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Objectives: The purpose of this study was to establish a scoring system for predicting axillary lymph node metastasis (ALNM) in patients with breast invasive ductal carcinoma with negative axillary ultrasound (US) results., Methods: In this retrospective study, 156 breast invasive ductal carcinoma lesions from 156 women were retrospectively enrolled. The features of conventional US and contrast-enhanced ultrasound (CEUS) qualitative enhancement patterns and quantitative enhancement parameters were analyzed. Subsequently, a scoring system was created by a multivariate logistic regression analysis., Results: The results found that 60 patients (38%) showed ALNM. A scoring system was defined as risk score = 1.75 × (if lesion size ≥20 mm) + 1.93 × (if uncircumscribed margin shown on conventional US) + 1.77 × (if coarse or twisting penetrating vessels shown on CEUS). When the risk scores were less than 1.75, 1.75 to 1.93, 1.94 to 3.70, and 3.70 or higher, the risk rates of ALNM were 0% (0 of 9), 10.7% (5 of 46), 29.2% (14 of 48) and 77.4% (41 of 53), respectively. In comparison with conventional US alone, the scoring system using the combination of conventional US and CEUS showed better discrimination ability in terms of the area under the curve (0.830 versus 0.777; P = .037)., Conclusions: A scoring system based on conventional US and CEUS may improve the prediction of ALNM., (© 2020 by the American Institute of Ultrasound in Medicine.)

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients ( n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT ( r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS , and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration., (Copyright © 2020 Guo, Zhang, Zhang, Zhou, Cai, Long, Guo, Yang, Zhao, Xie, Jiang, Zhu, Fan, Xie, Hu, Yao, Jia, Li, Cui, Sui, Lin, Cheng, Wang, Wang, Zhao, Qiao, Peng, Yang, Chen, Cai, Xu, Zhang, Feng, Zhou, Wu, Dong, Wang, Zhang, Gao, Jiang, Cang, Yang, Song, Liu, Zhu, Chen, Hu, Chen, Wu and Zhou.)

Background: Preventing relapse of schizophrenic patients is really a challenge. The present study sought to provide more explicit evidence and factors of different grades and weights by a series of step-by-step analysis through χ 2 test, logistic regression analysis and decision-tree model. The results of this study may contribute to controlling relapse of schizophrenic patients., Methods: A total of 1,487 schizophrenia patients were included who were 18-65 years of age and discharged from 10 hospitals in China from January 2009 to August 2009 and from September 2011 to February 2012 with improvements or recovery of treatment effect. We used a questionnaire to collect information about relapse and correlative factors during one year after discharge by medical record collection and telephone interview. The χ 2 test and logistic regression analysis were used to identify risk factors and high-risk factors firstly, and then a decision-tree model was used to find predictive factors., Results: The χ 2 test found nine risk factors which were associated with relapse. Logistic regression analysis also showed four high-risk factors further (medication adherence, occupational status, ability of daily living, payment method of medical costs). At last, a decision-tree model revealed four predictors of relapse; it showed that medication adherence was the first grade and the most powerful predictor of relapse (relapse rate for adherence vs. nonadherence: 22.9 vs. 55.7%, χ 2 = 116.36, p < 0.001). The second grade factor was occupational status (employment vs. unemployment: 19.7 vs. 42.7%, χ 2 = 17.72, p < 0.001); the third grade factors were ability of daily living (normal vs. difficult: 28.4 vs. 54.3%, χ 2 = 8.61, p = 0.010) and household income (household income ≥ 3000 RMB vs. <3000 RMB: 28.6 vs. 42.4%, χ 2 = 6.30, p = 0.036). The overall positive predictive value (PPV) of the logistic regression was 0.740, and the decision-tree model was 0.726. Both models were reliable., Conclusions: For schizophrenic patients discharged from hospital, who had good medication adherence, more higher household income, be employed and normal ability of daily living, would be less likely to relapse. Decision tree provides a new path for doctors to find the schizophrenic inpatient's relapse risk and give them reasonable treatment suggestions after discharge., (Copyright © 2020 Mi, Chen, Fan, Tabarak, Xiao, Cao, Li, Bao, Han, Li, Shi, Guo, Wang, Liu, Wang, Chen, Wu, Ma, Li, Xiao, Liu, Xie, Zhang and Lu.)

Objectives: To compare the imaging findings of Bowen's disease (BD) between ultrasound biomicroscopy (UBM) and conventional high-frequency ultrasound (HFUS)., Methods: A total of 29 pathologically proven BD lesions in 28 patients were retrospectively enrolled in the study, and all were after surgery. All the lesions were imaged with both UBM and HFUS. The imaging features on HFUS and UBM were analyzed and compared. The diagnostic results of ultrasound for BD were referenced with pathology results., Results: All the 29 (100%) BD lesions appeared hypoechogenicity, solid component, and superficial hyperechoic layer (ie, keratinization) on both UBM and HFUS. The typical imaging feature of BD lesions, that was, infiltration depth confined to the epidermis, was visualized in 25 (86.2%, 25/29) lesions on UBM whereas 15 (51.7%, 15/29) on HFUS (P = .002). A "wave sign," which corresponds to the surface keratinization of BD lesion, was visualized in 17 (58.6%, 17/29) of BD lesions on UBM whereas 6 (20.7%, 6/29) on HFUS (P = .001). UBM and HFUS correctly diagnosed 25 (86.2%, 25/29) and 15 (51.7%, 15/29) BD lesions, respectively (P = .002)., Conclusions: Bowen's disease has some typical imaging features on US. The "wave sign" of the superficial hyperechoic layer and the clear borderline between the tumor in epidermis and the slightly hyperechoic dermis layer are better depicted by UBM in comparison with HFUS, which leads to a more accurate diagnosis of BD. UBM has potential to be used as a diagnostic tool for characterization of BD on account of its high resolution., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In in vitro cell assays, nominal concentrations of a test chemical are most frequently used in the description of its dose-response curves. Although the biologically effective concentration (BEC) is considered as the most relevant dose metric, in practice, it is very difficult to measure. In this work, we attempted to determine the BEC of long-chain perfluoroalkyl carboxylic acids (PFCAs) in peroxisome proliferator-activated receptor γ (PPARγ) activity assays. In both adipogenesis and transcriptional activity assays with human and mouse cells, PPARγ activity of 7 PFCAs first increased and then decreased with their carbon chain length. The binding affinity of these PFCAs with the ligand-binding domain of PPARγ was measured by fluorescence competitive binding assay and showed very poor correlation with their receptor activity ( r 2 = 0.002-0.047). Internal concentrations of the PFCAs in the cells were measured by LC-MS/MS. Although their correlation with the receptor activity increased significantly, it is still low ( r 2 = 0.41-0.82). Using the binding affinity constant, internal concentration, and PPARγ concentration measured by immunoassays, concentrations of receptor-bound PFCAs in cells were calculated, which exhibited excellent correlation with PPARγ activity in both adipogenesis and transcriptional activity assays ( r 2 = 0.91-0.93). These results demonstrate that the concentration of receptor-bound PFCA is the BEC that dictates its activity on human and mouse PPARγ in cell assays. In the absence of any direct detection method, our approach can be used to calculate the target-site concentration of other ligands.

