Search

Background Papillary thyroid carcinoma (PTC) is one of most prevalent malignant endocrine neoplasms, and it is associated with a high frequency of BRAF gene mutations, which lead to lymphatic metastasis and distant metastasis that promote tumor progression. The molecular mechanism of PTC and the role of BRAF mutation in PTC progression and development need to be further elucidated. Methods In this study, a comprehensive bioinformatics analysis was performed to identify the differentially expressed genes and signaling pathways in thyroid cancer patients carrying mutant BRAF. Then, we confirmed the prognostic role of WT1 in thyroid cancer patients. Immunohistochemistry was performed to measure the expression profile of WT1 in PTC tissue. Lentivirus shWT1 was transfected into BRAFV600E (mutant) PTC cells to stably inhibit WT1 expression. CCK-8, EdU, immunofluorescence, colony formation, cell migration, cell wound healing, apoptosis and autophagy assays were performed to assess the biological functions of WT1 in BRAFV600E PTC cells. RNA sequencing, immunohistochemistry and immunoblotting were performed to explore the molecular mechanism of WT1 in BRAFV600E PTC cells. Results The results confirmed that “epithelial cell proliferation”, “apoptosis” and “selective autophagy” were closely associated with this BRAF mutant in these thyroid cancer patients. Knocking down BRAF-activated WT1 effectively inhibited the proliferation and migration of BRAFV600E PTC cells. Silencing WT1 significantly inhibited autophagy and promoted the apoptosis of BRAFV600E PTC cells. Mechanistic investigations showed that silencing WT1 expression remarkably suppressed the AKT/mTOR and ERK/P65 signaling pathways in BRAFV600E PTC cells. Conclusion All these results indicate that WT1 is a promising prognostic biomarker and facilitates PTC progression and development of cells carrying the BRAFV600E mutation.

BACKGROUND Lymphomas are the second most common malignancy of the head and neck. In this region, the vast majority of extranodal lymphomas are located in the palatine tonsil, accounting for about 51%. Tonsillar lymphomas are aggressive tumors with intermediate- or high-grade histology. We here report a case of primary non-Hodgkin’s lymphoma of the palatine tonsil and analyze its ultrasound features. CASE SUMMARY A 40-year-old man presented with right palatine tonsil swelling for 2 mo after a cold, accompanied by dysphagia, snoring, and suffocation. He had no sore throat, fever, or history of upper respiratory tract infection or tuberculosis. The patient was generally in good health and denied other diseases. He was diagnosed with acute tonsillitis initially and treated with antibiotics for 7 d. However, there was no improvement with the treatment. Tonsil biopsy and ultrasound-guided biopsy of the biggest lymph node of the right neck showed the typical pathology of non-Hodgkin lymphoma. CONCLUSION Primary lymphoma of the tonsils is rare, and its diagnosis is challenging. Ultrasound is a useful modality in diagnosing oropharyngeal diseases, and can clearly show the features of this tumor, but the final diagnosis should be established by histology.

Respiratory syncytial virus (RSV) infection is a major cause of lower respiratory tract disease. Although RSV causes major economic losses every year, effective treatments have not been found so far. Recent studies have shown that the tripartite motif-containing (TRIM) superfamily plays an essential role in the immune response. In this study, we found that TRIM22 had an inhibitory effect on RSV infection, and downregulation of TRIM22 moderately enhanced RSV replication. Our data further demonstrated that RSV infection induced TRIM22 expression through the activation of JAK-STAT1/2 signaling. RSV infection also induced TRIM22 expression. Taken together, these data points showed that the TRIM family member, TRIM22, had an essential role in resisting RSV infection, and this effect was closely related to the JAK-STAT1/2 pathway. Our results provide promising evidence for a novel target for the prevention and treatment of RSV.

This study was conducted to investigate the effect of quercetin on the triglyceride (TG) content through the peroxisome proliferator-activated receptor α (PPARα) signalling pathway in broiler hepatocytes. The trial included the following five groups: control, DMSO control, 5 mg/L quercetin, 10 mg/L quercetin and 20 mg/L quercetin. Compared with the control group, the PPARα protein content was significantly increased at 24 h in the groups that received quercetin at 5, 10 and 20 mg/L (p

