A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis.

Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a "quartet" of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the ß-galactoside-binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell-niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis.

Chemically treated carbon black waste and its potential applications.

In this work, carbon black waste - a hazardous solid residue generated from gasification of crude oil bottom in refineries - was successfully used for making an absorbent material. However, since the carbon black waste also contains significant amounts of heavy metals (especially nickel and vanadium), chemical leaching was first used to remove these hazardous impurities from the carbon black waste. Acid leaching with nitric acid was found to be a very effective method for removal of both nickel and vanadium from the carbon black waste (i.e. up to 95% nickel and 98% vanadium were removed via treatment with 2M nitric acid for 1h at 20°C), whereas alkali leaching by using NaOH under the same condition was not effective for removal of nickel (less than 10% nickel was removed). Human lung cells (MRC-5) were then used to investigate the toxicity of the carbon black waste before and after leaching. Cell viability analysis showed that the leachate from the original carbon black waste has very high toxicity, whereas the leachate from the treated samples has no significant toxicity. Finally, the efficacy of the carbon black waste treated with HNO3 as an absorbent for dye removal was investigated. This treated carbon black waste has high adsorption capacity (∼361.2mg dye/g carbonblack), which can be attributed to its high specific surface area (∼559m2/g). The treated carbon black waste with its high adsorption capacity and lack of cytotoxicity is a promising adsorbent material. Moreover, the carbon black waste was found to show high electrical conductivity (ca. 10S/cm), making it a potentially valuable source of conductive material.

Industrial demonstration plant for the gasification of herb residue by fluidized bed two-stage process.

A fluidized bed two-stage gasification process, consisting of a fluidized-bed (FB) pyrolyzer and a transport fluidized bed (TFB) gasifier, has been proposed to gasify biomass for fuel gas production with low tar content. On the basis of our previous fundamental study, an autothermal two-stage gasifier has been designed and built for gasify a kind of Chinese herb residue with a treating capacity of 600 kg/h. The testing data in the operational stable stage of the industrial demonstration plant showed that when keeping the reaction temperatures of pyrolyzer and gasifier respectively at about 700 °C and 850 °C, the heating value of fuel gas can reach 1200 kcal/Nm(3), and the tar content in the produced fuel gas was about 0.4 g/Nm(3). The results from this pilot industrial demonstration plant fully verified the feasibility and technical features of the proposed FB two-stage gasification process.

Preparation and characterization of n-hydroxyapatite/PCL-pluronic-PCL nanocomposites for tissue engineering.

In this paper, a new kind of polymeric nanocomposite materials based on nano-hydroxyapatite (n-HA) and PCL-Pluronic-PCL (PCFC) copolymer were prepared by in situ combination method. Firstly, the PCFC copolymer was synthesized by ring-opening polymerization of epsilon-caprolactone initiated by Pluronic (PEG-PPG-PEG); Secondly, n-HA powder were combined with PCFC to form polymeric composites in the presence of hexamethylene diisocyanate (HDI). The obtained composites were characterized by 1H-NMR, FTIR, XRD, TEM, SEM, DTA/TGA, and tensile testing. The results revealed that n-HA could be dispersed into polymer matrix uniformly, and the n-HA/PCFC composite showed great mechanical properties when the content of n-HA was 10 wt%. The microstructure and thermal properties of the composites were discussed in the paper too. The experimental results suggested that this polymeric nanocomposite might have great potential application in the field of tissue engineering.

Safety evaluation of amphiphilic three-armed star-shaped copolymer micelles.

In our previous work, we had prepared a biodegradable amphiphilic three-armed star-shaped copolymers (SPCE) based on poly(epsilon-caprolactone) (PCL) and poly(ethylene glycol) (PEG), which could form micelles by self-assembly method and it was a potential carrier for hydrophobic drug. For further application, the safety of SPCE micelles was evaluated in vitro and in vivo here. (13)C-NMR was used to confirm the formation of the micelles in aqueous solution, and the morphology was observed on transmission electron microscope (TEM). Also, thermostability of blank SPCE micelles was determined by Malvern Nano-ZS 90 laser particle size analyzer. In vitro toxicity evaluation included hemolytic test and cytotoxicity. In vivo acute toxicity tests and histopathological study of SPCE micelles were carried out on BALB/C mice which were administrated SPCE micelles (1 g/kg b.w.) intravenously. In acute toxicity test, the mice were observed continuously for 7 days, obtained their body weight every day, at last the mice was sacrificed for the following study: the blood of the mice was assigned for blood chemistry and routine analysis, the heart, liver, spleen, lung, and kidneys were used for histopathological study. All results indicated that the biodegradable self-assembled SPCE micelles were nontoxic; therefore, it might be used as a safe candidate for drug delivery system.

