Discovery of 4-((3,4-dichlorophenyl)amino)-2-methylquinolin-6-ol derivatives as EGFR and HDAC dual inhibitors.

In patients with non-small cell lung cancer (NSCLC), the standard therapy consists of selective tyrosine kinase inhibitors that target epidermal growth factor receptors (EGFR). Nonetheless, their clinical utility is primarily limited by the development of resistance to drugs. HDAC inhibitors have been shown in studies to reduce the level of EGFR that is expressed and downregulate the EGFR-induced phosphorylation of AKT and ERK. Therefore, dual inhibitors of EGFR and HDAC provide a potential approach as combination treatment synergistically inhibited the growth of NSCLC. Herein, we examined the EGFR inhibition effect of twenty compounds which designed and synthesized by us previously. Among them, compounds 12c and 12d exhibited powerful antiproliferative activity against the NCI-H1975 cell line with IC50 values of 0.48 ± 0.07 and 0.35 ± 0.02 µM, correspondingly. In cell-free kinase assays, both 12c and 12d demonstrated target-specific EGFR inhibition against wild type (EGFRwt). Furthermore, the expression of EGFR and phosphorylation of the EGF-induced pathways were significantly suppressed under the treatment of 12c and 12d. Besides, both histones H3 and H4 exhibited increased levels of acetylation following 12c and 12d treatment. The animal experiments shown that 12d could prevent the growth of tumor, inhibited the expression of EGFR and the phosphorylation levels of p70 S6K, AKT and p38 MAPK in vivo, and did not cause organ damage to the mice during the experiment. Overall, the results illustrated that compound 12c and 12d could serve as effective EGFR and HDAC dual inhibitors in NSCLC cells. Our work offers an alternative strategy for NSCLC therapy.

Selected rhizobacteria facilitated phytoremediation of barren and heavy metal contaminated gold mine tailings by Festuca arundinacea.

Gold mine tailings pose a significant challenge for phytoremediation due to their poor nutrition and heavy metal pollution. Rhizobacteria-assisted phytoremediation is a promising method, yet limited research has been conducted on its application in gold mine tailings. In this study, rhizobacteria R1 (Bacillus paramycoides) and R2 (Klebsiella michiganensisW14T) were isolated from the rhizosphere of Festuca arundinacea (F. arundinacea) to enhance the phytoremediation of gold mine tailings. Our results showed that inoculation of R1 and R2 led to a significant increase in the average germination rates of F. arundinacea by 36.9% and 16.5%, respectively. Furthermore, the average plant height increased by 68.3% and 53.4%, respectively. Importantly, after inoculation with rhizobacteria, the contents of Mn, Pb, and As in F. arundinacea increased by 13.2-33.9%, 40.1-41.0%, and 98.1%-124.5%, respectively, indicating that the rhizobacteria enhanced the plant uptake of heavy metals. The improved nutrient content and enzyme activity in the tailings after inoculation with rhizobacteria were positively correlated with the heavy metal content in F. arundinacea. In addition, inoculation of rhizobacteria significantly altered the microbial community structure of the tailings, with Bacillus becoming the dominant genus in the rhizosphere tailings of F. arundinacea after R1 inoculation. Overall, our findings demonstrated that rhizobacteria R1 was better to enhance the phytoremediation of gold mine tailings. These results offer valuable insights into the mechanism of rhizobacteria-assisted phytoremediation and provide a practical method to enhance remediation of gold mine tailings.

Feature-guided attention network for medical image segmentation.