Microplastic (MP) accumulation in the environment has become an issue of human and environmental importance. Great efforts were made recently to identify the sources of MP exposure to humans and their release into the environment. Here, we employed spectroscopic techniques to identify and characterize MP in consumer plastic food containers that are, in huge quantity, used for food delivery and disposable plastic cups for daily drinking. We determined the average weight of isolated MP per pack to be 12 ± 5.12 mg, 38 ± 5.29 mg, and 3 ± 1.13 mg for the round-shaped, rectangular-shaped plastic container and disposable plastic cups, respectively, with various morphological features including cubic, spherical, rod-like as well as irregular shapes, which may either be consumed by humans or released into the environment. This study demonstrates that new plastic containers can be an important source of direct human and environmental exposure to microplastics. Most importantly, our results indicated that necessary attention must be given to morphological features of realistic MPs when evaluating their risks to humans and the environment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

LncRNA plasmacytoma variant translocation 1 (PVT1) has been recognized as an oncogenic lncRNA, which participates in the migration and invasion of many kinds of cancer cells and the development of cancers. In the present study, we explored its clinical significance and prognostic value in muscle invasive bladder cancer (MIBC).A total of 98 MIBC patients' samples were collected, who had undergone radical cystectomy from the March 2013 to December 2018. The associations between PVT1 expression and clinical data were calculated using the Chi-test. Overall survival curves were determined by the Kaplan-Meier technique and contrasted via log-rank test. We utilized univariate and multivariate Cox proportional hazard models to examine the HR and 95% CI.The expression levels of PVT1 were significantly higher in MIBC tissues than that in normal bladder tissues (P < .001). PVT1 expression was significantly correlated with tumor grade (P = .009), margin (P = .002), T stage (P = .02), and lymph node metastasis (P < .001). MIBC patients with high PVT1 expression level had shorter overall survival than those with low PVT1 expression level (log-rank test, P = .004). Multivariate Cox regression analysis showed that PVT1 expression level (HR = 2.381, 95% CI: 1.821-7.012, P = .014) was an independent factor in predicting the overall survival of MIBC patients.In summary, increased PVT1 expression in MIBC patients is correlated with a higher MIBC stage and is significantly associated with poor prognosis for MIBC patients, which may provide new insights into new therapeutic strategy and postoperative intervention against bladder cancer.

Despite many studies on the toxicity of nanoplastic particles (NPPs) to aquatic invertebrates, the effects of ecological constituents such as humic substances (HSs) are often neglected. In our study, Daphnia magna was used to evaluate the effects of three HSs, natural organic matter (NOM), fulvic acid (FA), and humic acid (HA), on NPP toxicity and corona formation. Acute toxicities of NPPs were reduced by all HSs at environmentally relevant concentrations. NPPs elicited the upregulation of all genes related to detoxification, oxidative stress, and endocrine activity after 7 days of exposure. The presence of NOM or HA resulted in the mitigation of gene expression, whereas significantly higher upregulation of all of the genes was observed with FA. The presence of FA led to increased protein adsorption on NPPs in D. magna culture medium (eco-corona, EC) and homogenates (protein corona, PC), while there was less adsorption in the presence of HA. The highly abundant proteins identified in EC are involved in immune defense, cell maintenance, and antipredator response, while those in PC are responsible for lipid transport, antioxidant effects, and estrogen mediation. Our findings revealed the key influence of HSs on the toxicity of NPPs and provide an analytical and conceptual foundation for future study.

With XML becoming a promising standard for data storage, describing, transferring and exchanging information on the Internet, data security and privacy protection of XML become the focus of research in recent years. In order to achieve the authorization of legitimate user and ensure the secure access to sensitive information, in this paper, in the context of cloud storage, with the purpose of sharing sensitive XML information, a polynomial authorization scheme with Kerberos authentication was proposed, which was based on the users' access purpose and privacy policy. In this scheme, first, Kerberos authentication was used to identify the user, and then the polynomial whose coefficients were from the leaf node address was used to complete the authorization of user. For the legitimate user, under the interaction of authorization polynomials and the global structure view, authorization matrix is generated dynamically, its temporary and dynamic characteristics greatly improves the security of the system. Finally, with the help of authorization matrix and auxiliary information tables, security queries were successfully completed. The experimental results show that the scheme not only effectively protects XML sensitive data, but also reduces the server's storage pressure, at the same time it is beneficial to the rapid search and information positioning.

Objectives: The aim of this study was to develop an ultrasound consolidated score (UCS) in determining the activity of Crohn's disease (CD) and evaluate it with reference to simple endoscopic score (SES)., Methods: From June 2014 to June 2017, 66 patients with CD were retrospectively enrolled in this study. Each patient underwent endoscopy and transabdominal ultrasound (US) examination. The morphological symmetry, echogenicity of bowel wall, bowel wall layer structure, echogenicity of peri-bowel fat, bowel wall thickness (BWT), and Limberg type on power Doppler US were assessed with transabdominal US, and an UCS scoring system was developed based on these characteristics. Endoscopic results were used as the reference standard and SES was calculated to determine the CD activity. Receiver operating characteristic curve analysis was performed to assess the diagnostic performance for determining CD activity and the correlation between UCS and SES was assessed using Spearman correlation analysis., Results: 330 intestinal segments in 66 patients were included. The UCS of the segments in the remission phase ranged from 3.0 to 9.0 (mean, 3.6 ± 0.9) whereas in the active phase from 3.0 to 20.0 (mean, 10.6 ± 4.0) (p < 0.001). The cut-off value of UCS was 6. The associated area under ROC curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.980, 88.3%, 95.5%, 93.8%, 91.3%, and 92.3%, respectively. The correlation coefficient between UCS and SES was 0.90, which was higher than the correlation coefficient of 0.83 between BWT and SES., Conclusions: The newly developed UCS with transabdominal US has a good performance and potentially provides an effective alternative for evaluating the activity of CD., Advances in Knowledge: UCS is an effective method to evaluate the activity of CD because it provides comprehensive information of the disease. Therefore, it could be employed as an alternative for diagnosis of CD.

Purpose: To investigate the value of ultrasound (US) and clinicopathological features of papillary thyroid cancer (PTC) in predicting Telomerase Reverse Transcriptase (TERT) promoter mutations., Methods: Preoperative US images of 351 surgically confirmed PTCs were evaluated in terms of PTCs size and US features. The basic clinicopathological features were also retrieved. Univariate and multivariate analyses were performed to identify the risk factors for TERT promoter mutations. A scoring system was developed based on the cumulative number of risk factors. The area under the receiver operating characteristic curve (AUC) and cut-off value were calculated to evaluate the diagnostic performance of the scoring system for predicting TERT promoter mutations., Results: TERT promoter mutations were found in 4.84% (17/351) of patients with PTCs. Patient age >50 years (OR: 6.244, P = 0.006), multifocality (OR: 21.071, P = 0.022), taller-than-wide shape (OR: 4.934, P = 0.029), microlobulated margin (OR: 4786, P = 0.032), and capsule contact or involvement (OR: 4.668, P = 0.030) were independent risk factors for TERT promoter mutations. TERT promoter mutations were relevant to more suspicious US and clinicopathological features than TERT promoter wild-type PTC (median, 4 vs. 1, P < 0.001). The cut-off value was 2.5 and the associated AUC was 0.908 (P < 0.001)., Conclusions: The probability of TERT promoter mutations increases along with the suspicious US features and clinicopathological characteristics, which may help to recognize patients who deserve a different approach, in terms of management and follow-up, in view of the worst outcome associated to this mutation.

Objective: To evaluate the effect of comprehensive intervention combined with clinical preventive services and lifestyle adjustment on high-risk populations of cardiovascular disease. Methods: In 2015, 4 towns (streets) in Tongxiang City, of Zhejiang Province including Heshan Town, Longxiang Street, Wutong Street, and Fengming Street, were selected by using the typical sampling. The towns (streets) were allocated to the intervention group (Heshan Town and Longxiang Street) and the control group (Wutong Street and Fengming Street) by using the cluster random sampling. In each town (street), hypertension patients aged 50 to 74 years old who were taking community medicine management and with a 10-year cardiovascular disease risk ≥10% were recruited as subjects. There were 1 823 subjects in the intervention group and 1 883 in the control group. The intervention group was given a 1-year comprehensive intervention combining clinical preventive services and lifestyle adjustment, while the control group received routine chronic disease management. After the intervention, the final questionnaire investigation was conducted and health physical examination data were obtained. The death, acute coronary heart disease events and stroke incidence were the primary outcomes, and cardiovascular disease-related knowledge and behavior, clinical preventive services utilization, physical changes, blood fat index and 10-year cardiovascular disease risk were the secondary outcomes. The difference-in-difference model was used to evaluate the effects of interventions. Results: The age of subjects in the intervention and control group was (68.76±3.75) and (67.90±4.56) years old, respectively. After 1-year intervention, the incidence of mortality, acute coronary events and stroke in intervention group was 1.65% (30 cases), 0.27% (5 cases) and 2.69% (49 cases), respectively, which showed no statistical difference compared to the control group [1.33% (25 cases), 0.32% (6 cases) and 2.07% (39 cases)]. After adjusting for the age, gender, education, marital status, self-assessed family income level and situation of taking antihypertensive drugs, the difference-in-difference model showed that the body mass index and diastolic blood pressure in the intervention group decreased by 0.33 kg/m(2) and 1.49 mmHg (1 mmHg=0.133 kPa). Compared with the control group, daily vegetable consumption proportion, the awareness rates of aspirin, stains, salt intake, and oil intake increased by 4.76%, 26.22%, 29.56%, 10.80%, and 15.17%, respectively ( P< 0.05). Conclusion: After the 1-year comprehensive intervention, there was no significant change in primary outcomes among high-risk populations of cardiovascular disease. In secondary outcomes, body mass index and diastolic blood pressure declined and cardiovascular disease-related knowledge awareness increased.

