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ObjectiveThe Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum.DesignWe monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis.ResultsCC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκb1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS.ConclusionsCC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

Early descriptions of floating limb behaviors in monkeys were associated with isolation rearing, a practice that ended more than two decades ago. The present authors named various forms of behaviors in which a leg is elevated for no apparent reason: "Floating Limb Suite" (FLS). Floating limb behaviors, identified in laboratory monkeys at the Washington National Primate Research Center (WaNPRC), consist of two subcategories distinguished by whether monkeys seem to react to the elevated leg or ignore it. Given the past association of isolation rearing with both self-biting (SB) and floating limb, the investigators predicted that SB and FLS would be associated in monkeys not reared in isolation. The investigators tracked, over a period of 3 years, the presence of FLS and SB in macaques (Macaca nemestrina, M. fascicularis, M. mulatta) and Papio cynocephalus at WaNPRC. SB and both subcategories of FLS occurred in mother-reared and surrogate-peer-nursery-reared monkeys. We analyzed presence of FLS, the two subcategories of FLS, and SB in 1,117 macaques monitored for up to 3 years, and 781 macaques observed for 8 min of structured data collection. The Papio sample size was insufficient for statistical analysis. Both sampling methodologies found FLS and FLS subcategories to be associated with SB. Nearly half the monkeys only engaging in seemingly harmless nonreactive forms of FLS also performed the potentially injurious behavior of self-biting. The positive association between FLS and SB suggests that monkeys exhibiting one of these behaviors are at a heightened risk for developing the other. One impediment to studying floating limb behaviors is lack of consensus on definitions. This study defined seven forms of apparently functionless elevated limb behaviors. Continued research on factors associated with floating limb behaviors across demographic groups and settings may provide insights into the etiology and treatment of self-biting.

The space environment includes weightlessness and galactic cosmic radiation (GCR), both of which can have a negative impact on bone parameters. In particular, acute exposures to space-relevant doses (2 Gy or less) of simulated GCR lead to a rapid acceleration of bone resorption activity and suppression of bone forming osteoblasts, resulting in diminished bone mineral density (BMD), strength and altered microarchitecture. A key mechanism driving these changes may be a radiation-induced increase in pro-inflammatory cytokines, such as TNF-α. Consuming a diet rich in omega-3 fatty acids has been associated with attenuated reductions in bone parameters in astronauts, mice and elderly humans with corresponding reductions in circulating inflammatory cytokines. PURPOSE: To test the hypothesis that a diet high in omega-3 fatty acids will mitigate radiation-induced bone loss and reduce inflammatory cytokines in bone osteocytes and serum. METHODS: Adult (30-to 50-week-old) female Lgr5-EGFP C57BL/6 mice (n=4-6 per group) were acclimated to a corn oil/cellulose (COC) or fish oil/pectin (FOP) diet for 3 weeks. Animals were subsequently randomized to total body low dose high-energy radiation (0.1, 0.25, 0.5 Gy of 1000 MeV/n 56 Fe at 25 cGy/min at Brookhaven National Lab) or non-irradiated control (sham) and euthanized 8 weeks later. MicroCT (ScanCo, Switzerland) analyses were performed to assess bone geometry and microarchitecture at the mid-shaft and distal end of the femur. Significance was assessed using an α of 0.10. RESULTS: There was a significant main effect of diet on mid-shaft femur periosteal diameter (Peri.Dm) (p=0.001) and endocortical diameter (Endo. Dm.) (p<0.001). The FOP diet led to larger Peri.Dm. (p<0.051 for all) and Endo.Dm. (p<0.41 for all) than did the COC diet at all doses. We could not detect an impact of 56 Fe on cortical area or cancellous bone volume at the distal femur. Irradiation with 0.25 and 0.5 Gy in the FOP mice showed significant increases in distal femur volumetric BMD (p=0.014, p=0.063) and trabecular thickness (p=0.058, p=0.028), as compared with sham FOP mice. CONCLUSION: Though we did not detect a significant impact of radiation on bone parameters, these early data analyses suggest some modest benefits from a diet high in omega-3 fatty acids on cortical and cancellous bone parameters.