Identification of ASF1A and HJURP by global H3-H4 histone chaperone analysis as a prognostic two-gene model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis. Abnormal expression of H3-H4 histone chaperones has been identified in many cancers and holds promise as a biomarker for diagnosis and prognosis. However, systemic analysis of H3-H4 histone chaperones in HCC is still lacking. Here, we investigated the expression of 19 known H3-H4 histone chaperones in HCC. Integrated analysis of multiple public databases indicated that these chaperones are highly expressed in HCC tumor tissues, which was further verified by immunohistochemistry (IHC) staining in offline samples. Additionally, survival analysis suggested that HCC patients with upregulated H3-H4 histone chaperones have poor prognosis. Using LASSO and Cox regression, we constructed a two-gene model (ASF1A, HJURP) that accurately predicts prognosis in ICGC-LIRI and GEO HCC data, which was further validated in HCC tissue microarrays with follow-up information. GSEA revealed that HCCs in the high-risk group were associated with enhanced cell cycle progression and DNA replication. Intriguingly, HCCs in the high-risk group exhibited increased immune infiltration and sensitivity to immune checkpoint therapy (ICT). In summary, H3-H4 histone chaperones play a critical role in HCC progression, and the two-gene (ASF1A, HJURP) risk model is effective for predicting survival outcomes and sensitivity to immunotherapy for HCC patients.

Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC.

Although traditional EGFR-TKIs have advanced the treatment landscape of NSCLC with sensitive driver mutations (del19 or L858R), some NSCLC patients with EGFR exon 20 insertion mutations have been left with few effective therapies. The development of novel TKIs is still in progress. Herein, we describe the structure-guided design of a novel selective and orally bioavailable inhibitor, YK-029A, which could overcome both the T790 M mutations and exon 20 insertion of EGFR. YK-029A inhibited EGFR signaling, suppressed sensitive mutations and ex20ins of EGFR-driven cell proliferation, and was largely effective with oral administration in vivo. Furthermore, YK-029A exhibited significant antitumor activity in EGFRex20ins-driven patients-derived xenograft (PDX) models, preventing tumor progression or causing tumor regression at well-tolerated dosages. Based on the outcomes of preclinical efficacy and safety studies, YK-029A will enter phase Ⅲ clinical trials for the treatment of EGFRex20ins NSCLC.

How does Microcystis aeruginosa respond to elevated temperature?

Cyanobacteria and their toxins widely exist in freshwater ecosystems. Microcystis aeruginosa is among dominant bloom-forming cyanobacteria. Water temperature is a key factor influencing the life cycle of M. aeruginosa. We simulated elevated temperature (4-35 °C) experiment and cultured M. aeruginosa during the overwintering, recruitment and rapid growth phases. The results showed that M. aeruginosa recovered growth after overwintering at 4-8 °C and recruited at 16 °C. The total extracellular polymeric substance (TEPS) concentration increased rapidly at 15 °C. The actual quantum yield of photosystem II (Fv'/Fm') peaked at 20 °C during the rapid growth phase, and the optimum temperature of M. aeruginosa growth was 20-25 °C. Additionally, TEPS and microcystins (MCs) secretion peaked at 20-25 °C. The cell density accumulated rapidly from 26 °C to 35 °C. Furthermore, enzymes of RuBisCO and FBA related to photosynthetic activity were confirmed to contribute to the metabolism, as well as mcyB gene was affected by elevated temperature. Our results provide insights of the physiological effects and metabolic activity during annual cycle of M. aeruginosa. And it is predicted that global warming may promote the earlier recruitment of M. aeruginosa, extend the optimum growth period, enhance the toxicity, and finally intensify M. aeruginosa blooms.

Exploring the mechanism of Xiaoqinglong decoction in the treatment of infantile asthma based on network pharmacology and molecular docking.