INTRODUCTION: Hypobaric hypoxia training utilizing the environmental chamber is often preceded by prebreathing of 100% oxygen with the goal of reducing decompression illness (DCI). We aimed to study the impact of prebreathing 100% oxygen for 30 min prior to hypobaria exposure to 7600 m (25,000 ft) on the incidence rate of DCI, as well as the impact of prebreathing on hypoxia symptoms felt during training.METHODS: Records of participants who underwent hypobaric hypoxia training in the Republic of Singapore Air Force (RSAF) from 2011 to 2014 (before introduction of prebreathing) were compared to those who underwent similar training from 2014 to 2017 (after introduction of prebreathing) to determine the incidences of DCI for both groups. Participants who underwent hypobaric hypoxia training from January 2017 to July 2017 completed a survey to assess the impact of prebreathing on the presentation and severity of hypoxia symptoms.RESULTS: Two DCI events were recorded in 1530 hypobaric chamber exposures without prebreathing while two DCI events were recorded in 1729 exposures with prebreathing. There was no significant difference in the incidence of DCI between the two groups. The survey findings showed no significant difference in the presentation and severity of hypoxia symptoms with 30 min of prebreathing.DISCUSSION: Incidence of DCI remains low during hypobaric chamber training, with no statistical difference with or without prebreathing. Possible reasons were the short duration of hypobaric exposure of 10 min during hypoxia training, and that 30 min of prebreathing was insufficient to further decrease or eliminate the risk of DCI in short duration hypobaric exposures.Cheok LJ, Goh BLY, Soh FW, Chuan BTB. Decompression illness incidence and hypoxia symptoms after prebreathing in hypobaric hypoxia training. Aerosp Med Hum Perform. 2021; 92(5):289293.

Background:The pathogenesis of sarcopenia in the elderly has not yet been fully understood. This study aimed to explore the relationship between sarcopenia and several serum biomarkers in elderly population. Methods:It was an observational cross‐sectional study of data collected from 70 patients (>60 years old, 61.4% men) .According to the criteria of the Asian Working Group for Sarcopenia (AWGS), subjects were divided into a sarcopenia group and a non-sarcopenic group.We compared age, body mass index (BMI) ,biochemical indexes, skeletal muscle mass, handgrip strength (HS), gait speed (GS), skin-fold thickness, muscle thickness, bone mineral density(BMD) and IL-6,IL-10,IL-17A ,TNF-α levels between these groups.Results: Of the 70 subjects, 35 patients were diagnosed with sarcopenia according to the AWGS criteria. The number of men was higher than that of women in both groups. The patients with sarcopenia were older and had lower BMI and muscle thickness, but higher SARC-F questionnaire scores. However, the difference in BMD and skin-fold thickness between these two groups was not statistically significant. Higher IL-6, IL-17A, and TNF-α levels were observed in participants with sarcopenia (P < 0.05). Patients with sarcopenia seemed to have a lower IL-10 level. Positive associations were present between the severity of sarcopenia and IL-6, IL-17, and TNF-α levels, while there was an inverse correlation between the presence of sarcopenia and the IL-10 level. Conclusions: Our research found that in sarcopenic elderly subjects, the serum levels of several biomarkers, such as IL-6, IL-17A, and TNF-α, were higher than those in non-sarcopenic elderly persons.In summary, chronic inflammation plays an important role in the development of sarcopenia. Further studies are needed to explore the possible molecular mechanisms and discover new therapeutic targets.

Background In asthma, IL-6 is a potential cause of enhanced inflammation, tissue damage and airway dysfunction. IL-6 signalling is regulated by its receptor, which is composed of two proteins, IL-6R and GP130. In addition to their membrane form, these two proteins may be found as extracellular soluble forms. The interaction of IL-6 with soluble IL-6R (sIL-6R) can trigger IL-6 trans-signalling in cells lacking IL-6R. Conversely, the soluble form of GP130 (sGP130) competes with its membrane form to inhibit IL-6 trans-signalling. Objectives We aimed to analyse IL-6 trans-signalling proteins in the airways of subjects after an allergen challenge. Methods We used a model of segmental bronchoprovocation with an allergen (SBP-Ag) in human subjects with allergy. Before and 48 h after SBP-Ag, bronchoalveolar lavages (BALs) allowed for the analysis of proteins in BAL fluids (BALFs) by ELISA, and membrane proteins on the surface of BAL cells by flow cytometry. In addition, we performed RNA sequencing (RNA-seq) and used proteomic data to further inform on the expression of the IL-6R subunits by eosinophils, bronchial epithelial cells and lung fibroblasts. Finally, we measured the effect of IL-6 trans-signalling on bronchial fibroblasts, in vitro. Results IL-6, sIL-6R, sGP130 and the molar ratio of sIL-6R/sGP130 increased in the airways after SBP-Ag, suggesting the potential for enhanced IL-6 trans-signalling activity. BAL lymphocytes, monocytes and eosinophils displayed IL-6R on their surface and were all possible providers of sIL-6R, whereas GP130 was highly expressed in bronchial epithelial cells and lung fibroblasts. Finally, bronchial fibroblasts activated by IL-6 trans-signalling produced enhanced amounts of the chemokine, MCP-1 (CCL2). Conclusion and clinical relevance After a bronchial allergen challenge, we found augmentation of the elements of IL-6 trans-signalling. Allergen-induced IL-6 trans-signalling activity can activate fibroblasts to produce chemokines that can further enhance inflammation and lung dysfunction.