The coordination interactions between transition-metal ions (Cu 2+ , Ag + ) and sulfur atoms on ultrathin two-dimensional (2D) nanosheets of spin-crossover (SCO) metal-organic frameworks {[Fe(1,3-bpp) 2 (NCS) 2 ] 2 } n (1,3-bpp = 1,3-di(4-pyridyl)propane), which constructed the ultrathin 2D nanosheets into three-dimensional (3D) nanoparticles, have made a profound effect on the SCO performance. Compared with 2D nanosheets, both the intraligand π-π* transition band and the metal-to-ligand charge transition band from the d(Fe) + π(NCS) to π*(1,3-bpp), for the 3D nanoparticles, have shown dramatic blue-shifts; meanwhile, the d-d transition band for the high-spin (HS) state Fe(II) ions has been generated, suggesting significantly the influence of 3D assemble-caused dimensional changes on the solid-state SCO performance of ultrathin 2D nanosheets. More importantly, by loading on the ytterbium ion (Yb 3+ )-sensitized hexagonal phase upconverting nanoparticles in the aqueous colloidal suspension, the near infrared (NIR) light (980 nm) triggered HS (high spin) to LS (low spin) state transitions have been observed, demonstrating the achievement of challenging target of NIR light-triggered molecular conversion under environment conditions.

Chlorinated polyfluoroalkylether sulfonic acids (Cl-PFESAs) have been shown to have potential thyroid hormone (TH) disruption effects. Here, we further investigated their estrogenic effects and underlying mechanisms. In vivo results revealed that exposure of zebrafish to Cl-PFESAs induced disorder of sex hormones during the early embryonic stages and caused histopathological lesions in the gonads of adult zebrafish relative to control groups. To find out whether the estrogen receptor is the molecular target of Cl-PFESAs, the binding interaction between Cl-PFESAs and ERs was investigated using a series of in vitro assays. We found that all tested chemicals could bind directly to ERs and exhibit relatively weak agonistic activity toward ERs, suggesting that the ER-mediated signaling pathway is directly involved in the estrogenic effects of Cl-PFESAs. The internal dose of 8:2 Cl-PFESA was significantly higher than the others, which explained why it obviously displayed an ER agonistic effect despite its weak ER binding affinity. Taken together, these results uncover that, in addition to the TH disruption effect, Cl-PFESAs might also cause estrogenic effects by activating ER pathways.

The potential causal relationship between exposure to environmental contaminants and diabetes is troubling. Exposure of perfluoroalkyl substances (PFASs) is found to be associated with hyperinsulinemia and the enhancement of insulin secretion by islet β cells in humans, but the underlying mechanism is still unclear. Here, by combining in vivo studies with both wild type and gene knockout mice and in vitro studies with mouse islet β cells (β-TC-6), we demonstrated clearly that 1 h exposure of perfluorooctanesulfonate (PFOS) stimulated insulin secretion and intracellular calcium level by activating G protein-coupled receptor 40 (GPR40), a vital free fatty acid regulated membrane receptor on islet β cells. We further showed that the observed effects of PFASs on the mouse model may also exist in humans by investigating the molecular binding interaction of PFASs with human GPR40. We thus provided evidence for a novel mechanism for how insulin-secretion is disrupted by PFASs in humans.

Purpose: To investigate the occurrence and genetic characteristics of the bla IMP-26 -positive plasmid from a multidrug-resistant clinical isolate, Enterobacter hormaechei L51., Methods: Species identification was determined by MALDI-TOF MS and Sanger sequencing. Antimicrobial susceptibility testing was performed by the agar dilution and broth microdilution. Whole-genome sequencing was conducted using Illumina HiSeq 4000-PE150 and PacBio Sequel platforms, and the genome was annotated by the RAST annotation server. The ANI analysis of genomes was performed using OAT. Phylogenetic reconstruction and analyses were performed using the Harvest suite based on the core-genome SNPs of 61 publicly available E. hormaechei genomes., Results: The E. hormaechei L51 genome consists of a 5,018,729 bp circular chromosome and a 343,918 bp conjugative IncHI2/2A plasmid pEHZJ1 encoding bla IMP-26 which surrounding genetic context was intI1-bla IMP-26 -ltrA- qacE∆1-sul1 . A new sequence type (ST1103) was assigned for the isolate L51 which was resistant to cephalosporins, carbapenems, but sensitive to piperacillin-tazobactam, amikacin, tigecycline, trimethoprim-sulfamethoxazole and colistin. Phylogenetic analysis demonstrated that E. hormaechei L51 belonged to the same subspecies as the reference strain E. hormaechei SCEH020042, however 18,248 divergent SNP were identified. Resistance genes in pEHZJ1 including aac(3)-IIc, aac(6 ' ) -IIc, bla SHV-178 , bla DHA-1 , bla TEM-1 , bla IMP-26 , ereA2, catII, fosA5, qnrB4, tet(D), sul1 and dfrA19 ., Conclusion: In our study, we identified a conjugative IncHI2/2A plasmid carrying bla IMP-26 and bla SHV-178 in E. hormaechei ST1103, a novel multidrug-resistant strain isolated from China, and describe the underlying resistance mechanisms of the strain and detailed genetic context of mega plasmid pEHZJ1., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Gou et al.)

Objective: To compare the diagnostic performance and the unnecessary biopsy rates for recommending fine needle aspiration (FNA) of Thyroid Imaging Reporting and Data Systems proposed by American College of Radiology (ACR TI-RADS), American Thyroid Association (ATA) guidelines, TI-RADS proposed by Kwak (Kwak TI-RADS), and Korean Thyroid Association/Korean Society of Thyroid Radiology (KTA/KSThR) guidelines for malignancy risk stratification of thyroid nodules (TNs)., Methods: The study included 1271 TNs whose cytologic results or surgical pathologic findings were available. Ultrasound images of these TNs were retrospectively reviewed and categorized according to the four guidelines. The diagnostic performances and the unnecessary biopsy rates for recommending FNA of the four guidelines were evaluated., Results: After multivariate analysis, the most significant independent predictor for malignancy was hypoechogenicity/marked hypoechogenicity (OR: 9.37, 95% CI: 5.40-16.26) (P < 0.001) among the suspicious ultrasound images features. For all nodules and two subgroups (i.e. nodules <10 mm group and nodules ≥10 mm group), ACR TI-RADS demonstrated higher specificities (all P < 0.05) and lower sensitivities (all P < 0.001) than the other guidelines. In the all nodules group and the nodules<10 mm group, ACR TI-RADS and Kwak TI-RADS had higher Azs than the other guidelines (all P < 0.01). The unnecessary biopsy rates for recommending FNA of ACR TI-RADS in the all nodules (≥10 mm) group and the subgroup (10∼19 mm) were all lower than those of the others guidelines (P < 0.001 for all). For the subgroup (≥20 mm), the unnecessary biopsy rate of ACR was lower than that of ATA guidelines and KTA/KSThR guidelines (P < 0.001)., Conclusions: The four guidelines have good diagnostic efficiency in differentiating TNs. ACR TI-RADS and Kwak TI-RADS have better diagnostic performance than the other guidelines in the all nodules group and the nodules<10 mm group. Considering the comprehensive diagnostic efficacy and unnecessary biopsy rate, ACR TI-RADS is a more desirable classification guideline in clinical practice.

