Demethylzeylasteral (ZST93) Inhibits Cell Growth and Enhances Cell Chemosensitivity to Gemcitabine in Human Pancreatic Cancer Cells via Apoptotic and Autophagic Pathways

Abstract

The overall 5-year survival rate of patients with human pancreatic cancer remains less than 8% because of its aggressive growth, early metastasis, and resistance to conventional chemoradiotherapy. It is essential to develop innovative and effective therapeutic agents to improve its prognosis. Demethylzeylasteral (ZST93) is a novel triterpenoid monomer extracted from the xylem of Tripterygium roots. This study aimed to assess the effects of ZST93 on cell proliferation and its role in the chemosensitivity to gemcitabine in human pancreatic cancer cells. The effects of ZST93 on cancer cell proliferation, cell cycle distribution, apoptosis and autophagy were evaluated in various human pancreatic cancer cell lines, and the anti-tumor effects of ZST93 alone and in combination with gemcitabine were identified in a xenograft mouse model. The results showed that ZST93 could inhibit the proliferation of pancreatic cancer cells and arrest cell cycle at G0/G1 phase by regulating the expression of Cyclin D1 and Cyclin A2. Moreover, ZST93 killed pancreatic cancer cells through two different mechanisms: inducing autophagic cell death at low concentrations and apoptotic cell death at high concentrations. Furthermore, ZST93 could enhance the chemosensitivity of pancreatic cancer cells to gemcitabine both in vitro and in vivo through modulation of the cross-talk between autophagy and apoptosis. ZST93 is a potential therapeutic agent for developing novel therapeutic strategies in human pancreatic cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2AGhWuU

Sensory uncertainty impacts avoidance during spatial decisions

Abstract

When making risky spatial decisions, humans incorporate estimates of sensorimotor variability and costs on outcomes to bias their spatial selections away from regions that incur feedback penalties. Since selection variability depends on the reliability of sensory signals, increasing the spatial variance of targets during visually guided actions should increase the degree of this avoidance. Healthy adult participants (N = 20) used a computer mouse to indicate their selection of the mean of a target, represented as a 2D Gaussian distribution of dots presented on a computer display. Reward feedback on each trial corresponded to the estimation error of the selection. Either increasing or decreasing the spatial variance of the dots modulated the spatial uncertainty of the target. A non-target distractor cue was presented as an adjacent distribution of dots. On a subset of trials, feedback scores were penalized with increased proximity to the distractor mean. As expected, increasing the spatial variance of the target distribution increased selection variability. More importantly, on trials where proximity to the distractor cue incurred a penalty, increasing variance of the target increased selection bias away from the distractor cue and prolonged reaction times. These results confirm predictions that increased sensory uncertainty increases avoidance during risky spatial decisions.

http://ift.tt/2jSK17N

The Effects of Ex Vivo Administration of Granulocyte-Macrophage Colony-Stimulating Factor and Endotoxin on Cytokine Release of Whole Blood Are Determined by Priming Conditions

Background. Lipopolysaccharide- (LPS-) induced tumour necrosis factor alpha (TNF) secretion in critically ill patients can be considered as a measure of immune responsiveness. It can be enhanced by granulocyte-macrophage colony stimulating factor (GM-CSF). We investigated the effect of GM-CSF on ex vivo stimulated cytokine production using various preincubation regimens in healthy donors and patients with sepsis. Results. The maxima for the stimuli occurred 3 hours after stimulation. In donors, there was an increase of LPS-induced TNF levels following incubation with GM-CSF. The simultaneous incubation with GM-CSF and LPS caused an inhibition of TNF production . Postincubation with GM-CSF did not yield any difference. In patients, preincubation with GM-CSF yielded an enhanced ex vivo TNF-response when TNF levels were low. Patients with increased TNF concentrations did not show a GM-CSF stimulation effect. The GM-CSF preincubation yielded an increase of IL-8 production in patients and donors. Conclusions. This study demonstrates the immune-modulating properties of GM-CSF depending on the absence or presence of LPS or systemic TNF. The timing of GM-CSF administration may be relevant for the modulation of the immune system in sepsis. The lack of stimulation in patients with high TNF may represent endotoxin tolerance.

http://ift.tt/2yqQ1sD

High PD-L1 expression indicates poor prognosis of HIV-infected patients with non-small cell lung cancer

Abstract

Background

The status of antitumor immunity represented by the expression of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and immune cell (IC) infiltration is unknown in HIV-infected patients with non-small cell lung cancer (NSCLC).

Methods

Fifteen HIV-infected patients with NSCLC were compared with 29 non-HIV-infected patients with NSCLC. Analysis of 13 propensity-score-matched patients in the two groups was also compared. The expression of PD-1/PD-L1 and tumor infiltration by CD4⁺, CD8⁺, and CD56⁺ immune cells were examined by immunohistochemistry; score of ≥ 2 was defined as positive.