Acute lymphoblastic leukemia (ALL) as a common cancer is a heterogeneous disease which is mainly divided into BCP-ALL and T-ALL, accounting for 80–85% and 15–20%, respectively. There are many differences between BCP-ALL and T-ALL, including prognosis, treatment, drug screening, gene research and so on. In this study, starting with methylation and gene expression data, we analyzed the molecular differences between BCP-ALL and T-ALL and identified the multi-omics signatures using Boruta and Monte Carlo feature selection methods. There were 7 expression signature genes (CD3D, VPREB3, HLA-DRA, PAX5, BLNK, GALNT6, SLC4A8) and 168 methylation sites corresponding to 175 methylation signature genes. The overall accuracy, accuracy of BCP-ALL, accuracy of T-ALL of the RIPPER (Repeated Incremental Pruning to Produce Error Reduction) classifier using these signatures evaluated with 10-fold cross validation repeated 3 times were 0.973, 0.990, and 0.933, respectively. Two overlapped genes between 175 methylation signature genes and 7 expression signature genes were CD3D and VPREB3. The network analysis of the methylation and expression signature genes suggested that their common gene, CD3D, was not only different on both methylation and expression levels, but also played a key regulatory role as hub on the network. Our results provided insights of understanding the underlying molecular mechanisms of ALL and facilitated more precision diagnosis and treatment of ALL.

Objective: To observe the effects of seawater immersion on the pathophysiological changes in rats combined burns with open abdominal injury.Method: Eighty-eight male Sprague-Dawley(SD) rats combined burns with open abdominal injuries were randomly divided into the seawater immersion group (SI) and the control group (Ctl).Rats in SI group were immersed in seawater at 15℃ for 1 hour. The changes of respiration, blood pressure, rectal temperature, blood gases, blood electrolyte, liver and kidney function, coagulation function, heart damage and animal survival at different time points in the early stage (within 9 hours after injury) were observed.Result: After immersed in seawater, the body temperature of rats in SI group were significantly decreased, the respiration were remarkably inhibited and the blood pressure were obviously declined as compared to those in Ctl group. The blood pH of rats in SI group were significantly lower than those in Ctl group, showing severe acidosis(P3-, PCO2 and BE also presented the similiar trends(P2 and PCO2 in SI group were significantly higher than those in Ctl group (P2 in SI group were lower than those in Ctl group (PConclusion: Low-temperature seawater immersion might aggravate injury, accelerate animal death, induce hypothermia, respiratory depression, acidosis, hypernatremia and hyperchloremia. Immersing in low temperature seawater for 1 hour can cause myocardial damage, but it has protective effects on the liver and kidney. Therefore, more attentions should be paid to the secondary injury caused by seawater immersion in the emergency treatment of the wounded, such as rapidly rewarming, rectifying the acidosis and maintaining the stability of homeostasis of the wounded, so as to lay the foundation for the further definitive treatments.

A semi-micro high performance liquid chromatography (HPLC) was developed to determine clenbuterol in pork, beef and hog liver. The procedure included extraction with 0.4 N perchloric acid, partitionally separation with diethyl ether, and then back-extraction with 0.2 M sulphuric acid. Analytical procedure was performed by HPLC with a Waters Cosmosil column 5C18-MS (2.0×150 mm), a mobile phase of 0.05 M NaH2PO4 (pH3.0)/acetonitrile solution (80/20, v/v) and absorbance at 212 nm. The recoveries of clenbuterol in pork, beef and hog liver spiked with standards of 0.005~0.01 ppm were 80.9~90.6%. The detection limit of clenbuterol in tested samples was 0.0001 ppm, which is lower than the officially allowed level. The equation was linear for detecting 0.0002~0.001 ppm clenbuterol. The method was validated to be usable for market samples. Three out of 150 samples were detected to contain clenbuterol (0.000l~0.00015 ppm), which were less than both JECFA and Department of Health regulation levels (hog liver 0.0006 ppm and beef 0.0002 ppm).