Studies have shown the potential of nanomaterials for the accurate and early detection of cancer. The aim of the present study was to design and evaluate the value of prostate-specific membrane antigen (PSA)-targeted manganese oxide-mesoporous silica nanoparticles (Mn-Msns) for the detection of prostate cancer. Mn-Msns were prepared, and then conjugated with the PSA antibody and Cy7 to create the multimodality PSA-Mn-Msn-Cy7. Their particle size, zeta potential, stability and magnetic resonance imaging (MRI) features of the nanoparticles were characterized. Optical and MR imaging were evaluated in cell and tumor-bearing mouse models. The Mn in tissues was measured by inductively coupled plasma mass spectrometry. The fabricated nanoparticles were stable and showed good T 1 relaxivity. The targeted nanoparticles accumulated to a great extent in prostate cancer cells in vitro but not in noncancerous cells. In vivo studies further demonstrated a targeted distribution of PSA-Mn-Msn-Cy7 to cancer tissues as shown by high optical and T1 signals. The targeted distribution was also confirmed by determining the Mn content in the cancer tissues. Our data demonstrate that PSA targeted fluorescence and MR dual-functional nanoparticle can visualize prostate cancer and can be used as NIRF/MR contrast agents., (Copyright © 2019. Published by Elsevier Masson SAS.)

Objectives: The purpose of this study was to investigate the performance of ultrasound biomicroscopy (UBM) and high-frequency ultrasound (HFUS) in the assessment of extramammary Paget disease (EMPD) and to correlate the imaging features with pathologic findings., Methods: In this retrospective study, we described the imaging features from UBM and HFUS based on 17 pathologically proven EMPD cases. The performance for visualizing layer involvement by UBM and HFUS was compared. Additionally, we checked the consistency between layer involvement of the lesions on UBM images and the pathologic results. Additionally, blood flow and the status of lymph nodes were investigated with HFUS., Results: Ultrasound biomicroscopy revealed that all 17 lesions (100%) were hypoechoic and grew in a creeping form. The feature of layer involvement was shown in 10 lesions (58.8%) limited to the epidermis and 6 lesions (35.3%) involving the dermis, and the remaining lesion (5.9%) involved the full skin layers. Layer involvement was clearly displayed by UBM for all lesions (100%) but for only 5 lesions (29.4%) by HFUS (P < .001). Additionally, the layer involvement of 15 lesions (88.2%) on UBM was consistent with the pathologic results (κ = 0.746). High-frequency ultrasound revealed profuse blood flow in most lesions (64.7% [11 of 17]), and 1 case showed inguinal lymph node metastasis., Conclusions: Combined use of UBM and HFUS can provide key information on EMPD based on ultrasound features. Comparatively, UBM provides clearer morphologic information, whereas HFUS provides information on lymph node metastasis and blood flow., (© 2019 by the American Institute of Ultrasound in Medicine.)

Carbon nanomaterials (CNMs) are widely used in industrial and medical sectors. The increasing exposure of CNMs necessitates the studies of their potential environmental and health effects. High-mobility group box-1 (HMGB1) is a nuclear DNA-binding protein, but when released from cells, may cause sustained inflammatory response and promote cell migration and invasion. In this work, we found that 7-day exposure of 2.5 mg/kg/day CNMs, including C60, single-walled carbon nanotubes, and graphene oxides significantly elevated the level of HMGB1 in blood and lung lavage fluids in C57BL/6 mice. Subsequently, cellular effects and underlying mechanism were explored by using Raw264.7. The results showed that noncytotoxic CNMs enhanced HMGB1 intracellular translocation and release via activating P2X7 receptor. Released HMGB1 further activated receptor for advanced glycation endproducts (RAGE) and downstream signaling pathway by upregulating RAGE and Rac1 expression. Simultaneously, CNMs prepared the cells for migration and invasion by modulating MMP2 and TIMP2 gene expression as well as cytoskeleton reorganization. Intriguingly, released HMGB1 from macrophages promoted the migration of nearby lung cancer cell, which can be efficiently inhibited by neutralizing antibodies against HMGB1 and RAGE. Taken together, our work demonstrated that CNMs stimulated HMGB1 release and cell migration/invasion through P2X7R-HMGB1-RAGE pathway. The revealed mechanisms might facilitate a better understanding on the inflammatory property and subsequent cell functional alteration of CNMs., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To carry out the methodological quality evaluation and content analysis of the evidence-based clinical practice guidelines for acupuncture-moxibustion in China, and to provide reference for the development and updating of future guidelines., Methods: With Appraisal of Guidelines for Research and EvaluationⅡ(AGREEⅡ), 20 evidence-based clinical practice guidelines for acupuncture and moxibustion in China were evaluated from six aspects: scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability and editorial independence. In addition, the contents of 20 guidelines were systematically analyzed, and the characteristics of guidelines were summarized from the aspects of disease selection, operation technology type and safety., Results: The scores of six domains were scope and purpose (91.1%), stakeholder involvement (68.5%), rigour of development (68.6%), clarity of presentation (90.3%), applicability (34.5%) and editorial independence (16.7%). The recommendations of the 20 acupuncture guidelines covered common clinical problems such as diagnosis, treatment and precautions, which were in line with the clinical characteristics of acupuncture and moxibustion in terms of content structure., Conclusion: The methodology of the evidence-based clinical practice guidelines for acupuncture and moxibustion in China conformed to the requirements of AGREEⅡ on the quality evaluation, and the overall quality was moderate, but the aspects of applicability and editorial independence were still needed to be improved. The contents of recommendations in 20 guidelines were specific and clear, in line with the characteristics of acupuncture and moxibustion, presenting clinical reference value. In the future, in the process of guideline development, the method of developing acupuncture and moxibustion guidelines should be constantly improved to improve the quality of the guidelines; in the meantime, more attention should be paid to the generalization and clinical applicability evaluation.

A new fluorescence sensor (QDs-IIP), based on ion-imprinted polymers (IIP) as recognition element and Mn-doped ZnS quantum dots (QDs) as fluorophore, was synthesized for the selective and sensitive determination of hexavalent chromium (Cr(VI)) ions. The QD was first coated by SiO 2 layer, and then modified with Cr(VI)-imprinted polymer. Several parameters affecting fluorescence intensity such as tetraethylorthosilicate (TEOS) volume, ZnS:Mn@SiO 2 amount, and radiation time were investigated and optimized. The QDs-IIP was characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR), transmission electron microscope (TEM), and scanning electron microscope (SEM). Furthermore, the fluorescence quenching mechanism was investigated by using UV-VIS and fluorescence spectrophotometer, and it was found that internal filtration effect was the main fluorescence quenching mechanism. The relative fluorescence intensity (F 0 /F) increased linearly with the increase of Cr(VI) concentration in the range of 20 μg L -1 -1.0 mg L -1 . The QDs-IIP sensor showed high recognition selectivity for Cr(VI) in comparison with the QDs-NIP sensor with an imprinting factor (IF) of 2.53, and it could be reused 5 times. In addition, an analytical method of Cr(VI) based on the QDs-IIP sensor was established with a limit of detection of 5.48 μg L -1 , and was then applied to actual water samples with satisfactory results. Therefore, QDs-IIP can be deemed as a practicable fluorescent sensor for trace Cr(VI) detection. Graphical abstract.

Previously, perfluoroalkyl substances (PFASs) have been found to be associated with many adverse effects mediated by the peroxisome proliferator-activated receptor α (PPARα) and PPARγ. Here, we found another subtype of the peroxisome proliferator-activated receptors (PPARs); the PPARβ/δ mediated pathway might also be a potential adverse outcome pathway for PFASs. We investigated the direct binding and transcriptional activity of PFASs toward human PPARβ/δ, and further revealed the structure-binding and structure-activity relationship between PFASs and PPARβ/δ. The receptor binding experiment showed that their binding potency was dependent on the carbon chain length and the terminal functional group. For twelve perfluoroalkyl carboxylic acids (PFCAs), an inverted U-shaped relationship existed between the PPARβ/δ binding potency and the carbon chain length, with perfluorododecanoc acid (C12) showing the highest binding potency. The three perfluoroalkane sulfonic acids (PFSAs) exhibited a stronger binding potency than their PFCA counterparts. The two fluorotelomer alcohols (FTOHs) showed no binding potency. In receptor transcriptional activity assays, they enhanced the PPARβ/δ transcriptional activity. Their transcriptional activity was also related to the carbon chain length and the terminal functional group. Molecular docking analysis showed the PFASs fitted into the ligand binding pocket of PPARβ/δ with a binding geometry similar to a fatty acid.

