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Abstract The Taihangshan-Yanshan region (TYR) is an important ecological barrier area for Beijing-Tianjin-Hebei, and the effectiveness of its ecological restoration and protection is of great significance to the ecological security pattern of North China. Based on the FVC data from 2000 to 2021, residual analysis, parametric optimal geodetector technique (OPGD) and multi-scale geographically weighted regression analysis (MGWR) were used to clarify the the multivariate driving mechanism of the evolution of FVC in the TYR. Results show that: (1) FVC changes in the TYR show a slowly fluctuating upward trend, with an average growth rate of 0.02/10a, and a spatial pattern of "high in the northwest and low in the southeast"; more than half of the FVC increased during the 22-year period. (2) The results of residual analysis showed that the effects of temperature and precipitation on FVC were very limited, and a considerable proportion (80.80% and 76.78%) of the improved and degraded areas were influenced by other factors. (3) The results of OPGD showed that the main influencing factors of the spatial differentiation of FVC included evapotranspiration, surface temperature, land use type, nighttime light intensity, soil type, and vegetation type (q > 0.2); The explanatory rates of the two-factor interactions were greater than those of the single factor, which showed either nonlinear enhancement or bifactorial enhancement, among which, the interaction of evapotranspiration with mean air and surface temperature has the strongest effect on the spatial and temporal evolution of FVC (q = 0.75). Surface temperature between 4.98 and 10.4 °C, evapotranspiration between 638 and 762 mm/a, and nighttime light between 1.96 and 7.78 lm/m2 favoured an increase in vegetation cover, and vegetation developed on lysimetric soils was more inclined to be of high cover. (4) The correlation between each variable and FVC showed different performance, GDP, elevation, slope and FVC showed significant positive correlation in most regions, while population size, urban population proportion, GDP proportion of primary and secondary industries, and nighttime light intensity all showed negative correlation with FVC to different degrees. The results can provide data for formulating regional environmental protection and restoration policies.

Abstract Background There is still limited research on the prognostic value of Presepsin as a biomarker for predicting the outcome of COVID-19 patients. Additionally, research on the combined predictive value of Presepsin with clinical scoring systems and inflammation markers for disease prognosis is lacking. Methods A total of 226 COVID-19 patients admitted to Beijing Youan Hospital’s emergency department from May to November 2022 were screened. Demographic information, laboratory measurements, and blood samples for Presepsin levels were collected upon admission. The predictive value of Presepsin, clinical scoring systems, and inflammation markers for 28-day mortality was analyzed. Results A total of 190 patients were analyzed, 83 (43.7%) were mild, 61 (32.1%) were moderate, and 46 (24.2%) were severe/critically ill. 23 (12.1%) patients died within 28 days. The Presepsin levels in severe/critical patients were significantly higher compared to moderate and mild patients (p

Abstract Background Whether body mass index (BMI) is a risk factor for poor bowel preparation is controversial, and the optimal bowel preparation regimen for people with a high BMI is unclear. Methods We prospectively included 710 individuals with high BMIs (≥ 24 kg/m2) who were scheduled to undergo colonoscopy from January to November 2021 at 7 hospitals. Participants were randomly allocated into 3 L split-dose polyethylene glycol (PEG) group (n=353) and 2 L PEG group (n=357). The primary outcome was the rate of adequate bowel preparation, and the secondary outcomes included Boston Bowel Preparation Scale (BBPS) score, polyp detection rate, cecal intubation rate, and adverse reactions during bowel preparation. Furthermore, we did exploratory subgroup analyses for adequate bowel preparation. Results After enrollment, 15 individuals didn’t undergo colonoscopy, finally 345 participants took 3 L split-dose PEG regimen, and 350 participants took 2 L PEG regimen for colonoscopic bowel preparation. 3 L split-dose PEG regimen was superior to 2 L PEG regimen in the rate of adequate bowel preparation (81.2% vs. 74.9%, P = 0.045), BBPS score (6.71±1.15 vs. 6.37±1.31, P < 0.001), and the rate of polyp detection (62.0% vs. 52.9%, P = 0.015). The cecal intubation rate was similar in both groups (99.7%). Regarding adverse reactions, individuals were more likely to feel nausea in the 3 L PEG group (30.9% vs. 19.3%; P = 0.001); however, the degree was mild. In the subgroup analysis for adequate bowel preparation, 3 L split-dose PEG regimen performed better than 2 L PEG regimen in the overweight (BMI 25-29.9 kg/m2 ) (P = 0.006) and individuals with constipation (P = 0.044), while no significant differences were observed in relatively normal (BMI 24-24.9 kg/m2) (P = 0.593) and obese individuals (BMI ≥ 30 kg/m2) (P = 0.715). Conclusions 3 L split-dose PEG regimen is superior to 2 L PEG regimen for colonoscopic Bowel Preparation in relatively high-BMI individuals, especially overweight individuals (BMI 25-29.9 kg/m2 ). Trial Registration This trial was registered in the Chinese Clinical Trials Registry (ChiCTR2000039068). The date of first registration, 15/10/2020, http://www.chictr.org.cn