Resveratrol is a naturally occurring polyphenol compound which has been shown to possess antioxidant and anti-inflammatory properties. However, its pharmaceutical applications are limited by its poor water solubility. In this study, we used electrospinning technology to synthesize nanofibers of polyvinylpyrrolidone (PVP) and hydroxypropyl-&beta, cyclodextrin (HPBCD) loaded with resveratrol. We used X-ray diffractometry to analyze crystalline structure, Fourier transform infrared spectroscopy to determine intermolecular hydrogen bonding, antioxidant assays to measure antioxidant activity, and Franz diffusion cells to evaluate skin penetration. Our results showed that the aqueous solubility of resveratrol nanofibers was greatly improved (by more than 20,000-fold) compared to the pure compound. Analysis of physicochemical properties demonstrated that following nanofiber formation, resveratrol was converted from a crystalline to amorphous structure, and resveratrol formed new intermolecular bonds with PVP and HPBCD. Moreover, resveratrol nanofibers showed good antioxidant activity. In addition, the skin penetration ability of resveratrol in the nanofiber formulation was greater than that of pure resveratrol. Furthermore, resveratrol nanofibers suppressed particulate matter (PM)-induced expression of inflammatory proteins (COX-2 and MMP-9) in HaCaT keratinocytes. Therefore, resveratrol-loaded nanofibers can effectively improve the solubility and physicochemical properties of resveratrol, and may have potential applications as an antioxidant and anti-inflammatory formulation for topical skin application.

Recurrent and chronic major depressive disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P = 2.0 × 10−16). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genome-wide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future.

BACKGROUND The aim of this study was to explore whether letrozole and high-fat diets (HFD) can induce obese insulin-resistant polycystic ovary syndrome (PCOS) with all reproductive and metabolic phenotypes in a rat model. MATERIAL AND METHODS Twenty-four 3-week-old female Sprague-Dawley rats were randomized into 4 groups: control, Letrozole, HFD, and Letrozol+HFD. The PCOS model was induced by 12 weeks of Letrozole treatment (1 mg/kg p.o. dissolved in 0.5% CMC solutions once daily) and HFD. Ovarian morphology, estrous cyclicity, hormonal status, body weight, glucose and insulin tolerance, lipid profile, and insulin signaling pathway were investigated. RESULTS The rat model manifests anovulatory cycles and PCO morphology, increased body weight, elevated testosterone levels, abnormal glucose and lipid metabolism, and insulin resistance. The rat model also expresses significantly decreased phosphorylation of 6 essential signaling proteins - INSR, IRS, PI3K, AKT, ERK1, ERK2 - in the PI3K/AKT and MAPK/ERK pathways in the classic insulin-sensitive tissues (e.g., quadriceps femoris muscle, omentum majus, and liver), as well as non-classic target ovary tissues. Disrupted insulin signaling contributes to the decrease in insulin sensitivity and compensatory hyperinsulinemia in PCOS rats. CONCLUSIONS Continuous administration of letrozole and high-fat diets can induce PCOS, metabolic phenotypes, and disrupted activation of the insulin signaling pathway.

BACKGROUND Serum ferritin (SF) test has been widely used in clinical practice. However, its reference intervals (RIs) vary depending on the analytical method and ethnic origin. This study was to establish the RIs using indirect method for SF in Chinese adults. METHODS SF was assayed on Abbott i2000SR analyzer. The SF test results of all health examinees (8913 males aged 18-93 years and 5397 females aged 18-90 years) between December 2010 and April 2019 were obtained from our laboratory information system. After Box-Cox transformation of raw data and exclusion of outliers, parametric and non-parametric approaches were used to calculate 95% RIs. The correlation between SF levels and ages, and the differences in SF levels between subgroups were also analyzed. RESULTS SF levels in females were significantly different from those in males (Z = 88.96, Z* = 23.17; Z > Z*) and showed a weak positive correlation with age (r = .466, P

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.

Aim: To investigate the diagnostic roles of circulating inflammatory biomarkers in gallbladder carcinoma (GBC). Patients & methods: Circulating inflammatory cell count, fibrinogen, albumin, carcinoembryonic antigen (CEA) and CA199 were measured, neutrophil-to-lymphocyte ratio (NLR), dNLR, PLR, LMR and Alb-to-fib (AFR) were calculated in 306 GBC patients, 306 healthy and 305 benign controls. The reciever operating characteristic curve was used to determine diagnostic accuracy of them. Results: The area under curves of combined AFR, dNLR and lymphocyte were 0.943 and 0.985 for diagnosis of GBC from healthy and polyp controls, area under curve of combined AFR, CEA and CA199 was 0.90 for diagnosis of GBC from the cholecystitis patients. Conclusion: Circulating AFR combined with lymphocyte and dNLR or CEA and CA199 could effectively distinguish GBC from the healthy and benign controls.