Airborne lower-chlorinated PCBs are vulnerable to metabolization to PCB sulfates through further sulfation of the hydroxylated metabolites (OH-PCBs). However, studies on the toxic effects and mechanisms of PCB sulfates are still very limited. Here, we investigated for the first time the potential endocrine disruption effects of PCB sulfates through estrogen-related receptor γ (ERRγ) in comparison with their OH-PCBs precursors and PCB parent compounds. The binding affinity of thirteen PCBs/OH-PCBs/PCB sulfates was measured by using fluorescence competitive binding assays based on fluorescence polarization (FP). All of the tested chemicals could bind to ERRγ with the K d (dissociation constant) values ranging from not available (NA) to 3.2 μM 4'-OH-PCB 12 showed the highest binding affinity with K d value of 3.2 μM, which was comparable to that of a synthetic ERRγ agonist GSK4716. The effects of the thirteen chemicals on the ERRγ transcriptional activity were determined by using the luciferase reporter gene assay. We found the PCBs/OH-PCBs/PCB sulfates acted as agonists for ERRγ, with the lowest observed effective concentration reaching 3 μM. The binding affinity and agonistic activity of PCBs towards ERRγ were both enhanced after hydroxylation, while further sulfation of OH-PCBs decreased the activity instead. Molecular docking simulation showed that OH-PCBs had lower binding energy than the corresponding PCBs and PCB sulfates, indicating that OH-PCBs had higher binding affinity theoretically. In addition, OH-PCBs could form hydrogen bonds with amino acids Glu316 and Arg247 while PCBs and PCB sulfates could not, which might be the main factor impacting the binding affinity and agonistic activity. Overall, ERRγ is a novel target for lower-chlorinated PCBs and their metabolites., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

There has been long-standing evidence that the lower-chlorinated polychlorinated biphenyls (LC-PCBs) can be metabolized to hydroxylated metabolites (OH-PCBs), which play important roles in the LC-PCBs induced toxicity. Recently, multiple studies have demonstrated the further metabolic transformation of OH-PCBs to LC-PCB sulfates in vitro and in vivo. Several studies found LC-PCB sulfates could bind with thyroid hormone (TH) transport proteins in the serum, indicating the potential relevance of these metabolites in the TH system disruption effects. However, the interaction of LC-PCB sulfates with the TH nuclear receptor (TR), another kind of important functional protein in the TH system, has not been explored. Here, by using a fluorescence competitive binding assay, we demonstrated that LC-PCB sulfates could bind with TRα. Moreover, the LC-PCB sulfates had higher binding potency than their corresponding OH-PCB precursors. By using a luciferase reporter gene assay, we found the LC-PCB sulfates showed agonistic activity towards the TRα signaling pathway. Molecular docking simulation showed all the tested LC-PCB sulfates could fit into the ligand binding pocket of the TRα. The LC-PCB sulfates formed hydrogen bond interaction with arginine 228 residue of TRα by their sulfate groups, which might facilitate the TR binding and agonistic activity. The present study suggests that interaction with the TR might be another possible mechanism by which LC-PCB sulfate induce TH system disruption effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A formation model of O 2 ˙ - produced in TiO 2 photocatalysis was established, and then a custom built continuous flow chemiluminescence (CFCL) system was used to confirm the model's reliability by monitoring the O 2 ˙ - formation process. This model may give deeper insights into O 2 ˙ - formation for TiO 2 and other photocatalysts., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Bisphenol analogues including bisphenol A and its derivatives are ubiquitous environmental contaminants and have been linked to adverse neurodevelopment effects on animals and humans. Most toxicological research focused on estrogen receptor mediated pathways and did not comprehensively clarify the observed toxicity. O-GlcNAcase (OGA), the highest level in brain, plays a critical role in controlling neuronal functions at multi-levels from molecule to animal behaviors. In this work, we intend to investigate the underlying molecular mechanisms for the neurotoxicity of bisphenol analogues by identifying their cellular targets and the resultant effects. The inhibitory actions of seven bisphenol analogues on the OGA activity at molecular level were investigated by our developed electrochemical biosensor. We found that their potency varied with substituent groups, in which tetrabromo bisphenol A (TBBPA) was the strongest. The seven bisphenol analogues (0-100 μM exposure) significantly inhibited OGA activity and up-regulated protein O-GlcNAcylation level in PC12 cells. Inhibition of OGA by bisphenol analogues further induced intracellular calcium, ROS, inflammation, repressed proliferation, interfered with cell cycle, induced apoptosis. And especially, 10 μM tetrabromo bisphenol A (TBBPA) exposure could impair the growth and development of neurite in human neural stem cells (hNSCs). Molecular docking for OGA/bisphenol analogue complexes revealed the hydrophobicity-dominated inhibition potency. OGA, as a new cellular target of bisphenol analogues, would illuminate the molecular mechanism of bisphenol analogues neurotoxicity.

The mechanism of environmental pollution promoting gastric cancer incidence and difficulty of treatment is not fully understood. In the present article, perfluorodecanoic acid (PFDA), a common persistent environmental pollutant, was used to treat the gastric cell lines and mice to test its genotoxicity. The γ-H2AX immunoblot and plasmid fragment PCR results showed that PFDA had a promotion effect on the DNA double-strand breaks (DSBs) in human and mouse cells. Subsequent results showed that PFDA significantly altered the sensitivity of cells to chemotherapy. Microarray data showed that the expressions of some important DNA repair genes were changed. Further investigation discovered that PFDA inhibition of DNA repair was mediated by X-ray repair cross complementing 4 (XRCC4). The cells deficient in XRCC4 generally exhibited reduced proliferation and premature aging in culture; however, our results indicated that PFDA induced p53 inhibition rescued cells from the apoptosis that was triggered by nonhomologous end-joining (NHEJ) inactivation, and overexpression of p53 expression in PFDA-treated cells enhanced their apoptosis. Finally, T-cell specific factor 4 was suggested by the results as an upstream regulator of XRCC4. This article revealed for the first time that perfluorinated chemicals affect chemotherapeutic sensitivity and the NHEJ pathway, and p53 reduction rescues cells from death., (© 2019 Wiley Periodicals, Inc.)

As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide (HFPO) homologues, including hexafluoropropylene oxide dimer acid (HFPO-DA), hexafluoropropylene oxide trimer acid (HFPO-TA), and hexafluoropropylene oxide tetramer acid (HFPO-TeA), have been used in the fluoropolymer industry for a long period of time. These compounds have attracted widespread attention in recent years due to their environmental ubiquity and high bioaccumulation capability, as well as their toxicity. In our study, we evaluated the potential estrogenic effects of HFPOs in comparison to PFOA by ligand binding, transcriptional activity, and in vivo assays. Fluorescence ligand binding assays showed that both HFPO-TA and HFPO-TeA exhibited higher binding affinity to estrogen receptor ligand binding domains (ER-LBDs) than PFOA, with 2.5- and 57.5-fold higher affinity to ERα-LBD and 2.6- and 41.8-fold higher affinity to ERβ-LBD, respectively, whereas HFPO-DA exhibited weaker binding affinity than PFOA. Unlike PFOA, HFPO-TA and HFPO-TeA exhibited antagonistic activity toward the ERs' signaling pathway, with HFPO-TeA displaying the strongest potency. In silico study revealed that while PFOA binds with ERs in a similar fashion as 17β-estradiol, the HFPOs display an antagonistic binding mode. Using a zebrafish model, we further found that exposure to HFPO homologues significantly altered the levels of sex steroid hormones and vitellogenin. In general, both in vivo and in vitro results indicate that HFPO homologues might exert higher estrogenic effects than PFOA.

