Mesoporous cobalt-manganese layered double hydroxides promote the activation of calcium sulfite for degradation and detoxification of metronidazole.

Metronidazole (MNZ), a commonly used antibiotic, poses risks to water bodies and human health due to its potential carcinogenic, mutagenic, and genotoxic effects. In this study, mesoporous cobalt-manganese layered double hydroxides (CoxMny-LDH) with abundant oxygen vacancies (Ov) were successfully synthesized using the co-precipitation method and used to activate calcium sulfite (CaSO3) with slight soluble in water for MNZ degradation. The characterization results revealed that Co2Mn-LDH had higher specific areas and exhibited good crystallinity. Co2Mn-LDH/CaSO3 exhibited the best catalytic performance under optimal conditions, achieving a remarkable MNZ degradation efficiency of up to 98.1 % in only 8 min. Quenching experiments and electron paramagnetic resonance (EPR) tests showed that SO4•- and 1O2 played pivotal roles in the MNZ degradation process by activated CaSO3, while the redox cycles of Co2+/Co3+ and Mn3+/Mn4+ on the catalyst surface accelerated electron transfer, promoting radical generation. Three MNZ degradation routes were put forward based on the density functional theory (DFT) and liquid chromatography-mass spectrometer (LC-MS) analysis. Meanwhile, the toxicity analysis result demonstrated that the toxicity of intermediates post-catalytic reaction was decreased. Furthermore, the Co2Mn-LDH/CaSO3 system displayed excellent stability, reusability, and anti-interference capability, and achieved a comparably high removal efficiency across various organic pollutant water bodies. This study provides valuable insights into the development and optimization of effective heterogeneous catalysts for treating antibiotic-contaminated wastewater.

[Shelterbelt construction in the scenario of coordinated development of mountain, river, forest, farmland, lake, grassland, and sandy land ecosystems in semi-arid wind-sand areas: Principles and methods]. / 半干旱风沙区"山水林田湖草沙"建设中防护林营建的原理与方法.

We established the systematic concept framework of shelterbelt construction, with "shelterbelts" as the core concern in the construction of integrated ecosystems including mountain, river, forest, farmland, lake, grassland and sandy-land in semi-arid wind-sand areas. In the construction of shelterbelts, it is necessary to adhere to the principles of scientific coordination and systematic management, considering the carrying capacity of water resources, the demand for dust control, the greening and beautification effects, as well as the principle of improving economic benefits. In practice, the construction methods should base on the types and temporal-spatial distribution of shelterbelts, following the shelterbelts construction theory and technology to form different structure and service functions, achieving the functional goals of shelterbelts. By focusing on the key elements including people, forests, grass, fields, water, and sand, we put forward the timeliness, practicality, and scientificity of shelterbelt construction, proposing construction methods for farmland shelterbelts, pastureland shelterbelts, windbreak and sand-fixing forests and protective forest around village (city), which might provide production technical support for the high-quality construction of green ecological barrier in northern China.

Rapid degradation and detoxification of metronidazole using calcium sulfite activated by CoCu two-dimensional layered bimetallic hydroxides: Performance, mechanism, and degradation pathway.

In this study, cobalt copper-layered double hydroxides (CoCu-LDHs) were prepared by coprecipitation as catalysts to activate CaSO3 for metronidazole (MNZ) degradation. This is the first report on layered double hydroxides activating sulfite for the degradation of organic pollutants. Meanwhile, to address the issue of self-quenching reactions readily occurring in conventional sulfite advanced oxidation systems and resulting in low oxidant efficiency, CaSO3 with slightly soluble in water was used instead of commonly used Na2SO3, to improve the limitations of traditional systems. The results showed that in the CoCu-LDHs/CaSO3 system, the degradation rate of MNZ reached 98.7% within 5 min, representing a 23.0% increase compared to the CoCu-LDHs/Na2SO3 system. Owing to the excellent catalytic performance exhibited by CoCu-LDHs, characterizations including XRD, FTIR, SEM, TEM, BET and XPS were carried out to investigate this further. The results confirmed the successful synthesis of CoCu-LDH, and the activation mechanism study revealed that Co and Cu were considered to the main elements in activating CaSO3, demonstrating good synergistic effects. In addition, the oxygen vacancies on the catalyst surface also played a positive role in generating radicals and promoting electron transfer. Subsequently, the effects of Co/Cu ratio, catalyst dosage, oxidant concentration, pollutant concentration, pH and coexisting substances on MNZ degradation were investigated. Additionally, based on the LC-MS analysis of degradation products and toxicity tests, MNZ was transformed into different intermediates with low toxicity through four pathways, eventually mineralizing into inorganic small molecules. After six cycles, the MNZ degradation rate still reached 82.1%, exhibiting excellent stability and recyclability. In general, this study provides new ideas for activating sulfite, while providing theoretical support for subsequent research on sulfite advanced oxidation system.