Objective: Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue. Method: DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain. Results: Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. Conclusions: As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.

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

Aim: To investigate diagnostic value of preoperative inflammatory biomarkers in pancreatic cancer (PCC). Materials & methods: Preoperative circulating Alb/Fib ratio, neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), platelet/lymphocyte ratio and lymphocyte/monocyte ratio were detected and calculated in 226 PCC individuals, 232 healthy controls and 142 additional cancer controls. Receiver-operating characteristic curve and area under the curve (AUC) were used to evaluate the diagnostic efficacy of PCC. Results: Combined circulating dNLR and Alb could effectively improve the diagnosis of PCC (AUC = 0.931), single dNLR could distinguish early-stage PCC and the disease from healthy controls (AUC = 0.895) and additional cancer controls (AUC = 0.794). Conclusion: Circulating dNLR was an effective biomarker for diagnosis and identification of early-stage PCC. Combined dNLR and Alb could improve the diagnostic efficacy of the disease.

Objective Both COVID-19 and influenza are viral respiratory tract infections and the epidemics of viral respiratory tract infections remain highly prevalent with lethal consequences in susceptible individuals. Expression of ICAM-1 on vascular endothelium recruits leukocytes which initiates inflammation. IL-6 induces ICAM-1. Both ICAM-1 and IL-6 can be enhanced in influenza virus infection and COVID-19 patients. Besides initiation of virus entry host cells, whether HA alone, instead of whole virus, of influenza has the effects on expression of ICAM-1 and IL-6 in vascular endothelium with injury in the lungs, remains to be demonstrated. Methods RT-qPCR and Western blot as well as histopathologic examination were used to examine mRNA and protein of ICAM-1 and IL-6 as well as pathological injury in the lung tissues, respectively. Results After incubation of the Human Umbilical Vein Endothelial Cells (HUVECs) with HA of H1N1 for 24 h, the mRNA and protein of ICAM-1 and IL-6 in HUVECs were increased in group of 5 μg/ml concentration with statistical significance (p

Niclosamide (NIC), a helminthic drug used widely for controlling schistosomiasis, can reportedly disrupt the endocrine system. However, its underlying mechanisms are still unclear. In this study, we revealed the potential endocrine disruption mechanism of NIC by activating estrogen receptors (ERs) and estrogen-related receptors (ERRs). The binding potency of NIC with ERα, ERβ and ERRγ were determined by fluorescence competitive binding assays, which shows an IC50 (the concentration of NIC needed to displace 50 % of the probe from the receptor) of 90 ± 4.1, 10 ± 1.7 nM and 0.59 ± 0.07 nM respectively. The IC50 for ERRγ is the lowest one among the three detected receptors, which is three orders of magnitude lower than the known agonist GSK4716.The transcriptional activities of NIC on ERs and ERRs were detected by MVLN cells (stably transfected with ERs reporter gene) and HeLa cells (transiently transfected with ERRs reporter gene)-based luciferase reporter gene assay. The lowest observable effective concentration (LOEC) ranked as follows: ERRγ (0.5 nM)

Numerous studies have indicated estrogenic disruption effects of bisphenol A (BPA) analogues. Previous mechanistic studies were mainly focused on their genomic activities on nuclear estrogen receptor pathway. However, their nongenomic effects through G protein-coupled estrogen receptor (GPER) pathway remain poorly understood. Here, using a SKBR3 cell-based fluorescence competitive binding assay, we found six BPA analogues bound to GPER directly, with bisphenol AF (BPAF) and bisphenol B (BPB) displaying much higher (∼9-fold) binding affinity than BPA. Molecular docking also demonstrated the binding of these BPA analogues to GPER. By measuring calcium mobilization and cAMP production in SKBR3 cells, we found the binding of these BPA analogues to GPER lead to the activation of subsequent signaling pathways. Consistent with the binding results, BPAF and BPB presented higher agonistic activity than BPA with the lowest effective concentration (LOEC) of 10 nM. Moreover, based on the results of Boyden chamber and wound-healing assays, BPAF and BPB displayed higher activity in promoting GPER mediated SKBR3 cell migration than BPA with the LOEC of 100 nM. Overall, we found two BPA analogues BPAF and BPB could exert higher estrogenic effects than BPA via GPER pathway at nanomolar concentrations.

