Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations.

ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

The characteristics of solid-phase substrate during the co-fermentation of lignite and straw.

Co-fermentation of lignite and biomass has been considered as a new approach in achieving clean energy. Moreover, the study of the characteristics of solid phase in the synergistic degradation process is of great significance in revealing their synergistic relationship. Accordingly, in order to produce biogas, lignite, straw, and the mixture of the two were used as the substrates, the solid phase characteristics of which were analyzed before and after fermentation using modern analytical methods. The results revealed that the mixed fermentation of lignite and straw promoted the production of biomethane. Moreover, the ratios of C/O and C/H were found to be complementary in the co-fermentation process. Furthermore, while the relative content of C-C/C-H bonds was observed to be significantly decreased, the aromatics degree of lignite was weakened. Also, while the degree of branching increased, there found to be an increase in the content of cellulose amorphous zone, which, consequently, led to an increase in the crystallinity index of the wheat straw. Hence, the results provide a theoretical guidance for the efficient utilization of straw and lignite.

The characterization of organic nitrogen and sulfur functional groups in coals after biomethane production.

To study the change characteristics of nitrogen and sulfur functional types in the raw coal and coal residues after anaerobic fermentation, three different rank coals from Baiyinhua mine (BY coal), Qianqiu mine (QQ coal), and Malan mine (ML coal) in China were collected and treated with methanogenic microorganisms, then X-ray photoelectron spectroscopy (XPS) was used to test the nitrogen and sulfur functional types in raw coals and coal residues. The results show that the pyrrolic nitrogen (N-5) and aromatic sulfur are the main nitrogen type and sulfur type in three coals. The N-5 increases by 17.42% in BY coal residue and decreases by 2.37% and 8.51% in QQ and ML coal residues, respectively. The pyridinic nitrogen (N-6) in BY, QQ, and ML coal residues decreases by 2.18%, 5.44%, and 2.75%, respectively. The aromatic sulfur increases by 2.13%, 3.14%, and 4.02% in BY, QQ, and ML coal residues, respectively. The aliphatic sulfur has obvious changes in BY and QQ coal residues with the increment of 9.17% and decrement of 11.64%, respectively. The results reveal that the nitrogen and sulfur types have changed in the coal residues after the biomethane production, and the instable types such as N-5 and aliphatic sulfur have obvious changes in the low-rank BY and QQ coals. The research provides a sight to the changes about nitrogen and sulfur types after biomethane yield and more deep thoughts about the clean and effective utilization of coals.

Metagenomic insight of corn straw conditioning on substrates metabolism during coal anaerobic fermentation.

Increasing methane production from anaerobic digestion of coal is challenging. This study shows that the combined fermentation of coal and corn straw greatly enriched the substrates available to microorganisms. This was mainly manifested in the increased types and abundance of organic matter in the fermentation liquid, which enhanced methane production by 61%. Metagenomic analysis showed that the addition of corn straw enriched the abundance of Methanosarcina in the combined fermentation system and promoted the complementary advantages of the microorganisms. At the same time, the abundance of genes that convert glucose into acetic acid (K00927, K01689, K01905, etc.) in the combined fermentation system increased, which is conducive to acidification process and biomethane production. In addition, there were the two key methanogenic pathways, namely aceticlastic (57.1%-63.5%) and hydrogenotrophic (23.4%-25.1%) methanogenesis, identified in the single coal fermentation system and the combined coal and corn straw fermentation system. Combined fermentation enhanced the hydrogenotrophic and methylotrophic methanogenic pathways by increasing the gene abundance of K00200 (methane production from CO2 and oxidation of coenzyme M to CO2), K00440 (participates in the binding to other known physiological receptors with hydrogen as a donor), and K00577 (methyltransferase).

Analysis of methanogens adsorption and biogas production characteristics from different coal surfaces.

The aim of this study was to examine the biogas production and the adsorption aspect of microorganism from different coals. Coal samples were obtained from Qianqiu mine and Guandi mine. Microbial populations were cultured from the coal mine drainage. After an anaerobic reaction period at about 35 °C, adsorption rate was determined by the spectrophotometer, while a scanning electron microscopy was used to observe the microorganisms on the coal and the headspace methane was analyzed using gas chromatography. Results show that the coal rank and particle size serve as important factors influencing the adsorption of microorganism and biogenic methane production. With decreasing particle size, the Qianqiu coal produced a considerable adsorption rate between 75 and 79%, while the adsorption rate of Guandi coal was between 52 and 74%. Meanwhile, the density of microorganisms from the Qianqiu coal surface demonstrated a higher level of adsorption than that of Guandi coal following the scanning electron microscopy images. Additionally, Qianqiu coal produced a higher level of biogas production (391.766-629.199 µmol/g) than that of Guandi coal (292.835-393.744 µmol/g) and the Qianqiu coal also generated a higher concentration of methane during the incubation. When the adsorption rate decreasing, the biogas production from various pulverized coals appeared to be decreased and demonstrated a positive correlation to the adsorption rate. The results of this study suggest that the adsorption behavior of microorganisms is closely related to the effect of coal biodegradation and contributes to the biogenic methane production potential.