Designing low-carbon fly ash based geopolymer with red mud and blast furnace slag wastes: Performance, microstructure and mechanism.

In order to tackle the environmental problems induced by Portland cement production and industrial solid wastes landfilling, this study aims to develop novel ternary cementless fly ash-based geopolymer by recycling red mud and blast furnace slag industrial solid wastes. The fresh-state properties, mechanical strength, water permeability, phase assemblage and microstructure were systematically investigated to evaluate the performance variation and reveal the hydration mechanism for geopolymers with different mixing proportions. The results showed that a higher slag content or a lower red mud content could result in the higher fluidity and shorter setting time for fresh mixture. The existence of slag promoted the transformation of N-A-S-H to C-A-S-H gel, which contributed to higher compressive strength and better resistance to water penetration. However, an excessive incorporation of 30% red mud may impede the generation of N-A-S-H gel and form more flocculent-like loose hydrates, thus to mildly degrade the mechanical strength and anti-permeability. The synergetic utilization of red much and blast furnace slag in fly ash-based geopolymer led to much less CO2 emission compared with the condition that red much or slag was singly added, which demonstrated prominent environmental advantages for such kind of ternary cementless geopolymer with equivalent mechanical strength.

Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3Kα inhibitors in oesophageal squamous cell carcinoma.

Phosphoinositide-3 kinase alpha (PI3Kα) has been confirmed to be a potential therapeutic target for esophageal squamous cell carcinoma (ESCC), while the potency of PI3Kα inhibitors is often attenuated by concurrent oncogenic signalling pathways. We performed genome-wide gain-of-function screening with a CRISPR-SAM library and identified enhancer of zeste homolog 2 (EZH2) rendering ESCC cells resistant to the PI3Kα inhibitor CYH33. Enhanced expression of EZH2 frequently occurs in ESCC and is related to poor prognosis. Overexpression of full-length EZH2 but not methyltransferase-deficient EZH2 conferred resistance to CYH33, while downregulating EZH2 expression restored sensitivity. EZH2 expression was negatively related to the activity of CYH33 against the proliferation of ESCC cell lines and patient-derived cells. Transcriptomic analysis revealed that EZH2 abrogated CYH33-mediated cell cycle regulation. EZH2 epigenetically suppressed the transcription of CDKN1A, promoting RB phosphorylation and cell cycle progression. Concurrently targeting EZH2 significantly potentiated CYH33 to inhibit the growth of ESCC cells and patient-derived xenografts accompanied by enhanced cell cycle arrest. Taken together, our study demonstrated that an EZH2-p21-RB axis remodeled cell cycle regulation and rendered resistance to PI3Kα inhibitors in ESCC. Simultaneously targeting PI3Kα and EZH2 may provide an effective strategy for ESCC therapy with high expression of EZH2.

Property Regulation of Conjugated Oligoelectrolytes with Polyisocyanide to Achieve Efficient Photodynamic Antibacterial Biomimetic Hydrogels.

Fabricating antibacterial hydrogels with antimicrobial drugs and synthetic biocompatible biomimetic hydrogels is a promising strategy for practical medical applications. Here, we report a bicomponent hydrogel composed of a biomimetic polyisocyanopetide (PIC) hydrogel and a photodynamic antibacterial membrane-intercalating conjugated oligoelectrolyte (COE). The aggregation behavior and aggregate size of the COEs in water can be regulated using the PIC hydrogel, which could induce COEs with higher reactive oxygen species (ROS) production efficiency and increased association of COEs toward bacteria, therefore enhancing the antibacterial efficiency. This strategy provides a facile method for developing biomimetic hydrogels with high antibacterial capability.

One-step mechanochemical preparation and prominent antitumor activity of SN-38 self-micelle solid dispersion.

PURPOSE: The purpose of this study was to overcome the clinical defects of 7-ethyl-10-hydroxycamptothecin (SN-38) and explore its characteristics and antitumor effects. MATERIALS AND METHODS: An amorphous solid dispersion of SN-38 with disodium glycyrrhizin (Na2GA) was prepared by mechanical ball milling (Na2GA/SN-38-BM). Moreover, an untreated mixture of Na2GA and SN-38 (Na2GA/SN-38-UM), a pure drug SN-38, was prepared for comparison with Na2GA/SN-38-BM. The samples were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), dynamic light scattering, and transmission electron microscopy. Then, further in vitro and in vivo studies were performed including cell uptake, cytotoxicity, antitumor efficacy, tissue distribution, and histopathological evaluation (H&E staining). RESULTS: SN-38 loaded in Na2GA was self-formed as nano-micelles in water. The particle size of nano-micelle was 69.41 nm and ζ-potential was -42.01 mV. XRD and SEM analyses showed that the ball milling transformed SN-38 crystals into amorphous form and that solubility increased by 189 times. Compared with SN-38 and Na2GA/SN-38-UM, Na2GA/SN-38-BM has a stronger cytotoxicity to tumor cells and exhibited a significant inhibition of tumor growth. Then, pharmacokinetic studies showed that the bioavailability of Na2GA/SN-38-BM was about four times that of SN-38 suspension. CONCLUSION: Na2GA/SN-38-BM (69 nm, -42 mV) nanoparticles which had excellent phar-macokinetic and distribution properties can dramatically enhance the anticancer efficacy of SN-38 in vitro and in vivo, suggesting a promising formulation for efficient anticancer therapy.

Nanoformulation of a Novel Pyrano[2,3-c] Pyrazole Heterocyclic Compound AMDPC Exhibits Anti-Cancer Activity via Blocking the Cell Cycle through a P53-Independent Pathway.

Pyrano[2,3-c]pyrazole derivatives have been reported as exerting various biological activities. One compound with potential anti-tumor activity was screened out by MTT assay from series of dihydropyrazopyrazole derivatives we had synthesized before using a one-pot, four-component reaction, and was named as 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (hereinafter abbreviated as AMDPC). The IC50 of AMDPC against Bcap-37 breast cancer cells was 46.52 µg/mL. Then the hydrophobic AMDPC was encapsulated in PEG-PLGA block copolymers, and then self-assembled as polymeric micelle (mPEG-PLGA/AMDPC) to improve both physiochemical and release profiles. The effect of mPEG-PLGA/AMDPC on BCAP-37 cancer cells showed similar anti-tumor effects as AMDPC. Furthermore, the anti-tumor mechanism of mPEG-PLGA/AMDPC was investigated, which can probably be attributed to stimulating the expression of P21 gene and therefore protein production on BCAP-37 cells, and then blocked the cell cycle through the P53-independent pathway both in S phase and G2 phase. Thus, mPEG-PLGA/AMDPC is a promising therapeutic agent for cancer treatment, and further in vivo studies will be developed.