Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment

Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9 +/- 1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96 +/- 1.88)% compared with (0.99 +/- 0.10)% in PBS group, revealing the enhanced immune response against PCa. Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy

The Cell Cycle Checkpoint Gene, RAD17 rs1045051, Is Associated with Prostate Cancer Risk

Human RAD17, as an agonist of checkpoint signaling, plays an essential role in mediating DNA damage. This hospital-based case-control study aimed to explore the association between RAD17 rs1045051, a missense sin-gle nucleotide polymorphism (SNP), and prostate cancer risk. Subjects were 358 prostate cancer patients and 314 cancer-free urology patients undergoing treatment at the Zhujiang Hospital of Southern Medical University in China. RAD17 gene polymorphism rs1045051 was evaluated by the SNaPshot method. Compared with the RAD17 gene polymorphism rs1045051 AA genotype, there was a higher risk of prostate cancer for the CC gen-otype (adjusted odds ratio [AOR] = 1.731, 95% confidence interval [95%CI] = 1.031−2.908, p = 0.038). Compared with the A allele, the C allele was significantly associated with the disease status (AOR = 1.302, 95%CI = 1.037−1.634, p = 0.023). All these findings indicate that in the SNP rs1045051, both the CC genotype and C allele may have a substantial influence on the prostate cancer risk

Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment

Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9 +/- 1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96 +/- 1.88)% compared with (0.99 +/- 0.10)% in PBS group, revealing the enhanced immune response against PCa. Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy

Exploring the ex-situ components within Gaia DR3

The presence of Gaia DR3 provides a large sample of stars with complete 6D information, offering a fertile ground for the exploration of stellar objects that were accreted to the Milky Way through ancient merger events. In this study, we developed a deep learning methodology to identify ex-situ stars within the Gaia DR3 catalogue. After two phases of training, our neural network (NN) model was capable of performing binary classification of stars based on input data consisting of 3D position and velocity, as well as actions. From the target sample of 27 085 748 stars, our NN model managed to identify 160 146 ex-situ stars. The metallicity distribution suggests that this ex-situ sample comprises multiple components but appears to be predominated by the Gaia-Sausage-Enceladus. We identified member stars of the Magellanic Clouds, Sagittarius, and 20 globular clusters throughout our examination. Furthermore, an extensive group of member stars from Gaia-Sausage-Enceladus, Thamnos, Sequoia, Helmi streams, Wukong, and Pontus were meticulously selected, constituting an ideal sample for the comprehensive study of substructures. Finally, we conducted a preliminary estimation to determine the proportions of ex-situ stars in the thin disc, thick disc, and halo, which resulted in percentages of 0.1%, 1.6%, and 63.2%, respectively. As the vertical height from the Galactic disc and distance from the Galactic centre increased, there was a corresponding upward trend in the ex-situ fraction of the target sample

Repurposing of posaconazole as a hedgehog/SMO signaling inhibitor for embryonal rhabdomyosarcoma therapy

Posaconazole (POS) is a novel antifungal agent, which has been repurposed as an anti-tumor drug for its potential inhibition of Hedgehog signaling pathway. Hedgehog pathway is reported to be abnormally activated in embryonal rhabdomyosarcoma (ERMS), this study aimed to reveal whether POS could inhibit Hedgehog signaling pathway in ERMS. Following POS treatment, XTT viability assay was used to determine the cell proliferation of ERMS cell lines. Protein changes related to Hedgehog signaling, cell cycle and autophagy were detected by Western blot. The cell cycle distribution was analyzed by flow cytometry. Moreover, a subcutaneous tumor mouse model of ERMS was established to assess the anti-tumor effect of POS. POS was found to inhibit tumor progression by inducing G0/G1 arrest and autophagy of RD, RMS-YM, and KYM-1 cells dose-dependently. Western blot demonstrated that POS downregulated the expressions of SMO, Gli1, c-Myc, CDK4, and CDK6, while upregulated the expressions of autophagy-related proteins. Immunofluorescence microscopy revealed a significant increase of LC3B puncta in POS-treated ERMS cells. Furthermore, POS treatment led to a significant inhibition of tumor growth in mice bearing ERMS. Our findings could provide a theoretical basis and have important clinical implications in developing POS as a promising agent against ERMS by targeting Hedgehog pathway

Dkk3/REIC Deficiency Impairs Spermiation, Sperm Fibrous Sheath Integrity and the Sperm Motility of Mice

