biological measures. Differential weights are assigned to those proxies that reflect their evidential value for the determinants of welfare, such as the Delphi structured deliberation method with a panel of experts. The evidence should then be reviewed and its quality scored to ascertain whether particular taxa may possess the proxies in question to construct a taxon-level welfare range profile. Finally, using a Monte Carlo simulation, an overall estimate of comparative welfare range relative to a hypothetical index species can be generated. Interspecies welfare comparisons will help facilitate empirically informed decision-making to streamline the allocation of resources and ultimately better prioritize and improve animal welfare.