Activity

Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.Systemic sclerosis (SSc) is an inflammatory fibrotic disease characterized by an excessive extracellular matrix deposition in the skin and internal organs. One fibrotic key event remains the fibroblast-to-myofibroblast differentiation that is controlled by a combination of mechanical and soluble factors, such as transforming growth factor-β1 (TGF-β1) and interleukin-1β (IL-1β). One important myofibroblast biomarker is human xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan biosynthesis. Increased serum XT activity was quantified in SSc, but the underlying cellular mechanisms remain elusive. This study aims to determine the cellular basis of XT-I induction in SSc by using a myofibroblast cell culture model with SSc fibroblasts (SScF) and healthy control fibroblasts. We found that SScF exhibit a higher extracellular XT-I activity compared to control fibroblasts. This increased XT-I activity in SScF was demonstrated to be mediated by an enhanced autocrine TGF-β signaling. Upon IL-1β treatment, SScF showed an increased mRNA expression level of XT-I and TGF-β receptor II (TGFBR2), while healthy control fibroblasts did not, pointing towards an involvement of IL-1β in the cytokine-mediated XT-I induction. selleck products Performing microRNA (miRNA) inhibition experiments in the presence of TGF-β1, we showed that the pro-fibrotic effect of IL-1β may be mediated by a miRNA-21/TGF-β receptor II axis, enhancing the autocrine TGF-β signaling in SScF. Taken together, this study improves the mechanistic understanding of fibrotic XT-I induction in SSc by identifying a hitherto unknown IL-1β-mediated miRNA-21/TGFBR2 regulation contributing to the enhanced XYLT1 expression and XT-I activity in SScF.Fibroblast growth factor (FGF10)-mediated signals are essential for embryonic eyelid closure in mammals. Systemic SOX11-deficient mice are born with unclosed eyelids, suggesting a possible role of SOX11 in eyelid closure. However, the underlying mechanisms of this process remain unclear. In this study, we show that epithelial deficiency of SOX11 causes a defect in the extension of the leading edge of the eyelid, leading to failure of embryonic eyelid closure. c-Jun in the eyelid is a transcription factor downstream of FGF10 required for the extension of the leading edge of the eyelid, and c-Jun level was decreased in epithelial SOX11-deficient embryos. These results suggest that epithelial SOX11 plays an important role in embryonic eyelid closure.The aim of this study was to evaluate the impact of the genotype (guinea fowl, native breed Leghorn, and commercial hybrid hens), storage time (0, 14, 28 d) and storage temperature (fresh, 5, 20°C) on eggshell quality traits and microbiological contamination of eggshell, eggshell membranes, and albumen. A total of 150 hens (50 hens per genotype-divided into 2 equal groups because of the results replication) were used. There were 150 eggs (50 per genotype) used for microbial analysis and 600 eggs used for the analysis of eggshell quality. The effects of genotype, storage time, and storage temperature were observed. Moreover, interactions between these factors were calculated. The significant effect of genotype (P = 0.0001) was found in egg weight, in all observed parameters of eggshell quality (proportion, thickness, strength, surface, and index), eggshell contamination of Escherichia coli (EC) and total number of micro-organisms (TNM), penetration of TNM into eggshell membranes (P = 0.0014), and penetration oty of adaptation to different environmental conditions, and especially in terms of eggshell quality and therefore egg safety.Providing adequate feeder space in broiler production is important to ensure bird performance and well-being; however, the effect of feeder space on behavior responses of broilers remains unclear. The objective of this research was to investigate feeding behaviors of broilers provided with 4 feeder spaces, that are 2.3 cm/bird with one feeder (2.3FSO); and 2.3, 4.6, and 6.9 cm/bird with 3 feeders (2.3FST, 4.6FST, and 6.9FST, respectively). Number of feeder slots per feeder was 14 at 2.3FSO, 5 at 2.3FST, 9 at 4.6FST, and 14 at 6.9FST. Sixteen identical pens, each with 45 broilers (Ross 708, mixed sex), were used to accommodate the 4 feeder space treatments. Feeding behaviors were continuously monitored from weeks 4 to 8 using an ultra-high-frequency radio frequency identification system. The results show that the daily feeding time and number of feeder visits for broilers at 2.3FST were similar to those at 4.6FST and 6.9FST but higher than those at 2.3FSO (P less then 0.01). The feeder utilization ratio was the highest at 2.3FST, indicating the feeder being used most efficiently among the 4 treatments (P less then 0.01). Coefficient of variations (33.0-65.1%) of the feeding behavior responses was similar among the treatments (P ≥ 0.06), suggesting similar group uniformity of feeding behaviors of individual broilers. Feeders among all treatments may not be fully used because for most of the time, less than 6 birds chose to eat simultaneously at a more-than-five-slot feeder in all treatments. Given the same feeder space, increasing feeder number can accommodate more birds to eat simultaneously. The outcomes of this study provide insights into improvement of feeder design and management for broiler production.