BACKGROUND: U-Net and its variations have achieved remarkable performances in medical image segmentation. However, they have two limitations. First, the shallow layer feature of the encoder always contains background noise. Second, semantic gaps exist between the features of the encoder and the decoder. Skip-connections directly connect the encoder to the decoder, which will lead to the fusion of semantically dissimilar feature maps. PURPOSE: To overcome these two limitations, this paper proposes a novel medical image segmentation algorithm, called feature-guided attention network, which consists of U-Net, the cross-level attention filtering module (CAFM), and the attention-guided upsampling module (AUM). METHODS: In the proposed method, the AUM and the CAFM were introduced into the U-Net, where the AUM learns to filter the background noise in the low-level feature map of the encoder and the CAFM tries to eliminate the semantic gap between the encoder and the decoder. Specifically, the AUM adopts a top-down pathway to use the high-level feature map so as to filter the background noise in the low-level feature map of the encoder. The AUM uses the encoder features to guide the upsampling of the corresponding decoder features, thus eliminating the semantic gap between them. Four medical image segmentation tasks, including coronary atherosclerotic plaque segmentation (Dataset A), retinal vessel segmentation (Dataset B), skin lesion segmentation (Dataset C), and multiclass retinal edema lesions segmentation (Dataset D), were used to validate the proposed method. RESULTS: For Dataset A, the proposed method achieved higher Intersection over Union (IoU) ( 67.91 ± 3.82 % $67.91\pm 3.82\%$ ), dice ( 79.39 ± 3.37 % $79.39\pm 3.37\%$ ), accuracy ( 98.39 ± 0.34 % $98.39\pm 0.34\%$ ), and sensitivity ( 85.10 ± 3.74 % $85.10\pm 3.74\%$ ) than the previous best method: CA-Net. For Dataset B, the proposed method achieved higher sensitivity (83.50%) and accuracy (97.55%) than the previous best method: SCS-Net. For Dataset C, the proposed method had highest IoU ( 83.47 ± 0.41 % $83.47\pm 0.41\%$ ) and dice ( 90.81 ± 0.34 % $90.81\pm 0.34\%$ ) than those of all compared previous methods. For Dataset D, the proposed method had highest dice (average: 81.53%; retina edema area [REA]: 83.78%; pigment epithelial detachment [PED] 77.13%), sensitivity (REA: 89.01%; SRF: 85.50%), specificity (REA: 99.35%; PED: 100.00), and accuracy (98.73%) among all compared previous networks. In addition, the number of parameters of the proposed method was 2.43 M, which is less than CA-Net (3.21 M) and CPF-Net (3.07 M). CONCLUSIONS: The proposed method demonstrated state-of-the-art performance, outperforming other top-notch medical image segmentation algorithms. The CAFM filtered the background noise in the low-level feature map of the encoder, while the AUM eliminated the semantic gap between the encoder and the decoder. Furthermore, the proposed method was of high computational efficiency.

Rs2459976 in ZW10 gene associated with congenital heart diseases in Chinese Han population.

Congenital heart diseases (CHD) are a large group of prevalent and complex anatomic malformations of the heart, with the genetic basis remaining largely unknown. Since genes or factors associated with the differentiation of human embryonic stem (HES) cells would affect the development of all embryonic tissues, including cardiac progenitor cells, we postulated their potential roles in CHD. In this study, we focused on ZW10, a kinetochore protein involved in the process of proper chromosome segregation, and conducted comparative studies between CHD patients and normal controls matched in gender and age in Chinese Han populations. We identified three variations in the ZW10 gene, including rs2885987, rs2271261 and rs2459976, which all had high genetic heterozygosity. Association analysis of these genetic variations with CHD showed correlation between rs2459976 and the risk of CHD. We conclude that rs2459976 in the ZW10 gene is associated with CHD in Chinese Han populations.

Microarray analysis reveals altered circulating microRNA expression in mice infected with Coxsackievirus B3.

Coxsackievirus B3 (CVB3) is a common causative agent in the development of inflammatory cardiomyopathy. However, whether the expression of peripheral blood microRNAs (miRNAs) is altered in this process is unknown. The present study investigated changes to miRNA expression in the peripheral blood of CVB3-infected mice. Utilizing miRNA microarray technology, differential miRNA expression was examined between normal and CVB3-infected mice. The present results suggest that specific miRNAs were differentially expressed in the peripheral blood of mice infected with CVB3, varying with infection duration. Using miRNA microarray analysis, a total of 96 and 89 differentially expressed miRNAs were identified in the peripheral blood of mice infected with CVB3 for 3 and 6 days, respectively. Quantitative polymerase chain reaction was used to validate differentially expressed miRNAs, revealing a consistency of these results with the miRNA microarray analysis results. The biological functions of the differentially expressed miRNAs were then predicted by bioinformatics analysis. The potential biological roles of differentially expressed miRNAs included hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. These results may provide important insights into the mechanisms responsible for the progression of CVB3 infection.

Identification of long non-coding RNAs biomarkers for early diagnosis of myocardial infarction from the dysregulated coding-non-coding co-expression network.