Background: Endometriosis (EMs) is a common chronic inflammatory disease which is characterized by multiple clinical symptoms and high recurrence rate due to the absence of effective therapies. Huayu Jiedu Formula (HYJDF), is a traditional Chinese medicine prescription with five major herbs. It has been used as traditional medicine to treat EMs for more than twenty years and exerted a good therapeutic effect. However, the underlying mechanism is unclear. Here we aim to observe the effects of HYJDF on EMs and investigate the therapeutic mechanism. Methods: The extract components of HYJDF were identified and quantified by an UHPLC-QE-MS method. Network pharmacology was used to obtain the core targets of HYJDF for the treatment of EMs and the specific biologic processes involved. A total of 68 EMs cases were randomly divided into control (gestrinone) and observation (HYJDF) groups. The overall effectiveness, pain scores, cyst-size changes, serum CA125 levels, quality-of-life scores, safety, and adverse events were evaluated before and after treatment. For the mechanism research, DNA methylation-chip analysis was performed to determine the differential genes. EMs mice models and human ectopic stromal cells (ESCs) were treated with HYJDF and its pharmaceutical serum, respectively. The ectopic foci was measured via H&E staining while the expressions of the target genes were verified by real-time PCR and Western blot analysis. The inflammatory cytokine levels in the peritoneal fluid of mice were detected by ELISA. The proliferative potential of cells was analyzed by MTS whereas the apoptosis and cell cycle were determined through flow analysis. Results: The total number of components detected in positive and negative ion modes was 839 and 597, respectively. Network pharmacology suggested that HYJDF treated EMs through DNA methylation. We found that HYJDF and gestrinone exerted good therapeutic effect with no obvious difference, but the HYJDF treatment group had fewer side effects. GATA 6, which was hypomethylated and abundant in endometriotic cells, potently induced inflammatory response. This finding indicated the important role of GATA 6 in EMs development. Moreover, HYJDF ameliorated inflammatory response (i.e., reduced the levels of IL-1β and PGE2 in peritoneal fluid), suppressed ESCs proliferation, and increased cell apoptosis by down-regulating GATA 6 expression. Conclusion: We demonstrated that HYJDF has anti-inflammation activity and increased cell apoptosis through the reduction of GATA 6 expression in ectopic tissues, which showed good therapeutic effect without any obvious side effects. These findings suggest that HYJDF may be a new and efficient traditional Chinese medicine for the treatment of EMs.

Abstract Background We aimed to compare the effects of peripherally inserted central catheters (PICC) and implantable venous access devices (TIVADs) in terms of complications and shoulder function in patients with malignant bone and soft tissue tumors of the lower extremities. Methods We analyzed 65 cases of TIVADs (chest wall) and 65 cases of PICC at the orthopedic department of the Fourth Hospital of Hebei Medical University between June 2019 and December 2021, which were diagnosed with malignant bone tumors or soft tissue tumors of the lower extremities (tumors had to be relatively sensitive to chemotherapy), received regular chemotherapy, with ≥ 14 cycles (42 weeks). The two groups were compared in terms of catheter indwelling time, catheter-related complications, Constant-Murley shoulder function score, and displacement of the position of the catheter end on the catheterization side. Results Compared to the PICC group, at six months after catheterization, the TIVADs group reported better outcomes for catheter indwelling time, catheter-related complications, and Constant-Murley score for the catheterization-side shoulder joint (p

As a high efficiency hydrogen-to-power device, proton exchange membrane fuel cell (PEMFC) attracts much attention, especially for the automotive applications. Real-time prediction of output voltage and area specific resistance (ASR) via the on-board model is critical to monitor the health state of the automotive PEMFC stack. In this study, we use a transient PEMFC system model for dynamic process simulation of PEMFC to generate the dataset, and a long short-term memory (LSTM) deep learning model is developed to predict the dynamic performance of PEMFC. The results show that the developed LSTM deep learning model has much better performance than other models. A sensitivity analysis on the input features is performed, and three insensitive features are removed, that could slightly improve the prediction accuracy and significantly reduce the data volume. The neural structure, sequence duration, and sampling frequency are optimized. We find that the optimal sequence data duration for predicting ASR is 5 s or 20 s, and that for predicting output voltage is 40 s. The sampling frequency can be reduced from 10 Hz to 0.5 Hz and 0.25 Hz, which slightly affects the prediction accuracy, but obviously reduces the data volume and computation amount.