Results

Although high PD-L1 expression in tumor cells was observed in HIV and non-HIV cohorts, the association of PD-1/PD-L1 was significant only in the HIV cohort. In overall as well as the propensity-matched analyses, HIV-infected patients with high PD-L1 expression showed shorter survival than HIV-infected patients with low PD-L1 expression; no significant difference was observed in this respect in the non-HIV cohort.

Conclusion

High PD-L1 expression in tumor tissue was associated with poor prognosis in HIV-infected NSCLC patients but not in non-HIV-infected NSCLC patients. These results suggest that antitumor immunity by PD-1/PD-L1 axis might be suppressed more in HIV-infected NSCLC patients as compared to their non-HIV-infected counterparts.

http://ift.tt/2C4ao1g

Association between Two Resistin Gene Polymorphisms and Metabolic Syndrome in Jilin, Northeast China: A Case-Control Study

Metabolic syndrome (MetS) is a significant health care problem worldwide and is characterized by increased fasting glucose and obesity. Resistin is a protein hormone produced both by adipocytes and immunocompetent cells, including those residing in adipose tissue, and is believed to modulate glucose tolerance and insulin action. This study examined the association of resistin gene polymorphisms, rs1862513 and rs3745368, and related haplotypes with the development of metabolic syndrome in a Han Chinese population. This case-control study was performed on 3792 subjects, including 1771 MetS cases and 2021 healthy controls from the Jilin province of China. Metabolic syndrome was defined according to the criteria of the International Diabetes Federation (IDF). Logistic regression analysis was used to estimate the relationship between gene polymorphism and MetS. Our results showed that there were no significant associations between MetS and the genotype distributions in four kinds of inheritance models, allele frequencies, and related haplotypes of resistin gene polymorphisms rs1862513 and rs3745368 (all values > 0.05). Based on our study findings, we concluded that mutations in resistin genes are not associated with the presence of MetS in a Han Chinese population from Jilin province in China.

http://ift.tt/2o2BDqM

High PD-L1 expression indicates poor prognosis of HIV-infected patients with non-small cell lung cancer

Abstract

Background

The status of antitumor immunity represented by the expression of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and immune cell (IC) infiltration is unknown in HIV-infected patients with non-small cell lung cancer (NSCLC).

Methods

Fifteen HIV-infected patients with NSCLC were compared with 29 non-HIV-infected patients with NSCLC. Analysis of 13 propensity-score-matched patients in the two groups was also compared. The expression of PD-1/PD-L1 and tumor infiltration by CD4⁺, CD8⁺, and CD56⁺ immune cells were examined by immunohistochemistry; score of ≥ 2 was defined as positive.

Results

Although high PD-L1 expression in tumor cells was observed in HIV and non-HIV cohorts, the association of PD-1/PD-L1 was significant only in the HIV cohort. In overall as well as the propensity-matched analyses, HIV-infected patients with high PD-L1 expression showed shorter survival than HIV-infected patients with low PD-L1 expression; no significant difference was observed in this respect in the non-HIV cohort.

Conclusion

High PD-L1 expression in tumor tissue was associated with poor prognosis in HIV-infected NSCLC patients but not in non-HIV-infected NSCLC patients. These results suggest that antitumor immunity by PD-1/PD-L1 axis might be suppressed more in HIV-infected NSCLC patients as compared to their non-HIV-infected counterparts.

http://ift.tt/2C4ao1g

A New 3D Printing Strategy by Harnessing Deformation, Instability, and Fracture of Viscoelastic Inks

Abstract

Direct ink writing (DIW) has demonstrated great potential as a multimaterial multifunctional fabrication method in areas as diverse as electronics, structural materials, tissue engineering, and soft robotics. During DIW, viscoelastic inks are extruded out of a 3D printer's nozzle as printed fibers, which are deposited into patterns when the nozzle moves. Hence, the resolution of printed fibers is commonly limited by the nozzle's diameter, and the printed pattern is limited by the motion paths. These limits have severely hampered innovations and applications of DIW 3D printing. Here, a new strategy to exceed the limits of DIW 3D printing by harnessing deformation, instability, and fracture of viscoelastic inks is reported. It is shown that a single nozzle can print fibers with resolution much finer than the nozzle diameter by stretching the extruded ink, and print various thickened or curved patterns with straight nozzle motions by accumulating the ink. A quantitative phase diagram is constructed to rationally select parameters for the new strategy. Further, applications including structures with tunable stiffening, 3D structures with gradient and programmable swelling properties, all printed with a single nozzle are demonstrated. The current work demonstrates that the mechanics of inks plays a critical role in developing 3D printing technology.

A new 3D printing strategy is reported by harnessing deformation, instability, and fracture of viscoelastic inks. The new strategy allows a single nozzle printing of various fiber diameters and patterns for viscoelastic inks. Furthermore, selection parameters for the new 3D printing strategy can be rationally guided by a quantitative phase diagram.

http://ift.tt/2krQmGL