Long non-coding RNAs (lncRNAs) have recently been shown as novel promising diagnostic or prognostic biomarkers for various cancers. However, lncRNA expression patterns and their predictive value in early diagnosis of myocardial infarction (MI) have not been systematically investigated. In our study, we performed a comprehensive analysis of lncRNA expression profiles in MI and found altered lncRNA expression pattern in MI compared to healthy samples. We then constructed a lncRNA-mRNA dysregulation network (DLMCEN) by integrating aberrant lncRNAs, mRNAs and their co-dysregulation relationships, and found that some of mRNAs were previously reported to be involved in cardiovascular disease, suggesting the functional roles of dysregulated lncRNAs in the pathogenesis of MI. Therefore, using support vector machine (SVM) and leave one out cross-validation (LOOCV), we developed a 9-lncRNA signature (termed 9LncSigAMI) from the discovery cohort which could distinguish MI patients from healthy samples with accuracy of 95.96%, sensitivity of 93.88% and specificity of 98%, and validated its predictive power in early diagnosis of MI in another completely independent cohort. Functional analysis demonstrated that these nine lncRNA biomarkers in the 9LncSigAMI may be involved in myocardial innate immune and inflammatory response, and their deregulation may lead to the dysfunction of the inflammatory and immune system contributing to MI recurrence. With prospective validation, the 9LncSigAMI identified by our work will provide additional diagnostic information beyond other known clinical parameters, and increase the understanding of the molecular mechanism underlying the pathogenesis of MI.

Comparison of the efficacy of recombinant human brain natriuretic peptide with saline hydration in preventing contrast-induced nephropathy in patients undergoing coronary angiography with or without concomitant percutaneous coronary intervention.

The incidence of contrast-induced nephropathy has an increasing trend as a result of increased use of contrast media during coronary interventional procedures. Contrast-induced nephropathy is one of the major causes for hospital acquired renal failure after coronary interventional procedures. In this study, a total of 126 enrolled patients undergoing elective coronary angiography and/or percutaneous coronary intervention were randomly divided into two groups to investigate the efficacy of recombinant human brain natriuretic peptide in preventing contrast-induced nephropathy in patients undergoing elective coronary angiography and/or percutaneous coronary intervention. Our results showed that there was no statistically significant difference in the primary end points, with similar incidence of contrast-induced nephropathy in the two groups (P=0.770). In compared with the hydration group, the elevation of serum creatinine in the recombinant human brain natriuretic peptide group was less, especially at 48 hours (P=0.047) and at 72 hours (P=0.048) after the procedure. The creatinine clearance from baseline to 72 hours after the procedure was higher in the BNP group than in the hydration group. There were significant differences in creatinine clearance at 48 hours (P=0.016) and at 72 hours (P=0.019) between the two groups. In spite of similar incidence of contrast-induced nephropathy, recombinant human brain natriuretic peptide has its advantages for the protection of the renal function associated with better protection of renal function in patients undergoing elective coronary angiography and/or percutaneous coronary intervention, compared with saline hydration.

[Efficacy comparison with low and high dose nadroparin for patients with acute coronary syndrome underwent percutaneous coronary intervention].

OBJECTIVE: To evaluate the safety and optimal prior percutaneous coronary intervention (PCI) nadroparin dose in patients with acute coronary syndrome (ACS). METHODS: A total of 236 ACS patients were randomly treated with subcutaneously nadroparin 0.075 ml/10 kg (group I, n = 120) and 0.1 ml/10 kg (group II, n = 116) respectively (bid for 48 hours). PCI was the performed 1 h after final nadroparin injection. No additional nadroparin was applied during PCI. Plasmic anti-Xa level was assayed before and at 1, 2, 4 and 8 hours after final nadroparin administration. Adverse clinical events (death, myocardial infarction, need for revascularization) and bleeding events were recorded up to 30 days post PCI. RESULTS: Baseline clinical characteristics as well as the MACE and severe bleeding events between the two groups were similar (all P > 0.05). Plasmic anti-Xa level of group II was significantly higher than that of group I post nadroparin application (P < 0.01). CONCLUSION: Anticoagulation effects and MACE as well as severe bleeding events up to 30 days post PCI were similar with either 0.075 ml/10 kg or 0.1 ml/10 kg nadroparin dose in ACS patients.