Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. After pancreatic transplantation, mutant clones form lesions histologically similar to native PanINs, including prominent stromal responses. Gene expression profiling reveals molecular similarities of mutant clones with native PanINs, and identifies potential PanIN biomarker candidates including Neuromedin U, a circulating peptide hormone. Prospective reconstitution of human PanIN development from primary cells provides experimental opportunities to investigate pancreas cancer development, progression and early-stage detection.
Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in North American beef cattle. () is the bacterial pathogen most frequently isolated from cattle with BRD and the prevalence of antimicrobial resistance in this pathogen has been increasing. Administration of antimicrobials to prevent BRD is commonplace in stocker cattle, but the impact of this practice on emergence of resistance in is unknown. High risk, sale barn origin bull and steer calves ( = 169) were transported to a stocker facility in central Georgia and sampled via deep nasopharyngeal swab (NPS) at arrival processing. All calves received the macrolide antimicrobial tulathromycin (2.5 mg/kg subcutaneously) at arrival processing. A second NPS was collected from each calf 10 to 14 d after arrival. The occasional calves diagnosed and treated for BRD prior to 10 to 14 d were swabbed and cultured prior to treatment. Swabs were submitted for culture and antimicrobial susceptibility testing using the Kirby-Bauer disk diffusion method. Of the 169 cattle enrolled, 27 (16.0%) were culture positive for at arrival processing and of these, a multi-drug resistant (MDR) strain of was detected in 1 (3.7%). In contrast, 123 (72.8%) cattle were culture positive for at second sampling and of these, a MDR strain of was detected in 122 (99.2%). The proportions of cattle culture positive for and positive for MDR at arrival processing and at second sampling were significantly different ( < 0.001). At the level of the individual bacterial isolate, 366 individual isolates were collected from the calves at the time of the second sampling. Of these isolates, 361 (98.6%) were intermediate or resistant to all macrolides tested (tilmicosin, gamithromycin, tulathromycin) and the fluoroquinolone enrofloxacin. In addition, 254 isolates (69.4%) were intermediate or resistant to florfenicol and 4 (1.1%) were intermediate or resistant to ceftiofur. There was a significant difference in the proportion of isolates resistant to all of the drug classes except cephalosporins at arrival processing versus second sampling ( < 0.001). Our results show that there was an increase in the proportion of calves positive for from arrival processing to second sampling, and that there was an increase in the proportion of calves that had MDR strains of detected from arrival processing to second sampling. More research is needed to understand the role of metaphylaxis on MDR in and the impact of MDR on morbidity and mortality in stocker cattle.
Regenerative medicine aims to restore normal tissue architecture and function. However, the basis of tissue regeneration in mammalian solid organs remains undefined. Remarkably, mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration. Lineage tracing demonstrates that this regeneration derives from fate-restricted progenitor cells. Pharmacological or genetic disruption of Sdf1-Cxcr4 signaling enhances tissue repair, including full reconstitution of tissue architecture and all cell types. Our findings identify signaling and cellular mechanisms underlying appendage regeneration in mice and suggest new therapeutic approaches for regenerative medicine.
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