Rational design of MOF@COF composites with multi-site functional groups for enhanced elimination of U(VI) from aqueous solution.

Both environment and human beings were menaced by the widespread application of radioactive uranium, high-performance and effective elimination of uranium from wastewater is of important meaning for development of environmental sustainability in the future. In this study, the water-stable MOF material and the highly crystalline COF were compounded by a mild hydrothermal strategy, which achieved efficient removal of U(VI) through the synergistic effect. The composites showed the characteristics of both COFs and MOFs, which will possess higher stability, larger surface area and faster adsorption efficiency that cannot be carried out by a single component. Batch experiments and characterizations (SEM, TEM, XRD, FT-IR, BET, XPS, etc.) indicated that UiO-66-NH2@LZU1 had more stable and multi-layer pore structure and rich active functional groups. The Langmuir model and the pseudo-second-order kinetics fitting was more suitable for the U(VI) elimination process. The greatest uranium adsorbing capacity of UiO-66-NH2@LZU1 (180.4 mg g-1) was observed to exceed the UiO-66-NH2 (108.8 mg g-1) and COF-LZU1 (65.8 mg g-1), which reached the excellent hybrid effects. Furthermore, FT-IR and XPS analyses confirmed that the most nitrogen-containing group from COF-LZU1 and oxygen-containing group of UiO-66-NH2 could be combined with U(VI). In addition, electrostatic interaction was also a mechanism during the removal process. This work displayed that UiO-66-NH2@LZU1 was a prospective hybrid material for radioactive waste remediation. The compound method and application mentioned in this work had provided a theoretical basis for designing and developing multi-functional composite adsorbents, which contributed to the development of new materials for radioactive wastewater treatment technologies.

Influence of humic acid on U(VI) elimination by ZIF-8: Synergistic chemical effect.

ZIF-8, a sort of zeolitic imidazolate frameworks (ZIFs), had showed superior adsorptive property of typical radionuclide U(VI), but it reminded uncertain how the performance of ZIF-8 would be affected by adding humic acid (HA). HA could significantly change the surface charge of ZIFs and the transport of U(VI) in natural settings, which affected the eradication of U(VI) in aquatic ecology. Thus the impact of HA for the U(VI) removal by ZIF-8 as well as its mechanism had been analyzed by batch experiments and spectral analyses. It was demonstrated that the addition of HA increased the maximum removal capacity towards U(VI) from 781.2 mg g-1 to 1398.5 mg g-1. Moreover, removal property in acidic solution was improved, and the influence of background ions on ZIF-8 was reduced. The detailed mechanism was further explored by microscopic spectral analysis. The zeta potential showed that HA enhanced the electronegativity of ZIF-8 thus enhancing the electrostatic interaction with positive ions. Moreover, FT-IR and XPS further indicated that HA enhanced the removal capacity by affecting the surface complexation phenomena and strong chemical interactions between U(VI) and ZIF-8. Also, investigations indicated that the incorporation of HA improved the removal efficiency for U(VI), which had far-reaching significance for the application of ZIF-8 in practical environment.

Ubiquitous occurrence and functional dominance of comammox Nitrospira in full-scale wastewater treatment plants.