Background: Data on the pharmacological management of acute agitation in schizophrenia are scarce. The aim of this study is to investigate the prescription practices in the treatment of agitation in Chinese patients with schizophrenia., Methods: We conducted a large, multicenter, observational study in 14 psychiatry hospitals in China. Newly hospitalized schizophrenia patients with the PANSS-EC total score ≥ 14 and a value ≥4 on at least one of its five items were included in the study. Their drug treatments of the first 2 weeks in hospital were recorded by the researchers., Results: Eight hundred and 53 patients enrolled in and 847 (99.30%) completed the study. All participants were prescribed antipsychotics, 40 (4.72%) were prescribed benzodiazepine in conjunction with antipsychotics and 81 were treated with modified electric convulsive therapy (MECT). Four hundred and 12 (48.64%) patients were prescribed only one antipsychotic, in the order of olanzapine (120 patients, 29.13%), followed by risperidone (101 patients, 24.51%) and clozapine (41 patients, 9.95%). About 435 (51.36%) participants received antipsychotic polypharmacy, mostly haloperidol + risperidone (23.45%), haloperidol+ olanzapine (17.01%), olanzapine+ ziprasidone (5.30%), haloperidol + clozapine (4.37%) and haloperidol + quetiapine (3.90%). Binary logistic regression analysis suggests that a high BARS score (OR 2.091, 95%CI 1.140-3.124), severe agitation (OR 1.846, 95%CL 1.266-2.693), unemployment or retirement (OR 1.614, 95%CL 1.189-2.190) and aggressiveness on baseline (OR 1.469, 95%CL 1.032-2.091) were related to an increased antipsychotic polypharmacy odds. Male sex (OR 0.592, 95%CL 0.436-0.803) and schizophrenia in older persons (age ≥ 55 years, OR 0.466, 95%CL 0.240-0.902) were less likely to be associated with antipsychotic polypharmacy., Conclusion: The present study demonstrates that monotherapy and polypharmacy display equally common patterns of antipsychotic usage in managing agitation associated with schizophrenia in China. The extent and behavioral activities of agitation and several other factors were associated with polypharmacy.

Polybrominated diphenyl ethers (PBDEs) can be metabolized to hydroxylated PBDEs (OH-PBDEs), which play important roles in their disruption effects on the thyroid hormone (TH) system. Recently, multiple in vitro studies suggested that OH-PBDEs might be further metabolically transformed to PBDE sulfates. However, information about the bioactivity of PBDE sulfate metabolites is limited. In the present study, we explored the possible disruption effects of PBDE sulfates to the TH system by studying their binding and activity towards TH transport proteins and nuclear receptors. We found PBDE sulfates could bind to two major TH transport proteins (thyroxine-binding globulin and transthyretin). Besides, PBDE sulfates could also bind to two subtypes of TH nuclear receptors (TRα and TRβ) and showed agonistic activity towards the subsequent signaling pathway. Moreover, the PBDE sulfates showed higher binding potency to TH transport proteins and TRs compared with their corresponding OH-PBDE precursors. Molecular docking results showed that replacement of hydroxyl groups with sulfate groups might lead to more hydrogen bond interactions with these proteins. Overall, our study suggested that PBDE sulfates might disturb the TH system by binding to TH transport proteins or TRs. Our finding indicated a possible mechanism for the TH system disruption effects of PBDEs through their sulfate metabolites.

Reactive oxygen species (ROS) play an essential role in TiO 2 photocatalysis. They arise from the transfer of light-initiated carriers to the TiO 2 surface and react with oxygen or water, in which the TiO 2 surface is crucial. However, how the TiO 2 surface affects ROS production is unclear. Herein, dynamic generation of ROS in suspensions of TiO 2 of different particle sizes was investigated under ultraviolet-light irradiation. It is surprising to find that more ROS were produced more quickly for 100-140 nm TiO 2 than for 20-60 nm TiO 2 . Further research suggested that ROS production was intrinsically correlated with the surface bridging hydroxyls per unit area. More bridging hydroxyls induced lower IEP and more negative charges on the TiO 2 surface, which favored the transfer of photogenerated carriers, resulting in the promotion of ROS and photocatalytic activity. This provided insight into designing high-efficiency photocatalysts to solve the problem of small particle sizes causing loss and blockage in wastewater treatment.

Pentachlorophenol (PCP) caused water quality problems owe to its past widespread application and stability, harmful to human health. Photocatalysis, which was mainly involved in the reactive oxygen species (ROS) reaction, has large potential as water treatment process. However, the roles of ROS on the degradation process of PCP are not yet clearly defined. The main objectives of this work were to investigate the roles of ROS involved in the whole degradation of PCP and main toxic intermediates and elucidate the degradation mechanisms. Tetrachloro-1,4-benzo/hydroquinone (TCBQ/TCHQ), trichlorohydroxy-1,4-benzoquinone (OH-TrCBQ) and 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (OH-DCBQ) were identified as main intermediates. The roles of generated ROS including OH, O 2 - and H 2 O 2 were systematically explored for the degradation of PCP and its main intermediates using radical quenchers. The results showed that, OH played the dominant role for the degradation of PCP, O 2 - played more contributing roles for the degradation of TCBQ, H 2 O 2 exhibited major contribution for the degradation of OH-TrCBQ and OH-DCBQ. These results offered us an insight into the degradation mechanism of PCP involved with ROS. It can also serve as the basis for controlling and blocking the generation of highly toxic substances through regulating the ROS generation during the PCP degradation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hexafluoropropylene oxide trimer acid (HFPO-TA) and hexafluoropropylene oxide dimer acid (HFPO-DA) have been used as perfluorooctanoic acid (PFOA) alternatives in the fluoropolymer industry for years. Their widespread environmental distribution, high bioaccumulation capability, and human exposure have caused great concern. Nevertheless, their potential toxicity and health risk remain largely unknown. In the present study, we compared potential disruption effects of HFPO-TA, HFPO-DA, and PFOA on peroxisome proliferator-activated receptor γ (PPARγ) via the investigation of receptor binding, receptor activity, and cell adipogenesis effects. The receptor binding experiment showed HFPO-TA exhibited 4.8-7.5 folds higher binding affinity with PPARγ than PFOA, whereas HFPO-DA exhibited weaker binding affinity than PFOA. They also showed agonistic activity toward PPARγ signaling pathway in HEK 293 cells in the order of HFPO-TA > PFOA > HFPO-DA. Molecular docking simulation indicated HFPO-TA formed more hydrogen bonds than PFOA, whereas HFPO-DA formed fewer hydrogen bonds than PFOA. HFPO-TA promoted adipogenic differentiation and lipid accumulation in both mouse and human preadipocytes with potency higher than PFOA. Adipogenesis in human preadipocytes is a more sensitive end point than mouse preadipocytes. Collectively, HFPO-TA exerts higher binding affinity, agonistic activity, and adipogenesis activity than PFOA. The potential health risk of HFPO-TA should be of concern.

Graphene quantum dots (GQDs) possess great potential in various applications due to their superior physicochemical properties and wide array of available surface modifications. However, the toxicity of GQDs has not been systematically assessed, thus hindered their further development; especially, the risk of surface modifications of GQDs is largely unknown. In this study, we employed a lung carcinoma A549 cells as the model to investigate the cytotoxicity and autophagy induction of three types GQDs, including cGQDs (COOH-GQDs), hGQDs (OH-GQDs), and aGQDs (NH 2 -GQDs). The results showed hGQDs was the most toxic, as significant cell death was induced at the concentration of 100 μg/mL, determining by WST-1 assay as well as Annexin-V-FITC/PI apoptosis analysis, whereas cGQDs and aGQDs were non-cytotoxic within the measured concentration. Autophagy detection was performed by TEM examination, LC3 fluorescence tracking, and Western-blot. Both aGQDs and hGQDs induced cellular autophagy to various degrees except for cGQDs. Further analysis on autophagy pathways indicated all GQDs significantly activated p-p38MAPK; p-ERK1/2 was inhibited by aGQDs and hGQDs but activated by cGQDs. p-JNK was inhibited by aGQDs and cGQDs, while activated by hGQDs. Simultaneously, Akt was activated by hGQDs but inhibited by aGQDs. Inhibition of autophagy by 3-MA significantly increased the cytotoxicity of GQDs, suggesting that autophagy played a protective role against the toxicity of GQDs. In conclusion, cGQDs showed excellent biocompatibility and may be considered for biological applications. Autophagy induction may be included in the health risk assessment of GQDs as it reflects the stress status which may eventually lead to diseases., (Copyright © 2018. Published by Elsevier B.V.)

