The intensive hike-ponds in the Pearl River Delta are taken to establish a water quality model for pond farming.The results of model verification indicate that the simulation of the model fits the real situation well and it can be used as a research tool for pond aquaculture ecosystem or as a decision support tool for the management of pond farming.The model established is used to research main factors affecting the water quality and the carrying capacity of farming ponds.Results show that DO is generated mainly from phytoplankton photosynthesis and artificial oxygen enhancement,and consumed mainly by fish respiration.DO contents are influenced by various factors.TAN and SRP are generated mainly from fish metabolization and consumed mainly by absorption of phytoplanktons.They change much slowly compared with DO.The farming capacity of the farming ponds is influenced by many factors,including internal factors such as feed digestion and utilization and external factors such as the DO level and the TAN accumulation.The farming capacity of the mainly farmed fish increases with the increase of feed digestion rate and is restricted by the lack of DO and the high TAN concentration.The farming capacity of secondarily farmed fish increases with increasing availability of the heterotrophic feed caused by the decrease of digestion of feed for mainly farmed fish,and is restricted by the lack of DO.Mixed,rotational fishing model makes full exploitation of farming space,which can further extend the farming capacity in fish ponds.
Colonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.
Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion. p-Niclosamide, a water-soluble niclosamide, exerted potent in vivo antitumor activity in a UM xenograft mouse model. Mechanistically, niclosamide abrogated the activation of the NF-κB pathway induced by tumor necrosis factor α (TNFα) in UM cells, while niclosamide elevated the levels of intracellullar and mitochondrial reactive oxygen species (ROS) in UM cells. Quenching ROS by N-acetylcysteine (NAC) weakened the ability of niclosamide-mediated apoptosis. Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells. Furthermore, our results showed that niclosamide eliminated cancer stem-like cells (CSCs) as reflected by a decrease in the Aldefluor+ percentage and serial re-plating melanosphere formation, and these phenotypes were associated with the suppressed Wnt/β-catenin pathway by niclosamide in UM. Niclosamide caused a dose- and time-dependent reduction of β-catenin and the key components [e.g., DVLs, phospho-GSK3β (S9), c-Myc and Cyclin D1] in the canonical Wnt/β-catenin pathway. Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of β-catenin at S552 and S675 which determine the stability of β-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler. Taken together, our results shed light on the mechanism of antitumor action of niclosamide and warrant clinical trial for treatment of UM patients.
<p>Figure S1 - Biological and pharmacological inhibition of EZH2 potently dampens growth of IM-sensitive and -resistant CML cells; Figure S2 - GSK126 induces apoptosis in CML cells in a dose- and time-dependent manner; Figure S3 - GSK126 elicits cytochrome c release and mitochondrial damage; Figure S4 - Administration of GSK126 in CML mice reduces LSCs in spleen nucleated cells from CML mice; Figure S5 - Knockdown of EZH2 reduces in vivo LSCs in CML mice; Figure S6 - Pharmacological and biological inhibition of EZH2 in CML mice has minimal effect on LSCs and progenitor cells in BM and spleen nucleated cells from CML mice; Figure S7 - BCR-ABL is not involved in the EZH2 knockdown-enabled PTEN transcriptional elevation; Figure S8 - Knockdown of PTEN weakens the effect of LSCs reduction mediated by silencing EZH2.</p>
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