Objectives To evaluate the safety and efficacy of high-dose amoxicillin-proton pump inhibitor dual therapy, and to provide a new eradication regimen as a first-line option for patients with H. pylori infection. Methods A total of 971 H. pylori positive patients who received initial treatment were recruited from March to August 2020, and randomly divided into treatment group and control group. The treatment group received of 20 mg esomeprazole four times daily and 750 mg amoxicillin four times daily for 14 days. Control group received of 220 mg bismuth potassium citrate twice daily, 20 mg esomeprazole twice daily, 1000 mg amoxicillin twice daily and 250 mg clarithromycin capsule twice daily for 14 days. Four weeks after the end of treatment, the urea breath test was reviewed to detect whether H. pylori was eradicated. Results There were no statistical differences in age, gender, the total clinical symptom scores before and after initial treatment, the compliance, and the degree of remission of symptoms before and after initial treatment between the two groups. The eradication rates of H. pylori between dual therapy and quadruple therapy were 88.31% and 85.26% (p=.158) by intention-to-treat (ITT) analysis, 88.66% and 85.44% (p=.186) by modified intention-to-treat (mITT) analysis, and 91.63% and 90.60% (p=.116) by PP analysis, respectively. Adverse events in dual therapy group were significantly lower than quadruple therapy group (13.3% vs. 28.2% (p

Abstract Objective The incidence of open reduction and internal fixation (ORIF) in flexion-type supracondylar humerus fractures (SCHF) in children is significantly higher than that of extension-type fractures. This study aimed to identify risk factors for ORIF in flexion-type SCHF. Methods One hundred seventy-one patients with Wilkins type III flexion-type SCHF from January 2012 to December 2021 were retrospectively enrolled in a tertiary paediatric hospital. Patients were divided into ORIF group versus closed reduction and internal fixation (CRIF) group. Then, patients data of age, sex, injury side, obesity, deviation of displacement, fracture level, rotation, nerve injury, and delay from injury to surgery were reviewed. Univariate analysis and multivariate logistic regression were used to identify independent risk factors and odds ratios (OR) of ORIF. Results Overall, 171 children with type III flexion-type SCHF were analyzed (average aged 7.9 ± 2.8 years). Displacement was lateral in 151 cases, medial in 20. 20 cases had combined ulnar nerve injury. The failed closed reduction rate was 20%. Univariate analysis indicated age, distal fracture fragment rotation, and ulnar nerve injury were significantly associated with ORIF. (P = 0.047, P = 0.009, and P = 0.001, respectively). Multivariate logistic regression analysis showed that distal fracture fragment rotation (OR, 3.3; 95%CI:1.1–9.5; P = 0.028) and ulnar nerve injury (OR, 6.4; 95%CI:2.3–18.3; P = 0.001) were independent risk factors; however, the age was not an independent one (OR, 1.5; 95%CI:0.6–3.5; P = 0.397) for ORIF in the Wilkins type III flexion-type SCHF. Conclusion Distal fracture fragment malrotation on initial x-rays and ulnar nerve injury were significant risk factors for ORIF in Wilkins type III flexion-type SCHF. Surgeons should prepare tourniquets or other open reduction instruments when treating these types of fractures. Level of evidence Level IV