The recent discovery of complete ammonia oxidation (comammox) bacteria has fundamentally upended the traditional two-step nitrification conception, but their functional importance in wastewater treatment plants (WWTPs) is still poorly understood. This study investigated distributions of comammox Nitrospira, ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) in activated sludge samples collected from 25 full-scale WWTPs. Using quantitative PCR (qPCR) and 16S rRNA gene amplicon sequencing, our results revealed that comammox Nitrospira ubiquitously occurred in all of 25 WWTPs and even outnumbered AOB and AOA with an average abundance of 1∼183 orders of magnitude higher in 19 WWTPs. Moreover, DNA-based stable isotope probing (DNA-SIP) assays validated that comammox Nitrospira actively participated in ammonia oxidation in the three microcosms seeding with activated sludge from three typical WWTPs, in which the ratios of comammox amoA to AOB amoA were at the range of 1∼10, 10∼100 and >100, respectively. Phylogenetic analysis in heavy fractions further indicated that Nitrospira nitrosa (N. nitrosa) was the dominant and active species. We quantified the contribution of ammonia oxidizers based on the currently available kinetic parameters of the representative species and found that comammox made major contributions to ammonia oxidation than other nitrifiers (5 ∼ 106 times that of AOB). The findings not only demonstrate the ubiquitous occurrence of comammox, but also highlight their functional dominance in ammonia oxidation in WWTPs.

Pre-clinical Formulation Development of an in situ Meglumine Salt of AZD5991: A Novel Macrocyclic Mcl-1 Inhibitor.

PURPOSE: AZD5991 is a potent and selective macrocyclic inhibitor of Mcl-1 in clinical development. Developing an intravenous solution formulation for AZD5991 proved to be challenging primarily due to the poor intrinsic solubility of AZD5991. In this article are described studies performed to select a suitable crystalline form and to assess physicochemical properties of AZD5991 to aid in the design of a solution formulation for preclinical studies. METHODS: It is preferable that the preclinical formulation has a line of sight for clinical formulation. For AZD5991, a concentration of at least 20 mg/ml was required for toxicology studies. Toward this goal, extensive pre-formulation characterization of AZD5991 including solid form analysis, pH-solubility profiling and solubility determination in cosolvents and other solubilizing media were carried out. RESULTS & DISCUSSION: Crystalline Form A, which is more stable in aqueous solution and possesses acceptable thermal stability, was selected for preclinical and clinical development of AZD5991. Extensive solubility evaluation revealed an interesting pH-solubility profile that significantly enhances solubilization at pH > 8.5 to allow solution concentrations of at least 30 mg/ml by in situ meglumine salt formation. CONCLUSION: Developing pre-clinical formulations to support in vivo studies requires a good understanding of the physicochemical properties of the drug candidates. Candidates with challenging pharmaceutic properties like the novel macrocycle molecule AZD5991, demand extensive characterization in its polymorph landscape, solubility profile and suitability evaluation of the excipients. Meglumine, a pH-adjusting and solubilizing agent, was found to be the best choice for formulating AZD5991 into an intravenous product to support preclinical studies.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Xylem hydraulics strongly influence the niche differentiation of tree species along the slope of a river valley in a water-limited area.

Xylem hydraulic characteristics govern plant water transport, affecting both drought resistance and photosynthetic gas exchange. Therefore, they play critical roles in determining the adaptation of different species to environments with various water regimes. Here, we tested the hypothesis that variation in xylem traits associated with a trade-off between hydraulic efficiency and safety against drought-induced embolism contributes to niche differentiation of tree species along a sharp water availability gradient on the slope of a unique river valley located in a semi-humid area. We found that tree species showed clear niche differentiation with decreasing water availability from the bottom towards the top of the valley. Tree species occupying different positions, in terms of vertical distribution distance from the bottom of the valley, showed a strong trade-off between xylem water transport efficiency and safety, as evidenced by variations in xylem structural traits at both the tissue and pit levels. This optimized their xylem hydraulics in their respective water regimes. Thus, the trade-off between hydraulic efficiency and safety contributes to clear niche differentiation and, thereby, to the coexistence of tree species in the valley with heterogeneous water availability.

Inhibitory effect and mechanism of action of juniper essential oil on gray mold in cherry tomatoes.