The present study aimed to investigate the effects of astragaloside IV on osteoblast‑like cell proliferation and migration, in addition to the underlying signaling pathway. In order to observe the effect on proliferation, a Cell Counting Kit‑8 assay and flow cytometry were used. To detect cell migration ability, cell scratch and Transwell cell migration assays were performed. The RNA and protein expression levels of hedgehog signaling molecules, including Sonic hedgehog (SHH) and GLI family zinc finger 1 (GLI1), were examined by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. To inhibit the hedgehog signaling pathway, cyclopamine was used. Astragaloside IV, at a dosage of 1x10‑2 µg/ml in MG‑63 cells and 1x10‑3 µg/ml in U‑2OS cells, resulted in the enhanced proliferation and migration of cells, and the gene expression levels of the SHH and GLI1 were significantly increased. The combination of astragaloside IV and cyclopamine reduced MG‑63 and U‑2OS cell proliferation and migration, and inhibited the gene expression of SHH and GLI1. Astragaloside IV enhanced the proliferation and migration of human osteoblast‑like cells through activating the hedgehog signaling pathway. The results of the present study provide a rational for the mechanistic link in astragaloside IV promoting the proliferation and migration of osteoblasts via the hedgehog signaling pathway.

Objective: To investigate the stiffness distribution in the ablated zone after radiofrequency ablation (RFA), we used a device called tissue elastometer based on gross liver samples., Materials: AND METHODS: Twelve freshly excised porcine livers were subject to RFA under a same setup to form elliptic ablated samples. Each sample was cut open for gross examination, and then the surface of the section plane was sliced into one piece for Young's modulus test using the tissue elastometer. Five test points along the long- and short-axis on each piece were selected to evaluate stiffness distribution respectively. Among them, four points distributed equidistantly from center to boundary in the ablated zone and one was in the unablated zone., Results: In the ablated zone, we found the Young's moduli were significantly different among the four test points both in long- (F = 99.04, p <0.001) and short-axis (F = 79.47, p <0.001) directions. The Young's modulus showed a downtrend in each direction, and was linearly related to the distance from the center to the test point (for long axis, R2 = 0.968; for short axis, R2 = 0.984, both p <0.001). A more significant downtrend was observed in short-axis direction. The Young's moduli gained from the inner edge of ablated zone were comparable and significantly higher than those from the outer edge for both directions. The maximum value of 24.71kPa for Young's modulus was the appropriate threshold to ensure the tissues were necrotic completely., Conclusion: The stiffness inside the ablated zone represented a radial distribution with downtrend, following a linear law. The stiffness at the inner edge of ablated zone is stable and significantly higher than that at the outer edge. The maximum value of 24.71 kPa close to the inner edge of Wz may be used as the standard of complete ablation.

Objectives: To prospectively evaluate the diagnostic performance of three-dimensional (3D) shear wave elastography (SWE) for breast lesions with quantitative stiffness information from transverse, sagittal and coronal planes., Methods: Conventional ultrasound (US), two-dimensional (2D)-SWE and 3D-SWE were performed for 122 consecutive patients with 122 breast lesions before biopsy or surgical excision. Maximum elasticity values of Young's modulus (Emax) were recorded on 2D-SWE and three planes of 3D-SWE. Area under the receiver operating characteristic curve (AUC), sensitivity and specificity of US, 2D-SWE and 3D-SWE were evaluated. Two combined sets (i.e., BI-RADS and 2D-SWE; BI-RADS and 3D-SWE) were compared in AUC. Observer consistency was also evaluated., Results: On 3D-SWE, the AUC and sensitivity of sagittal plane were significantly higher than those of transverse and coronal planes (both P < 0.05). Compared with BI-RADS alone, both combined sets had significantly (P < 0.05) higher AUCs and specificities, whereas, the two combined sets showed no significant difference in AUC (P > 0.05). However, the combined set of BI-RADS and sagittal plane of 3D-SWE had significantly higher sensitivity than the combined set of BI-RADS and 2D-SWE., Conclusions: The sagittal plane shows the best diagnostic performance among 3D-SWE. The combination of BI-RADS and 3D-SWE is a useful tool for predicting breast malignant lesions in comparison with BI-RADS alone.

Objectives: To evaluate the value of ultrasound (US) in differentiating the acute phase of gout from the intercritical phase, particularly using shear wave elastography (SWE)., Methods: 57 gout patients were prospectively enrolled and divided into acute phase and intercritical phase groups. The patients underwent US and SWE examinations for the first metatarsophalangeal joints with the same protocol. Maximum synovial thickness was measured. US features were reviewed by two radiologists independently. The maximum (E max ) and mean (E mean ) elastic moduli of synovium were calculated. Diagnostic performances of US, SWE and combined US and SWE were evaluated., Results: US findings demonstrated that the colour Doppler flow signal grade in the acute phase was higher than that in the intercritical phase (p = 0.001), whereas no differences were found for B-mode US features between the two groups (all p > 0.05). For SWE, E max and E mean were significantly higher in the intercritical phase than in the acute phase (both p < 0.001). The areas under the receiver operating characteristic curve (AUROCs) were 0.494-0.553 for B-mode US, 0.735 for colour Doppler US (CDUS), 0.887 for E max and 0.882 for E mean . The combination of CDUS and SWE increased the AUROC, sensitivity and accuracy significantly in comparison with CDUS alone (all p < 0.001). However, the combined set did not show stronger diagnostic performance in comparison with SWE alone., Conclusion: SWE increases the diagnostic performance in differentiating the acute phase of gout from the intercritical phase in comparison with conventional US., Key Points: • Colour Doppler flow signal grade is higher in acute phase of gout than in intercritical phase. • SWE demonstrates that synovium stiffness is higher in intercritical phase of gout than in acute phase. • SWE increases diagnostic performance in differentiating acute phase of gout from intercritical phase in comparison with conventional US.

Wide application of perfluoroalkyl acids (PFAAs) has raised great concerns on their side-effects on human health. PFAAs have been shown to accumulate mainly in the liver and cause hepatotoxicity. However, PFAAs can also deposit in lung tissues through air-borne particles and cause serious pulmonary toxicity. But the underlying mechanisms are still largely unknown. Autophagy is a type of programmed cell death parallel to necrosis and apoptosis, and may be involved in the lung toxicity of PFAAs. In this study, lung cancer cells, A549, were employed as the model to investigate the effects of three PFAAs with different carbon chain lengths on cell autophagy. Through Western blot analysis on LC3-I/II ratio of cells exposed to non-cytotoxic concentration (200 µM) and cytotoxic concentration (350 µM), we found concentration-dependent increase of autophagosomes in cells, which was further confirmed by TEM examination on ultra-thin section of cells and fluorescence imaging on autophagosomes in live cells. The abundance of p62 increased with the PFAAs concentration indicating the blockage of autophagy flux. Furthermore, we identified the mitochondrial autophagy (mitophagy) and endoplasmic reticulum autophagy (ER-phagy) morphologically as the major types of autophagy, suggesting the disruption on mitochondria and ERs. These organelle damages were confirmed by the overgeneration of ROS, hyperpolarization of mitochondrial membrane potential, as well as the up-regulation of ER-stress-related proteins, ATF4 and p-IRE1. Further analysis on the signaling pathways showed that PFAAs activated the MAPK pathways and inhibited the PI3K/Akt pathway, with potencies following the order of PFDA > PFNA > PFOA. Anti-oxidant (NAC) treatment did not rescue cells from death, indicating that oxidative stress is not the reason of cytotoxicity. Inhibition of autophagy by Atg5 siRNA and chloroquine even increased the toxicity of PFAAs, suggesting that PFAAs-autophagy was induced as the secondary effects of organelle damages and played a protective role during cell death.

Underlying a cancer phenotype is a specific gene regulatory network that represents the complex regulatory relationships between genes. However, it remains a challenge to find cancer-related gene regulatory network because of insufficient sample sizes and complex regulatory mechanisms in which gene is influenced by not only other genes but also other biological factors. With the development of high-throughput technologies and the unprecedented wealth of multi-omics data give us a new opportunity to design machine learning method to investigate underlying gene regulatory network. In this paper, we propose an approach, which use biweight midcorrelation to measure the correlation between factors and make use of nonconvex penalty based sparse regression for gene regulatory network inference (BMNPGRN). BMNCGRN incorporates multi-omics data (including DNA methylation and copy number variation) and their interactions in gene regulatory network model. The experimental results on synthetic datasets show that BMNPGRN outperforms popular and state-of-the-art methods (including DCGRN, ARACNE and CLR) under false positive control. Furthermore, we applied BMNPGRN on breast cancer (BRCA) data from The Cancer Genome Atlas database and provided gene regulatory network.