Preparation and characterization of vitamin-12 loaded biodegradable pH-sensitive microgels.

This paper prepared novel biodegradable and pH-sensitive microgels based on Poly(epsilon-caprolactone)-Pluronic-Poly(epsilon-caprolactone)-dimethacrylate (PCFC-DMA), Poly(ethylene glycol) dimethacrylate (PEG-DMA) and methylacrylic acid (MAA) cross-linked with N,N'-methylenebisacrylamide (BIS), initiated by NaHSO(3), K(2)S(2)O(8). The blank microgels were prepared by inversed-phase suspension polymerization method and pH sensitivity of microgels was characterized. Then the blank microgels were loaded with hydrophilic model drug vitamin-12 (VB-12) and in vitro drug release behaviour was also studied here.

Novel composite drug delivery system for honokiol delivery: self-assembled poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) micelles in thermosensitive poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) hydrogel.

This study aims to develop a novel composite drug delivery system (CDDS) for hydrophobic honokiol delivery: honokiol loaded micelles in thermosensitive hydrogel (honokiol micelles/hydrogel) based on biodegradable poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) copolymers. In our work, we found that PECE copolymers with different molecular weight and PEG/PCL ratios could be administered to form micelles or thermosensitive hydrogel, respectively. Honokiol loaded PECE micelles (honokiol micelles) were prepared by self-assembly of biodegradable PECE copolymer (PEG5000-PCL5000-PEG5000) triggered by its amphiphilic characteristic assisted by ultrasonication without using any organic solvents and surfactants. Meanwhile, biodegradable and injectable thermosensitive PECE hydrogel (PEG550-PCL2400-PEG550) with a lower sol-gel transition temperature at around physiological temperature was also prepared successfully. Furthermore, the obtained honokiol micelles/hydrogel CDDS was a free-flowing sol at ambient temperature and became a nonflowing gel at body temperature. The cytotoxicity results showed that the CDDS was a safe carrier and the encapsulated honokiol retained its potent antitumor effect. In addition, the in vitro release profile demonstrated a significant difference between rapid release of free honokiol and much slower and sustained release of honokiol micelles/hydrogel. The results suggested that the CDDS might have great potential applications in cancer chemotherapy.

Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogel. Part 2: sol-gel-sol transition and drug delivery behavior.

In this work, a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) hydrogel was studied. The prepared PCEC hydrogel undergoes temperature-dependent sol-gel-sol transition, which is a flowing sol at ambient temperature and turns into a non-flowing gel at around physiological body temperature. Furthermore, the sol-gel phase transition mechanism was investigated using (13)C-nuclear magnetic resonance imaging and a laser diffraction particle size analyzer. The in vitro release behaviors of several model drugs, including a hydrophilic small-molecule drug, a hydrophobic small-molecule drug and a macromolecular protein drug, from PCEC hydrogel were also investigated in detail. The results showed that the model drugs could be released from the PCEC hydrogel system over a sustained period. In addition, an anaesthesia assay was conducted using the tail flick latency (TFL) test to evaluate the in vivo controlled drug delivery effect of the PCEC hydrogel system. In the TFL assay, a lidocaine-loaded PCEC hydrogel produced significantly longer-lasting local anaesthetic effects compared with lidocaine aqueous solution at the same dose. Therefore, PCEC hydrogel is promising for use as an injectable local drug delivery system.

Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel.

In this work, a series of biodegradable triblock poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) copolymers were successfully synthesized by ring-opening copolymerization, and were characterized by (1)H NMR, FT-IR, GPC, and DSC. Aqueous solutions of PECE copolymers underwent thermosensitive sol-gel-sol transition as temperature increases when the concentration was above corresponding critical gel concentration (CGC). Sol-gel-sol phase transition diagrams were recorded using test tube inverting method, which depended on hydrophilic/hydrophobic balance in macromolecular structure, as well as some other factors, including topology of triblock copolymers and solution composition of the hydrogel. As a result, the sol-gel-sol transition temperature range could be varied, which might be very useful for its application as injectable drug delivery systems. The in vivo gel formation and degradation behavior was conducted by injecting aqueous PECE solution into KunMing mice subcutaneously. In vitro degradation behavior, in vitro drug release behavior, and cytotoxicity were also investigated in this paper. Therefore, owing to great thermosensitivity and biodegradability of these copolymers, PECE hydrogel is believed to be promising for in situ gel-forming controlled drug delivery system.