Juniper essential oil (JEO), which is mostly known as an immune system booster and effective detoxifier, has substantial antimicrobial activity. A comparison of the inhibitory effects of three plant essential oils from juniper (Juniperus rigida), cedarwood (Juniperus virginiana), and cypress (Crupressus sempervirens) on four plant pathogenic fungi indicated that JEO was the most effective at inhibiting the growth of gray mold (Botrytis cinerea). Additional studies were subsequently conducted to explore the in vivo and in vitro antifungal activity and possible mechanism of JEO against B. cinerea. The results show that JEO inhibited the germination of spores and mycelial growth of B. cinerea in a concentration-dependent manner and exhibited strong inhibition when its concentration exceeded 10 µL/mL. JEO also significantly inhibited the incidence of disease and diameters of gray mold lesions on cherry tomato fruit (Solanum lycopersicum). After 12 h of treatment with JEO, the extracellular conductivity, and the contents of soluble protein, malondialdehyde, and hydrogen peroxide were 3.1, 1.2, 7.2, and 4.7 folds higher than those of the control group, respectively (P < 0.05), which indicated that JEO can damage membranes. Scanning electron microscopy observations revealed that JEO affected the morphology of mycelia, causing them to shrivel, twist and distort. Furthermore, JEO significantly improved the activities of the antioxidant-related enzymes superoxide dismutase and catalase but reduced the pathogenicity-related enzymes polygalacturonase (PG), pectin lyase and endoglucanase of B. cinerea (P < 0.05). In particular, PG was reduced by 93% after treatment with JEO for 12 h. Moreover, the 18 constituents of JEO were identified by gas chromatography/mass spectrometry (GC-MS) analysis, mainly limonene (15.17%), γ-terpinene (8.3%), ß-myrcene (4.56%), terpinen-4-ol (24.26%), linalool (8.73%), α-terpineol (1.03%), o-cymene (8.35%) and other substances with antimicrobial activity. Therefore, JEO can be an effective alternative to prevent and control gray mold on cherry tomato fruit.

Preparation of magnetic copper ferrite nanoparticle as peroxymonosulfate activating catalyst for effective degradation of levofloxacin.

Magnetic CuFe2O4 nanoparticles were successfully synthesized with a coprecipitation method at 500 °C calcination temperature, and were utilized to degrade levofloxacin (LEV) as a peroxymonosulfate (PMS) activator. The structure and composition of the nanocatalyst were characterized by a series of methods, including scanning electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, vibrating sample magnetometer and thermogravimetric analysis. The effects of the PMS concentration, the catalyst dosage, the LEV initial concentration, the pH value and the inorganic anions on the LEV degradation were also explored. The results revealed that the designed CuFe2O4/PMS system had high activity and excellent stability in the complex conditions. The degradation efficiency of LEV still reached above 80% after four recycles of CuFe2O4 catalyst. The reactive species quenching experiments and electron paramagnetic resonance analysis suggested the existence of superoxide radicals, single oxygen, hydroxy radicals and sulfate radicals, and the first two were dominant radical oxygen species. Based on the mechanism analyses, the efficient degradation of LEV was probably due to the continuous generation of reactive species under the condition of Fe(III)/Fe(II) and Cu(II)/Cu(I) redox cycles. The research provided a reasonable reference for the PMS activation mechanism-based spinel-type ferrite catalysis.

Bibliometric analysis of global research on white rot fungi biotechnology for environmental application.

In recent years, white rot fungi (WRFs) have received tremendous attention as a biotechnological tool for environmental pollution control. In order to systematically and comprehensively describe the progress, trends, and hotspots of WRF biotechnology in the field of environmental pollution control, the 3967 related publications from 2003 to 2020 were collected from Web of Science Core Collection database, and the bibliometric characteristics including publication output, country, institution, journal, author, citation frequency, h-index, and research focus were evaluated by using Excel 2007, CiteSpace V, and VOSviewer. The results indicated that the number of research publications increased rapidly before 2009, but after that, the number of publications fluctuated in a certain range. China and USA were the most productive countries and the most active country in international cooperation. In this field, most authors tend to cooperate within a small group. The journal and subject category with the largest number of publications are "International Biodeterioration & Biodegradation" and "Biotechnology Applied Microbiology", respectively. The analysis of high-frequency keywords revealed that "laccase", "biodegradation", "decolorization", and "Phanerochaete chrysosporium" were the most cited terms among all publications. The pretreatment of biomass waste, decolorization of dye wastewater, and bioremediation of polluted environment are the key research directions of WRF biotechnology. Finally, the frontier topics and active authors in this research field were identified using burst detection. We believe that this bibliometric study provides a comprehensive and systematic overview and promoted the future cooperative research and knowledge exchange in this field of WRF biotechnology for environmental applications.

Oxidative degradation of tetracycline using peroxymonosulfate activated by cobalt-doped pomelo peel carbon composite.