To explore the mechanism of Xiaoqinglong decoction (XQLD) in the treatment of infantile asthma (IA) based on network pharmacology and molecular docking. The active ingredients of fdrugs in XQLD were retrieved from Traditional Chinese Medicine Systems Pharmacology database and then the targets of drug ingredients were screened. The disease targets of IA were obtained from OMIM and Gencards databases, and the intersection targets of XQLD in the treatment of IA were obtained by Venny 2.1 mapping of ingredient targets and disease targets. Cytoscape software was used to construct active ingredient-intersection target network. The potential targets of XQLD in the treatment of IA were analyzed by protein-protein interaction network using STRING platform, and the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were obtained by R Studio software. AutoDock was used to perform molecular docking for verification. In this study, 150 active ingredients of XQLD were obtained, including quercetin, kaempferol, ß-sitosterol, luteolin, stigmasterol, and so on. And 92 intersection targets of drugs and diseases were obtained, including interleukin 6 (IL6), cystatin 3, estrogen receptor 1, hypoxia inducible factor 1A, HSP90AA1, epidermal growth factor receptor and so on. There were 127 items of Gene Ontology enrichment analysis and 125 Kyoto Encyclopedia of Genes and Genomes enrichment results, showing that apoptosis, IL-17 signaling pathway, tumor necrosis factor signaling pathway, P13K-Akt signaling pathway and other pathways may play a key role in the treatment of IA by XQLD. The results of molecular docking showed that the key active ingredients including quercetin, kaempferol, ß-sitosterol, luteolin, stigmasterol, and the core targets including IL6, cystatin 3, estrogen receptor 1, hypoxia inducible factor 1A, HSP90AA1, and epidermal growth factor receptor had good binding activity. Through network pharmacology and molecular docking, the potential targets and modern biological mechanisms of XQLD in the treatment of IA were preliminarily revealed in the study, which will provide reference for subsequent animal experiments and clinical trials.

Global trends of researches on radioactive enteritis: A bibliometric and visualization study.

BACKGROUND: Radiation enteritis (RE) caused by radiation therapy, can seriously affect human health. Recently, studies on RE have been growing rapidly, but there are no bibliometric studies on RE. This study aims to explore the development trends and research hotspots of RE. METHODS: Academic papers on the Web of Science were retrieved on the topic of "radioactive enteritis" from the establishment of the database to December 2020. Countries, institutions, and subjects selected in this field were visualized using Citespace, HistCite, and Vosviewer. The annual trends in publications, distribution, co-authorship status, and research hotspots were analyzed. RESULTS: The authors ranked first in terms of publication amount were Delaney, Francois, Milliat, and Vozenin-Brotons. The United States had the highest number of posts, followed by China, France, the United Kingdom, and Spain. CONCLUSION: Future research in the field of RE will focus on double-blind clinical trials of RE, and the related mechanisms, such as oxidative stress and apoptosis.

Effects of extracellular polymeric substances on the aggregation of Aphanizomenon flos-aquae under increasing temperature.

Aphanizomenon flos-aquae (A. flos-aquae) blooms are serious environmental and ecological problems. Extracellular polymeric substances (EPSs) are among the most important indicators for the growth and aggregation of A. flos-aquae. In this study, the secretion of the EPS matrix under temperature rise (7-37°C) was investigated and the role of this matrix in A. flos-aquae aggregation was quantified. First, when the temperature increased, the aggregation ratio increased from 41.85 to 91.04%. Meanwhile, we found that when soluble EPSs (S-EPSs), loosely bound EPSs (LB-EPSs), and tightly bound EPSs (TB-EPSs) were removed successively, the aggregation ratio decreased from 69.29 to 67.45%, 61.47%, and 41.14%, respectively. Second, the content of polysaccharides in the EPS matrix was higher than the content of proteins under temperature change. The polysaccharide in TB-EPSs was closely related to the aggregation ability of A. flos-aquae (P < 0.01). Third, PARAFAC analysis detected two humic-like substances and one protein-like substance in EPSs. Furthermore, Fourier transforms infrared spectroscopy (FTIR) showed that with increasing temperature, the polysaccharide-related functional groups increased, and the absolute value of the zeta potential decreased. In conclusion, these results indicated that a large number of polysaccharides in TB-EPSs were secreted under increasing temperature, and the polysaccharide-related functional groups increased correspondingly, which reduced the electrostatic repulsion between algal cells, leading to the destruction of the stability of the dispersion system, and then the occurrence of aggregation. This helps us to understand the process of filamentous cyanobacterial aggregation in lakes.

Paper mill sludge-based carbon quantum dots as a specifically ratiometric fluorescent probe for the sensitive and selective detection of coptisine.