Chlorinated polyfluoroalkylether sulfonates (Cl-PFAESs) have been used as perfluorooctanesulfonate (PFOS) alternatives in the chrome plating industry for years. Although Cl-PFAESs have become ubiquitous environmental contaminants, knowledge on their toxicological mechanism remains very limited. We compared potential thyroid hormone (TH) disruption effects of Cl-PFAESs and PFOS via the mechanisms of competitive binding to TH transport proteins and activation of TH receptors (TRs). Fluorescence binding assays revealed that 6:2 Cl-PFAES, 8:2 Cl-PFAES and F-53B (a mixture of 6:2 and 8:2 Cl-PFAES) all interacted with a TH transport protein transthyretin (TTR), with 6:2 Cl-PFAES showing the highest affinity. It was also found that the chemicals interacted with TRs, with the affinity following the order of 6:2 Cl-PFAES > PFOS > 8:2 Cl-PFAES. In reporter gene assays the chemicals exhibited agonistic activity toward TRs, with the potency of 6:2 Cl-PFAES comparable to that of PFOS. The chemicals also promoted GH3 cell proliferation, with 6:2 Cl-PFAES displaying the highest potency. Molecular docking and molecular dynamic simulation revealed that both Cl-PFAESs fit into the ligand binding pockets of TTR and TRs with the binding modes similar to PFOS. Collectively, our results demonstrate that Cl-PFAESs might cause TH disruption effects through competitive binding to transport proteins and activation of TRs.

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor having functional cross-talk with classical estrogen receptors. Here, we investigated whether ERRγ is a potential target of polybrominated diphenyl ethers (PBDEs) and their hydroxylated metabolites (OH-PBDEs). By using a fluorescence competitive binding method established in our laboratory, the binding potencies of 30 PBDEs/OH-PBDEs with ERRγ were determined for the first time. All of the tested OH-PBDEs and some PBDEs bound to ERRγ with K d values ranging from 0.13-13.61 μM. The OH-PBDEs showed much higher binding potency than their parent PBDEs. A quantitative structure-activity relationship (QSAR) model was developed to analyze the chemical binding potencies in relation to their structural and chemical characteristics. The QSAR model indicated that the molecular size, relative ratios of aromatic atoms, and hydrogen bond donors and acceptors were crucial factors for PBDEs/OH-PBDEs binding. By using a reporter gene assay, we found that most of the low-brominated PBDEs/OH-PBDEs exerted agonistic activity toward ERRγ, while high-brominated PBDEs/OH-PBDEs had no effect on the basal ERRγ activity. The docking results showed that the low-brominated PBDEs/OH-PBDEs tended to take an agonistic binding mode while the high-brominated ones tended to take an antagonistic binding mode. Overall, our results suggest ERRγ to be a potential novel target for PBDEs/OH-PBDEs.

Objective: To observe the in vivo effect of Danlou Tablet (, DLT) on myocardial ischemia and reperfusion (I/R) injury., Methods: DLT effects were evaluated in mouse heart preparation using 30-min coronary occlusion followed by 24-h reperfusion and compared among sham group (n=6), I/R group (n=8), IPC group (ischemia preconditioning, n=6) and DLT group (I/R with DLT pretreatment for 3 days, 750 mg•kg -1 •day -1 , n=8). The effects of DLT were characterized in infarction size (IS) compared with risk region (RR) and left ventricle using the Evans blue/triphenyltetrazolium chloride double dye staining method in vivo. Furthermore, the dose-dependent effect of DLT on I/R injury was evaluated by double staining method. Five different concentrations of DLT (0.625, 1.25, 2.5, 5 and 10 g•kg -1 •day -1 ) were chosen in this study, and dose-response curve of DLT was obtained on these data., Results: The ratio of IS to left ventricle was significantly smaller in the DLT and IPC groups than the I/R group (P<0.05 or P<0.01), the ratio of IS to RR was also reduced in the DLT and IPC groups (P<0.01), while there were no differences in RR among the four groups (P>0.05). Experiments showed incidence of arrhythmias was reduced in the DLT group (P<0.01). Furthermore, DLT produced a dose-dependent inhibitory effect with a half maximal inhibitory concentration of 1.225 g•kg -1 •day -1 ., Conclusions: Our research concluded that DLT was effective in reducing I/R injury in mice, and provided experimental supports for the clinical use of DLT.

Human amniotic epithelial cells (hAECs), derived from the innermost layer of the term placenta closest to the fetus, have been shown to be potential seed cells for allogeneic cell therapy. Previous studies have shown a certain therapeutic effect of hAECs. However, no appropriate isolation and culture system for hAECs has been developed for clinical applications. In the present study, we established a serum-free protocol for hAEC isolation and cultivation, in which better cell growth was observed compared with that in a traditional culture system with serum. In addition to specific expression of cell surface markers (CD29, CD166 and CD90), characterization of the biological features of hAECs revealed expression of the pluripotent markers SSEA4, OCT4 and NANOG, which was greater than that in human mesenchymal stem cells, whereas very low levels of HLA-DR and HLA-DQ were detected, suggesting the weak immunogenicity of hAECs. Intriguingly, CD90+ hAECs were identified as a unique population with a powerful immunoregulatory capacity. In a systemic safety evaluation, intravenous administration of hAEC did not result in hemolytic, allergy, toxicity issues or, more importantly, tumorigenicity. Finally, the therapeutic effect of hAECs was demonstrated in mice with radiation-induced damage. The results revealed a novel function of hAECs in systemic injury recovery. Therefore, the current study provides an applicable and safe strategy for hAEC cell therapy administration in the clinical setting.

Heterogeneous catalytic reactions usually proceed at the surfaces of materials, where many intermediates, such as free radicals, usually were believed to be short-lived. Herein, surface long-lived superoxide radicals (O2˙-) were identified in UV-irradiated aqueous suspensions of TiO2 and other metal oxide nanoparticles using an online chemiluminescence system. From the decay dynamics process of O2˙-, a long-lived O2˙- radical was observed on anatase TiO2 at pH = 12. After separation of the photo-excited suspension via filtration, CL was detected from the particles but not the filtrate, thus confirming O2˙- surface adsorption. The unusual stability of O2˙- was also verified using density functional theory (DFT) calculations. The lifetimes of the radicals were estimated on the different kinds of semiconductor surface according to the decay dynamics curves, and followed the order: TiO2 > ZnO > SnO2 > CeO2 > Fe2O3. Furthermore, the function of surface long-lived O2˙- in TiO2 suspensions with regards to photochemical conversion was investigated using NBT as a chemical model; it was found that half of the molecules were reduced by the surface-adsorbed O2˙-. The finding of surface-stabilized, long-lived superoxide radicals may have important implications in relation to the chemistry, biology and toxicology of these radicals.

Objective: Diabetic nephropathy (DN), as the most common and serious diabetic microvascular complication, has become the first cause of end-stage renal disease (ESRD) in many countries and regions. However, the pathogenesis of renal fibrosis during the development of DN remains unknown., Materials and Methods: The expression levels of miR-192 and early growth response factor 1 (Egr1) were determined by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blotting in the renal tissues of Otsuka-Long-Evans-Tokushima-Fatty (OLETF) and Long-Evans-Tokushima-Otsuka (LETO) rats. The diabetic kidney environment was simulated by a high-sugar medium. The expression levels of miR-192 and Egr1 were further measured in the HK-2 cell line. Egr1 was verified as a potential target of miR-192 by using bioinformatics analysis and luciferase activity assay. The expression level of Egr1 was determined by overexpressing and knocking down the expression of miR-192. In addition, Western blotting was used to determine changes in Transforming growth factor-beta 1 (TGF-β1) and fibronectin (FN)., Results: Compared with the kidney tissue of LETO rats, the expression of miR-192 was decreased in OLETF rats, whereas the expression of Egr1 was increased. We found the same phenomenon in the HK-2 cell line cultured in the high-glucose medium. Next, miR-192 can act on Egr1 through 3'-UTR to reduce the expression of Egr1 verified by luciferase assay. In addition, the expression levels of TGF-β1 and FN changed significantly, as the expression level of Egr1 increased or decreased., Conclusions: MiR-192 causes degradation of TGF-β1 and FN through targeting Egr1 and affects the progression of TIF and even DN.