Tetracycline (TC) is a typical ecotoxic antibiotic, which easily causes bacterial resistance. Therefore, it is necessary to remove TC from the water environment. In recent years, advanced oxidation processes (AOPs) rely on the use of highly reactive oxidizing sulfate radical which is turning into an increasingly popular as a tool of the removal of TC. In this study, cobalt-doped pomelo peel carbon composite (Co-PPCC) was prepared by the impregnation coprecipitation method to activate peroxymonosulfate (PMS) to remove TC. SEM, BET, XRD, FTIR, XPS, TGA, and other analytical techniques indicated that a carbon composite catalyst with excellent performance has been successfully prepared. TC was removed by the synergistic effect of adsorption and catalytic degradation processes. The adsorption capacity was limited (only approximately 20% within 60 min) and tending to saturation, which indicated that the removal of TC in the Co-PPCC/PMS system was mainly due to oxidative degradation. The influence of the Co-PPCC and PMS dosage, initial TC concentration, initial pH values, and coexisting anions on the removal efficiency of TC was investigated. When the Co-PPCC catalyst dosage was 1 g/L, PMS concentration was 2 g/L, and pH value was 11, the removal efficiency of TC with a concentration of 50 mg/L reached 99% within 60 min. Free radical quenching experiment and electron paramagnetic resonance (EPR) analysis indicated that the free radical and non-radical degradation processes exist in the Co-PPCC/PMS/TC system. The main degradation products and the possible transformation pathways of TC were explored by LC-MS. In addition, after four cycles of Co-PPCC tests, the removal efficiency of TC can reach 64%. This study provides a new method to reuse abandoned pomelo peels and synthesize an economical and environmentally friendly catalyst for activating peroxymonosulfate to remove TC antibiotics in water.

Greater hydraulic safety contributes to higher growth resilience to drought across seven pine species in a semi-arid environment.

Quantifying inter-specific variations of tree resilience to drought and revealing the underlying mechanisms are of great importance to the understanding of forest functionality, particularly in water-limited regions. So far, comprehensive studies incorporating investigations in inter-specific variations of long-term growth patterns of trees and the underlying physiological mechanisms are very limited. Here, in a semi-arid site of northern China, tree radial growth rate, inter-annual tree-ring growth responses to climate variability, as well as physiological characteristics pertinent to xylem hydraulics, carbon assimilation and drought tolerance were analyzed in seven pine species growing in a common environment. Considerable inter-specific variations in radial growth rate, growth response to drought and physiological characteristics were observed among the studied species. Differently, the studied species exhibited similar degrees of resistance to drought-induced branch xylem embolism, with water potential corresponding to 50% loss hydraulic conductivity ranging from -2.31 to -2.96 MPa. We found that higher branch hydraulic efficiency is related to greater leaf photosynthetic capacity, smaller hydraulic safety margin and lower woody density (P < 0.05, linear regressions), but not related to higher tree radial growth rate (P > 0.05). Rather, species with higher hydraulic conductivity and photosynthetic capacity were more sensitive to drought stress and tended to show weaker growth resistance to extreme drought events as quantified by tree-ring analyses, which is at least partially due to a trade-off between hydraulic efficiency and safety across species. This study thus demonstrates the importance of drought resilience rather than instantaneous water and carbon flux capacity in determining tree growth in water-limited environments.

Bevacizumab biosimilar LY01008 compared with bevacizumab (Avastin) as first-line treatment for Chinese patients with unresectable, metastatic, or recurrent non-squamous non-small-cell lung cancer: A multicenter, randomized, double-blinded, phase III trial.

BACKGROUND: Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC). METHODS: Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). RESULTS: Between December 15th , 2017, and May 15th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. CONCLUSIONS: LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.

Influence of polyethylene-microplastic on environmental behaviors of metals in soil.