Coptisine (COP), one of the bioactive components in Rhizoma Coptidis, has many pharmacological effects. Meanwhile, the determination of COP is essential in pharmacological and clinical applications. Herein, we prepared carbon quantum dots (CQDs) by one-step oil-thermal method using paper mill sludge (PMS) as precursor, and developed a ratiometric fluorescence method for the determination of COP. The structural and optical properties of PMS-CQDs were evaluated through high-resolution transmission electron microscopy (HRTEM), Fourier-transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), X-ray powder diffraction (XRD), ultraviolet-visible (UV-vis), fluorescence, zeta potential and fluorescence lifetime experiments. Fluorescence intensity ratio at 550 nm and 425 nm (I550 /I425 ) was recorded as an index for quantitative detection of COP. The detection concentration of COP ranges from 0.1 to 50 µM in good linear correlation (R2  = 0.9974) with a limit of detection of 0.028 µM (3σ/k). The quenching mechanism was deduced to be inner filter effect and static quenching. The ratiometric fluorescent probe showed impressive selectivity and sensitivity towards COP, and was successfully applied to the detection of COP in human urine with expected recoveries (95.22-111.00%) and relative standard deviations (0.46-2.95%), indicating that our developed method has a great application prospect in actual sample detection.

Multiclass retinal disease classification and lesion segmentation in OCT B-scan images using cascaded convolutional networks.

Disease classification and lesion segmentation of retinal optical coherence tomography images play important roles in ophthalmic computer-aided diagnosis. However, existing methods achieve the two tasks separately, which is insufficient for clinical application and ignores the internal relation of disease and lesion features. In this paper, a framework of cascaded convolutional networks is proposed to jointly classify retinal diseases and segment lesions. First, we adopt an auxiliary binary classification network to identify normal and abnormal images. Then a novel, to the best of our knowledge, U-shaped multi-task network, BDA-Net, combined with a bidirectional decoder and self-attention mechanism, is used to further analyze abnormal images. Experimental results show that the proposed method reaches an accuracy of 0.9913 in classification and achieves an improvement of around 3% in Dice compared to the baseline U-shaped model in segmentation.

Simultaneous determination of the novel tyrosine kinase inhibitor meditinib and its active metabolite demethylation meditinib in monkey plasma by liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies.

Meditinib (ME) is a novel tyrosine kinase inhibitor used as an antichronic myeloid leukemia drug. A simple, sensitive and specific LC/MS/MS method was developed and validated for the analysis of ME and its metabolite demethylation meditinib (PI) in monkey plasma using naltrexone as the internal standard. Sample preparation involved protein precipitation with methanol. The analysis was carried out on an Agilent C8 column (3.5 µm, 2.1 × 50 mm). Elution was achieved with a mobile phase gradient varying the proportion of a water solution containing 0.1% formic acid (solvent A) and a 0.1% formic acid in methanol solution (solvent B) at a flow rate of 300 µL/min. The method had a linear calibration curve over the concentration range of 2-1000 ng/mL for ME and 2-1000 ng/mL for PI. The lower limits of quantification of ME and PI were 2 and 2 ng/mL, respectively. The intra- and inter-day precision values were <15% and accuracy values were within ±10.0%. The mean recoveries of ME and PI from plasma were >85%. The assay has been successfully used for pharmacokinetic evaluation of ME and PI using the monkey as an animal model, and those data are reported for the first time.

Antiobesity action of a daidzein derivative on male obese mice induced by a high-fat diet.

Emerging evidence suggests that consumption or supplementation of foods rich in iso flavones may has a beneficial effect on obesity and glucose levels in animals and humans. It has been demonstrated that genistein, the main component of iso fl avones, could significantly reduce body weight and fat pad size. However, there is no evidence as to whether daidzein, which is also a main component of isoflavones, has the same effect. We hypothesize that LRXH609 (Dzd; a daidzein derivative) also has an antiobesity effect. In this study, we investigate the effects of Dzd on body weight, adipose tissue, blood, and liver lipid levels in obese mice fed a high-fat diet. Activities of pancreatic lipase and lipoprotein lipase, as well as lipolysis, were verified to clarify the potential mechanism of the daidzein. The results indicate that Dzd can significantly reduce body and fat pad weight and ameliorate the high-fat diet-induced hyperlipoidemia. We also found that Dzd inhibits the activity of pancreatic lipase and lipoprotein lipase in a dose-dependent manner, inhibits the differentiation of rat preadipocytes, and stimulates lipolysis by activating hormone-sensitive lipase.