Aims Atypical ductal hyperplasia (ADH) of breast is increasingly diagnosed in core needle biopsy (CNB). As higher-grade lesions were found in the excision in a substantial proportion of ADH on CNB, factors predicting risk of subsequent upgrade are clinically significant. This study aims to investigate relevant histopathological factors in CNB that could predict diagnostic upgrade at excision. Methods and results One hundred and forty-three cases of CNB with paired subsequent excision were evaluated for multiple clinicopathological parameters related to CNB sampling, ADH morphology, calcification and other co-existing histological features, and which of these parameters were associated with diagnostic upgrade at subsequent excisions were determined. Forty-eight cases (34.3%) were upgraded to malignancy, including 15 invasive cancers and 33 ductal carcinomas in situ (DCIS). An increased tissue area occupied by ADH (P = 0.026), a higher number of ADH foci (P = 0.004), the presence of solid pattern (P = 0.037) and older age (P = 0.012) were positively associated with upgrade, while negative associations were found with the presence of micropapillary pattern (P = 0.025), co-existing columnar cell lesions (CCL) (P = 0.001) and the presence of calcifications (P = 0.009). Multivariate logistic regression analysis showed that the number of ADH foci (HR = 2.810, P = 0.013) was an independent positive predictor, while co-existing CCL (HR = 0.391, P = 0.013) was an independent negative predictor for upgrade. Conclusions Patients with ADH in CNB showing the presence of co-existing CCL and a lower number of ADH foci have a lower risk of disease upgrade at excision, and are potential candidates for observation-only management.

Huoxuezhitong rubber patch, a well-known traditional Chinese medicine (TCM) prescription, is utilized to treat pain and inflammation. In this study, a microdialysis-ultra-high-performance liquid chromatography-tandem mass spectrometry (MD-LC-MS/MS) method was designed for the simultaneous determination of active constituents in the rubber patch, such as paeonol (Pae), eugenol (Eug), and piperine (Pip). A microdialysis probe was implanted in the subcutaneous tissue of a rat, which is intended to detect the subcutaneous concentrations of target components. Saline containing 30% ethanol acted as perfusion fluid. Analytes in the microdialysate were completely separated over an ACQITY UPLC RBEH C18column (2.1mm×100mm, 1.7μm). The mobile phase was composed of 0.01% ammonia aqueous and acetonitrile-0.01% ammonia with gradient elution. The single-run analysis time was 10.0 minutes. The linear regression displayed good linear relationships in the ranges of 0.25–100 ng/mL for paeonol and eugenol and 0.001–5 ng/mL for piperine. The interday and intraday precision of the quality control samples exhibited relative standard deviations (RSD) Tmax(488.00±150.73) min was greater than that of Pae (186.67±48.44) min and Eug (240.00±138.56) min, and the rank order of t1/2was Pae > Pip > Eug. The rank order of AUC0-720andCmaxwas both Eug > Pae > Pip. MRT0-∞of Pip was higher than that of Pae and Eug. Eugenol showed a faster elimination and a shorter half-life. Paeonol showed a stronger drug reservoir function after removing the drug source.

To explore the biological properties of rosin derivatives, two dehydroabietic acid derivatives N-(5-dehydroabietyl-1,3,4-thiadiazole)-yl-pyridine-2-carboxamide (DTPC) and di-N-(5-dehydroabietyl-1,3,4-thiadiazole)-yl-pyridine-2,6-carboxamide (DDTPC) with 1,3,4-thiadiazole, pyridine and amide moieties were designed and synthesized according to superposition principle of activity group. They interact with calf thymus DNA (CT DNA) via intercalation based on the results of circular dichroism (CD) and fluorescence spectroscopy, DNA denaturation and viscosity studies. Fluorescence and CD spectral experiments indicate that they might be transported and stored by protein like bovine serum albumin (BSA). MTT assay was further carried out to examine their cytotoxicity, they both showed selective cytotoxicity and DTPC exhibited better cytotoxicity. The antiproliferative effect of DTPC toward A431 cell line was stronger than that of clinically used cisplatin and oxaliplatin. In addition, the cytotoxicity of DTPC and DDTPC was closely related with their DNA binding ability.