Microplastics (MPs) in terrestrial ecosystems have attracted increasing attention all over the world. The adsorption-desorption behavior and bioavailability of metals in soil would affect its toxicity to organisms. However, the influences of MPs on adsorption-desorption behavior between metals and soil as well as bioavailability of metals in soils are scarcely investigated. Herein, different percentage (0, 0.1%, 1%, 10%) of polyethylene-microplastic (PE-MP) were thoroughly mixed into the soil to investigate the impacts of PE-MP on adsorption-desorption and bioavailability of metals (Zn2+, Pb2+) in the soil. A series of characterization were carried out to determine the change of PE-MP before and after adsorption to investigate the mechanisms. When MP100 (average size: 129 µm) content in soil increased to 10%, the adsorption capacities of soil with Pb2+ and Zn2+ were 3.73 and 4.56 mg/g, respectively, which were significantly (p < 0.05) lower than that of pure soil. When MP300 (average size: 293 µm) content in soil increased to 10%, the extraction fraction of Zn2+ and Pb2+ from soil by diethylenetriaminepentaacetic acid reached 12.35% and 23.96%, respectively, which were significantly (p < 0.05) higher than that of pure soil, indicating high concentration (10%) of MPs in soil would decrease the adsorption capability of soil to metals and increase the mobility of metals in terrestrial environment. However, when MPs content in soil was 0.1%, the extraction fraction of Zn2+ and Pb2+ showed no significant difference with that of pure soil, indicating that actual MPs in soil is unlikely to bring significant influence on metal bioavailability.

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.

A comprehensive analysis of the microbiota composition and gene expression in colorectal cancer.

BACKGROUND: The dysregulation of gut microbiota is pivotal in colorectal carcinogenesis. Meanwhile, altered gut microbiome may affect the development of intestinal diseases through interaction with the host genes. However, the synergy between the altered gut microbiota composition and differential expression of specific genes in colorectal cancer (CRC) remains elusive. Thus, we integrated the data from 16S rRNA gene sequences and RNA sequences to investigate the potential relationship between genes and gut microbes in patients with CRC. RESULTS: Compared with normal samples, the presence of Proteobacteria and Fusobacteria increased considerably in CRC samples; conversely, the abundance of Firmicutes and Spirochaetes decreased markedly. In particular, the genera Fusobacterium, Catenibacterium, and Shewanella were only detected in tumor samples. Meanwhile, a closely interaction between Butyricimonas and Clostridium was observed in the microbiome network. Furthermore, a total of 246 (differentially expressed genes) DEGs were identified between tumor and normal tissues. Both DEGs and microbiota were involved in bile secretion and steroid hormone biosynthesis pathways. Finally, genes like cytochrome P450 family 3 subfamily A member 4 (CYP3A4) and ATP binding cassette subfamily G member 2 (ABCG2) enriched in these two pathways were connected with the prognosis of CRC, and CRC patients with low expression level of CYP3A4 and ABCG2 had longer survival time. CONCLUSION: Identifying the complicated interaction between gut microbiota and the DEGs contributed to further understand the pathogenesis of CRC, and these findings might enable better diagnosis and treatment of CRC patients.

Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

LINC00689 induces gastric cancer progression via modulating the miR-338-3p/HOXA3 axis.

BACKGROUND: LINC00689 acts one critical regulatory role in several tumors. However, the functional, regulatory mechanism and expression of LINC00689 remains unknown in gastric cancer. METHODS: LINC00689 and miR-338-3p levels were determined using a quantitative reverse transcriptase-polymerase chain reaction analysis and an enzyme-linked immunoassay and a cell-counting kit-8 assay were utilized to detect interleukin (IL)-8, IL-6 and IL-1ß expression and cell proliferation, respectively. RESULTS: We found that LINC00689 and HOXA3 are overexpressed and miR-338-3p is decreased in gastric cancer cells. Compared to control specimens, LINC00689 is overexpressed in gastric cancer specimens and the level of LINC00689 was up-regulated in 32 cases (32/40; 80.0%) compared to control samples. LINC00689 increased cell growth, epithelial-mesenchymal transition (EMT) development and secretion of inflammatory factors in gastric cancer. Compared to control specimens, miR-338-3p expression was decreased in gastric cancer specimens and a Pearson's correlation assay revealed that miR-338-3p was negatively correlated with LINC00689 expression in gastric cancer specimens. HOXA3 was identified as one target gene of miR-338-3p and Ectopic expression of LINC00689 suppressed miR-338-3p and enhanced HOXA3 expression in HGC-27 cells. LINC00689 enhanced cell growth, EMT development and secretion of inflammatory factors by promoting HOXA3. CONCLUSIONS: LINC00689 may present a potential future target for gastric cancer treatment.