The role of Dickkopf-3 (Dkk3)/REIC (The Reduced Expression in Immortalized Cells), a Wnt-signaling inhibitor, in male reproductive physiology remains unknown thus far. To explore the functional details of Dkk3/REIC in the male reproductive process, we studied the Dkk3/REIC knock-out (KO) mouse model. By examining testicular sections and investigating the sperm characteristics (count, vitality and motility) and ultrastructure, we compared the reproductive features between Dkk3/REIC-KO and wild-type (WT) male mice. To further explore the underlying molecular mechanism, we performed RNA sequencing (RNA-seq) analysis of testicular tissues. Our results showed that spermiation failure existed in seminiferous tubules of Dkk3/REIC-KO mice, and sperm from Dkk3/REIC-KO mice exhibited inferior motility (44.09 +/- 8.12% vs. 23.26 +/- 10.02%, p 0.05) nor the difference in the sperm vitality rate (72.83 +/- 1.55% vs. 72.50 +/- 0.71%, p > 0.05) were statistically significant. The RNA-seq and GO (Gene Oncology) enrichment results indicated that the differential genes were significantly enriched in the GO terms of cytoskeleton function, cAMP signaling and calcium ion binding. Collectively, our research demonstrates that Dkk3/REIC is involved in the process of spermiation, fibrous sheath integrity maintenance and sperm motility of mice

A diffusive predator-prey system with prey refuge and gestation delay

Abstract The dynamics of a diffusive predator-prey system with prey refuge and gestation delay is investigated in this paper. For a non-delay system, global stability, Turing instability and Hopf bifurcation are studied. For a delay system, time delay induced instability and Hopf bifurcation are discussed. By the theory of normal form and the center manifold method, the direction and stability of the bifurcating periodic solution are discussed

An Improved Weighted K-Nearest Neighbor Algorithm for Indoor Localization

The weighted K-nearest neighbor (WKNN) algorithm is the most commonly used algorithm for indoor localization. Traditional WKNN algorithms adopt received signal strength (RSS) spatial distance (usually Euclidean distance and Manhattan distance) to select reference points (RPs) for position determination. It may lead to inaccurate position estimation because the relationship of received signal strength and distance is exponential. To improve the position accuracy, this paper proposes an improved weighted K-nearest neighbor algorithm. The spatial distance and physical distance of RSS are used for RP selection, and a fusion weighted algorithm based on these two distances is used for position calculation. The experimental results demonstrate that the proposed algorithm outperforms traditional algorithms, such as K-nearest neighbor (KNN), Euclidean distance-based WKNN (E-WKNN), and physical distance-based WKNN (P-WKNN). Compared with the KNN, E-WKNN, and P-WKNN algorithms, the positioning accuracy of the proposed method is improved by about 29.4%, 23.5%, and 20.7%, respectively. Compared with some recently improved WKNN algorithms, our proposed algorithm can also obtain a better positioning performance

Effect of Laser Welding Parameters on Joint Structure of AZ31B Magnesium Alloy and 304 Stainless Steel

The effects of laser welding parameters on the interface microstructure of AZ31B magnesium alloy and 304 stainless steel were investigated. After welding, a scanning electron microscope and ultra-depth of field microscope were used to observe the microstructure of the welded material, to analyze the effects of power on the interface morphology. The simulation of laser welding of magnesium and steel was carried out by the COMSOL software. The results showed that when the power was 15 W–20 W, the temperature did not reach the melting point of magnesium alloy, there was MgO at the welding, and the interface had poor connection strength. When the power was 35 W–50 W, the temperature reached or even exceeded the boiling point of magnesium alloy, and the interface formed hot cracks, pores, and oxides and had poor joint strength. When the power was 25 W–30 W, the temperature was between the melting point and boiling point of magnesium, and the interface had excellent connection strength

Assessing Growth and Water Productivity for Drip-Irrigated Maize under High Plant Density in Arid to Semi-Humid Climates

Determining the water productivity of maize is of great significance for ensuring food security and coping with climate change. In 2018 and 2019, we conducted field trials in arid areas (Changji), semi-arid areas (Qitai) and semi-humid areas (Xinyuan). The hybrid XY335 was selected for the experiment, the planting density was 12.0 × 104 plants ha−1, and five irrigation amounts were set. The results showed that yield, biomass, and transpiration varied substantially and significantly between experimental sites, irrigation and years. Likewise, water use efficiency (WUE) for both biomass (WUEB) and yield (WUEY) were affected by these factors, including a significant interaction. Normalized water productivity (WP*) of maize increased significantly with an increase in irrigation. The WP* for film mulched drip irrigation maize was 37.81 g m−2 d−1; it was varied significantly between sites and irrigation or their interaction. We conclude that WP* differs from the conventional parameter for water productivity but is a useful parameter for assessing the attainable rate of film-mulched drip irrigation maize growth and yield in arid areas, semi-arid areas and semi-humid areas. The parametric AquaCrop model was not accurate in simulating soil water under film mulching. However, it was suitable for the prediction of canopy coverage (CC) for most irrigation treatments