Saprolegnia infections cause severe economic losses among freshwater fish farming. In this study, two known compounds, rhein and aloe-emodin, were isolated from Rheum palmatum, and the in vitro inhibitory activity of both compounds against mycelial growth and spore germination of Saprolegnia was tested. Both rhein and aloe-emodin were able to decrease Saprolegnia mycelial growth and spore activity in all tested concentrations after exposure for 48 h. Complete inhibition of mycelial growth was observed at 20 mg/L for rhein and at 50 mg/L for aloe-emodin, while spore germination was 100% prevented at 16 and 40 mg/L for rhein and aloe-emodin, respectively. Because rhein showed stronger in vitro anti-Saprolegnia activity, it was further tested in vivo to measure the prevention and treatment efficacy on Saprolegnia infection of grass carp. Its acute activity to grass carp was also evaluated. The results revealed that exposure to rhein at 20 mg/L for 7 d could prevent 93.3% of infections by Saprolegnia in abraded grass carp, while 67.7% of infected fish could be recovered by treatment with rhein. The 48-h median lethal concentration (48 h-LC50) to grass carp was 148.5 mg/L, which is about 7.4 times the effective dose indicating the safety for the use of rhein. This study suggests that rhein has promising anti-Saprolegnia activity and may be an option in preventing and controlling Saprolegnia infection.

The laser-induced damage threshold of a calcium fluoride (CaF2) single crystal was obtained by a 193 nm ArF excimer laser. The damage morphology of the crystal was analyzed. The results showed that the surface of CaF2 single crystal broke along the natural cleavage plane under ArF excimer laser irradiation, some fragments fell off, and Newton’s rings were observed on the curved fragments. Laser-induced periodic stripe structures (LIPSS) appeared on the surface layer beneath the fragments that peeled off. The spacing of LIPSS was measured, and the formation mechanism of LIPSS was analyzed based on the interference model.

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 Kd (dissociation constant) values ranging from not available (NA) to 3.2 μM 4′–OH–PCB 12 showed the highest binding affinity with Kd 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.

Vibration causes problems, and the technology of dynamic vibration absorber is always used to control it. So far, the technology is mature, but based on the known of modes, mass, stiffness, damping and other parameters of the vibration system. For an unknown system or complicated system, how to use this technology is what the paper mainly discusses. The dynamic vibration absorber of this paper is a single-degree-of-freedom, and only one direction is to be controlled. The evaluation function is the ratio between the system vibration response after adding dynamic vibration absorber and the original exciting force, which can reflect the effect of dynamic vibration absorber. After separating the unknown system and the dynamic vibration absorber, based on force analysis, we analyze them separately and deduce the calculating formula of the evaluation function. The order of parameters to be determined is mass, stiffness, and damping. Flow chart is presented on how to use the method. The method is validated by a known system of two degree-of-freedom vibration system. The main innovation of this paper is to propose a method of predicting the effect of adding a single-degree-of-freedom dynamic vibration absorber to an unknown system to control a certain direction. This method doesn’t need to consider the system damping factor. This paper extends the scope of technology application of dynamic vibration absorber.

Our previous studies have shown that the 3′ end of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in colorectal cancer (CRC) cell proliferation and migration/invasion in vitro. The role and mechanism of MALAT1 in CRC metastasis in vivo, however, remain largely unknown. In the present study, we found that MALAT1 was up-regulated in human primary CRC tissues with lymph node metastasis. Overexpression of MALAT1 via RNA activation promoted CRC cell proliferation, invasion and migration in vitro, and stimulated tumor growth and metastasis in mice in vivo. Conversely, knockdown of MALAT1 inhibited CRC tumor growth and metastasis. MALAT1 regulated at least 243 genes in CRC cells in a genome-wide expression profiling. Among these genes, PRKA kinase anchor protein 9 (AKAP-9) was significantly up-regulated at both mRNA and protein levels. AKAP-9 was highly expressed in CRC cells with metastatic potential and human primary CRC tissues with lymph node metastasis, but not in normal cells or tissues. Importantly, knockdown of AKAP-9 blocked MALAT1-mediated CRC cell proliferation, migration and invasion. These data indicate that MALAT1 may promote CRC tumor development via its target protein AKAP-9.

This study evaluated the correlation of UGT1A1, OATP2 gene mutations and hyperbilirubinemia in newborns in Northern China. Gene mutations were analyzed at the 211 locus of UGT1A1 (Gly71Arg) and 388 locus of OATP2 (Asn130Asp). The 226 enrolled infants were divided into high, moderate, and low risk subgroups according to American Academy of Pediatrics guideline. Blood samples of the enrolled infants were collected for the analysis of the PCR-restriction fragment length polymorphism. The genotypes and allele frequencies of the polymorphisms were compared in each group. Both UGT1A1 and OATP2 gene mutations occur more often in high risk group and moderate risk group than in low risk group. The results suggested that Gly71Arg and Asn130Asp mutations in UGT1A1 and OATP2 genes might be involved in the development of hyperbilirubinemia in neonates.

