Monolayers of dipalmitoyl-phosphatidylethanolamine (DPPE) mixing with various mole percentages of distearoyl-phosphatidylethanolamine (DSPE)-conjugated poly-(ethylene glycol) (PEG m.w. 750-5000) were deposited on DPPE-coated glass surfaces by the Langmuir-Blodgett method. Increasing percentages of grafted PEG in these supported lipid surfaces increasingly inhibit the adsorption of bovine serum albumin (BSA), laminin, and fibronectin. Increasing percentages of grafted PEG also inhibit the adhesion of erythrocytes, lymphocytes, and macrophages to these supported lipid surfaces. The adsorption of proteins on lipid coated glass surfaces were assayed by the fluorescence of FITC-labelled proteins. Cell adhesion was measured mainly by microscopic counting. The concentration of PEG-grafted lipids required for the inhibition of erythrocyte adhesion decreases with increasing molecular weight of the grafted PEG. The inhibitory effects are strongly dependent on the graft density of PEG at low concentrations, but weakly dependent on graft density at higher concentrations. For DSPE-PEG5000, the change of graft density dependency occurs approximately at the complete coverage of the lipid surface by the grafted polymer in the mushroom conformation (0.7 mol%), and the transition to partial brush conformation. The change-overs become less distinctive for grafted PEG of lower molecular weights, probably due to the failure of strictly mushroom and brush models of the polymer. The relative inhibitory efficiency is protein or cell dependent. The implication on the function of stealth liposomes is discussed.
We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDAPatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.
Although immune checkpoint blockade have demonstrated promising results, their effects on gastric cancer (GC) are under investigation. Understanding the clinical significance of PD1 and its ligands' expression, together with T cell infiltration might provide clues for biomarkers screening in GC immunotherapy. Immunohistochemistry were performed on a tissue microarray including 1,014 GC specimens using PD1, PDL1 and PDL2 antibodies. T cell markers CD3 and CD8 were also stained and quantified by automated image analysis. Correlation with clinical features and outcome were analyzed after controlling for potential confounders including EBV infection, HER2, C-met and PCNA expression. 37.8% of the cases showed membranous PD-L1 expression in tumor cells and 74.9% in infiltrating immune cells. PDL1 expression rate was rather higher in patients without metastasis, in EBV positive group and those with C-met and PCNA expression. GC patients with high level PDL1 expression exhibited better survival. GC Patients with higher T cell infiltration also showed elevated PDL1, PDL2 and PD1 expression and predict favorable outcome, indicating an adaptive immune resistance mechanism may exist. The group of patients infiltrated with lower density CD3+ T cells also without PDL1 expression in tumor cells predict the worst outcome in the subgroup of different PTNM stage, which may suggest an inactive immune status. These results highlights the need to assess both PDL1 expression in all tumor context and the characterization of the GC immune microenvironment.
Bone metastasis is associated with cancer‐related death in patients with prostate cancer (PCa). Long noncoding RNAs (lncRNAs) play critical roles in tumor progression of PCa. Nevertheless, the biological function of lncRNAs in PCa bone metastasis remains unclear. PCAT7 was identified as a bone metastasis‐related lncRNA via analyzing TCGA dataset. Meanwhile, PCAT7 was found to be elevated in primary PCa tissues with bone metastasis and associated with bone metastasis status and poor prognosis of patients with PCa. Functionally, our results reveal that PCAT7 overexpression promotes PCa bone metastasis in vivo, as well as migration, invasion, and EMT of PCa cells in vitro; on the contrary, PCAT7 knockdown has an inverse effect. Mechanistically, PCAT7 activates TGF‐β/SMAD signaling by upregulating TGFBR1 expression via sponging miR‐324‐5p. In turn, TGF‐β signaling forms a positive feedback loop with PCAT7 via SMAD3/SP1 complex‐induced PCAT7 upregulation. Finally, the clinical positive correlation between PCAT7 and TGFBR1 and TGF‐β signaling activity, and the negative association with miR‐324‐5p are further demonstrated in PCa tissues and clinical primary PCa cells. This study reveals a novel mechanism that is responsible for the constitutive activation of TGF‐β signaling in PCa bone metastasis, implying that PCAT7 can act as a potential therapeutic target against bone metastasis of PCa via disrupting the constitutive active loop between PCAT7 and TGF‐β signaling.
Abbreviations: SA-J schweinfurthin A-J; TGN trans-Golgi-network; PTEN phosphatase and tensin homolog; DLBCL diffuse large B cell lymphoma; mTOR mammalian target of rapamycin; PDK1 phosphoinositide-dependent kinase 1; PIP3 phosphatidylinositol (3,4,5)-triphosphate; WGA wheat germ agglutinin; ConA concanavalin; MAA Maackia amurensis agglutinin; PNA peanut agglutinin; ORPs oxysterol-binding protein related family proteins Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golginetwork trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTENdeficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/ AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.
Comparing hospitalised, community and staff COVID-19 infection rates during the early phase of the evolving COVID-19 epidemicDear Editor,
Postoperative adhesions are most common issues for almost any types of abdominal and pelvic surgery, leading to adverse consequences. Pharmacological treatments and physical barrier devices are two main approaches to address postoperative adhesions but can only alleviate or reduce adhesions to some extent. There is an urgent need for a reliable approach to completely prevent postoperative adhesions and to significantly improve the clinical outcomes, which, however, is unmet with current technologies. Here we report that by applying a viscous, cream-like yet injectable zwitterionic polymer solution to the traumatized surface, postoperative adhesion was completely and reliably prevented in three clinically relevant but increasingly challenging models in rats. The success rate of full prevention is over 93% among 42 animals tested, which is a major leap in antiadhesion performance. Clinically used Interceed film can hardly prevent the adhesion in any of these models. Unlike current antiadhesion materials serving solely as physical barriers, the “nonfouling” zwitterionic polymer functioned as a protective layer for antiadhesion applications with the inherent benefit of resisting protein/cell adhesions. The nonfouling nature of the polymer prevented the absorption of fibronectins and fibroblasts, which contribute to the initial and late-stage development of the adhesion, respectively. This is the key working mechanism that differentiated our “complete prevention” approach from current underperforming antiadhesion materials. This work implies a safe, effective, and convenient way to fully prevent postoperative adhesions suffered by current surgical patients.
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