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.
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 “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.
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.
Effects of growth hormone (GH) overexpression on internal morphology were examined in homozygous and hemizygous GH transgenic Coho Salmon Oncorhynchus kisutch aided by clearing and staining and magnetic resonance imaging methodologies. Morphological effects of transgenesis were observed in pin bones in fast‐growing hemizygous transgenic salmon, in vertebral column and swim bladder deformities in homozygotes, and as nonproportional modifications to some cranial structures examined among groups. These data provide further examples of the complex pleiotropic effects arising from GH overexpression in transgenic salmon.
<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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).</p><p><b>Results:</b> A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (<i>n</i> = 20) and other sarcomas (<i>n</i> = 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(12); 2972–80. ©2016 AACR</i>.</p></div>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.