HBx is a multifunctional regulator that interacts with host factors to contribute to the development of hepatocellular carcinoma. In this study, to explore the co-localization of HBx and COXIII in HepG2 cells and to investigate the molecular mechanism of HBx in HepG2 cell growth promotion, we first constructed a HepG2 cell line stably expressing the HBx gene in vitro by lentivirus vectors. In addition, we found that HBx co-localized with the inner mitochondrial protein, COXIII, in HepG2 cells by confocal laser scanning microscopy. It led to changes of mitochondrial biogenesis and morphology, including upregulation of COXIII protein expression, increased cytochrome c oxidase activity and higher mitochondrial membrane potential. The upregulation of COX-2 caused by HBx through generation of mitochondrial reactive oxygen species promoted cell growth. Thus, we conclude that co-localization of HBx and COXIII leads to upregulation of COX-2 that promotes HepG2 cell growth. Such a mechanism provides deeper insights into the molecular mechanism of HBV-associated hepatocellular carcinoma.

Background Hypoxic-ischemic brain injury in neonates, especially in premature infants, is one of the main contributors to the mortality of newborns and can cause nervous system dysfunction in children. The major pathogenesis seems to be cerebral ischemia/reperfusion in the immature white matter that preferentially targets vulnerable premyelinating oligodendrocytes. Objectives The goal of this study was to culture oligodendrocyte type 2 astrocyte cells in an oxygen and glucose deprivation environment to simulate ischemia injury and examine the cellular and molecular mechanisms involved in the neuroprotective effects of neuregulin-1s on ischemia-induced immature oligodendrocytes. Methods Oligodendrocyte type 2 astrocyte cells were cultured from neonatal Sprague-Dawley rat cerebra. The cells were divided into two groups: one was subjected to oxygen and glucose deprivation for 9 hours and the other was treated with 50 ng/mL or 100 ng/mL neuregulin-1β during oxygen and glucose deprivation. Cell survival was determined by Trypan Blue staining and cell apoptosis were observed by fluorescein isothiocyanate-Annexin V and propidium iodide double staining. To study if the PI3K-Akt signaling pathway was involved in the mechanism of protective effect of neuregulin-1s, Western blot analysis was used to quantitative the changes of protein. Results Treatment with neuregulin-1s within the period of oxygen and glucose deprivation significantly increased cell survival and also resulted in a significant decrease in cell apoptosis. The neuroprotective effects of neuregulin-1s were prevented by treatment with Ly294002, an inhibitor of the phosphatidylinositol-3-kinase/Akt pathway. Conclusions These results suggest that neuregulin-1s could protect the oligodendrocyte type 2 astrocyte progenitors against hypoxic injury, and the mechanism may be associated with the PI3K-Akt signaling pathway.

Saikosaponin-d (Ssd) is a triterpenoid saponin derived from Bupleurum falcatum L., which has been shown to exhibit a variety of pharmacological properties, including anti-inflammatory, antibacterial and antiviral properties. The aim of the present study was to investigate the effect of Ssd on the differentiation, maturation and function of human monocyte-derived dendritic cells (DCs) isolated from condylomata acuminata patients. The results of the present study demonstrated that Ssd reduced the differentiation of DCs, as evidenced by decreased expression levels of cluster of differentiation (CD)1a, CD80 and CD86 molecules and increased CD14 expression. Expression levels of the mannose receptor and CD32 were also significantly elevated , which was associated with enhanced fluorescein isothiocyanate -dextran endocytic activity. Furthermore, Ssd treatment promoted DC maturation by increasing the expression levels of CD40, CD83, CD80 and CD86. In addition, the function of mature DCs, including the secretion of IL-12 and the stimulation of lymphocyte proliferation, was significantly increased following Ssd administration. In conclusion, the present study indicated that Ssd exhibited immunomodulatory effects and may be a novel potent chemopreventive drug candidate for the treatment of condylomata acuminata.

Convolutional networks are powerful visual models that transform images into more effective representations. To make full use of this technique, we propose a new method based on deep learning and convolutional network to effectively get the discharge information of an ultraviolet (UV) image. We firstly segment the equipment region and the UV spot region separately by using the DeepLab network, and then several properties which can show the discharge information are extracted on the basis of the segmentation. The use of the DeepLab network helps to get a reliable segmentation result, and more accurate discharge information. We take 5000 UV images to test our network, and use the concept mean IOU to evaluate its performance. The results show the advantage of the method, and it can meet the demands of further fault diagnosis.