Objective: This study was aimed to explore the role of AhR in the neurotoxicity of adult zebrafish induced by three typical bisphenol compounds (BPA, BPS, TBBPA) at environmentally relevant doses. Methods: The adult zebrafish were randomly divided into solvent control group (DMSO) and AhR inhibitor CH223191 (CH) group (0.05 μmol/L), bisphenol exposure groups (10, 100, 1000 nmol/L) and combined exposure groups (0.05 μmol/L CH and 1000 nmol/L bisphenol compounds). Each tank contained 8 fish (4 male and 4 female), and two parallel tanks were set synchronously. After 30 days of exposure, zebrafish were put on ice plate for anesthesia, weighed and measured for body length, and dissected for brain tissue. The gene expression was detected by RT-qPCR, and the activities of antioxidant enzymes were detected by commercial kits. SPSS 26.0 was used to analyze the data. Additionally, GO, KEGG and principal component analysis (PCA) were carried out. Results: Compared with the solvent control group, there were no significant differences in body weight and length among the exposed groups. In general, exposure to bisphenol compounds could affect the expression of Ahr2 and AhR target genes (cyp1a1, cyp1a2, and cyp1c1), key genes of neural function (elavl3, gfap, mbp, syn2a, gap43, Zn5, shha, and ache), oxidative stress related genes (nrf2, gpx1a, gstp1/gstp1.2, gstp2/gstp1.1, sod1, sod2, and cat), and the activities of antioxidant enzymes (SOD, CAT and GSH-Px/GPX) in zebrafish brain tissue to some extent. Compared with the groups exposed to bisphenols alone, CH could antagonize the above interference effects caused by bisphenols to some extent. Therefore, the toxic effects of BPA, BPS and TBBPA might be produced through similar mechanisms. Conclusion: Environmentally related doses of bisphenols (BPA, BPS, TBBPA) could disturb the expression of key molecules of oxidative stress and neural function through activating the AhR signaling pathway, and ultimately lead to neurotoxicity.

Notch signaling is known to control neuroendocrine fate in the lungs. Shue and colleagues further identify the REST and YAP transcriptional regulators as key components of the Notch signaling pathway in the control of the neuroendocrine cell fate in lung development, lung injury response, and small-cell lung cancer.

Glaucomatous optic neuropathy (GON) can be diagnosed and monitored using fundus photography, a widely available and low-cost approach already adopted for automated screening of ophthalmic diseases such as diabetic retinopathy. Despite this, the lack of validated early screening approaches remains a major obstacle in the prevention of glaucoma-related blindness. Deep learning models have gained significant interest as potential solutions, as these models offer objective and high-throughput methods for processing image-based medical data. While convolutional neural networks (CNN) have been widely utilized for these purposes, more recent advances in the application of Transformer architectures have led to new models, including Vision Transformer (ViT,) that have shown promise in many domains of image analysis. However, previous comparisons of these two architectures have not sufficiently compared models side-by-side with more than a single dataset, making it unclear which model is more generalizable or performs better in different clinical contexts. Our purpose is to investigate comparable ViT and CNN models tasked with GON detection from fundus photos and highlight their respective strengths and weaknesses. We train CNN and ViT models on six unrelated, publicly available databases and compare their performance using well-established statistics including AUC, sensitivity, and specificity. Our results indicate that ViT models often show superior performance when compared with a similarly trained CNN model, particularly when non-glaucomatous images are over-represented in a given dataset. We discuss the clinical implications of these findings and suggest that ViT can further the development of accurate and scalable GON detection for this leading cause of irreversible blindness worldwide.

Abstract Background Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide. This study aimed to investigate whether supplementation of n-3 polyunsaturated fatty acids (n-3 PUFAs) in parenteral nutrition may have beneficial effects on ROP in preterm infants. Methods A total of 89 preterm infants, admitted to Neonatal Intensive Care Unit (NICU) in Anhui Provincial Children’s Hospital from September 2017 to August 2020, were recruited in the study. Based on the medical documents, the subjects were categorised into two groups: administration of the fish oil emulsion (n=43) containing soy oil, medium-chain-triglycerides (MCT), olive oil and fish oil (6g/dL, 6g/dL, 5g/dL and 3g/dL respectively), and the soy oil emulsion (n=46) containing 10g/dL of soy oil and MCT each. At 4 weeks of hospitalization, ROP was screened and diagnosed. Fatty acids in erythrocytes were determined using gas chromatography. Results The averaged birth weight and gestational age were 1594±296 g and 31.9±2.3 wk, 1596±263 g and 31.6±2.3 wk respectively for preterm infants in the fish oil group and soy oil group. After 4 to 6 weeks of hospitalization, among all the preterm infants, 52 developed ROP (all stages) indicating an incidence of ROP at 58.43%. Although the incidence of ROP with any stages showed no differences between the two groups, the severe ROP incidence in the group with fish oil emulsions (2.33%) was significantly lower than that in the group with soy oil emulsions (23.91%) (P

Objective: This study was aimed to investigate the role of non-neuronal cholinergic system (NNCS) in the early stage response of epithelial-mesenchymal transformation (EMT) related markers in human lung adenocarcinoma A549 cells induced by coal particles. Methods: A549 cells were exposed to different concentrations of GBW11110K, GBW11126D and exogenous acetylcholinesterase (AChE) (the exposure doses were determined according to the results of CCK-8 experiment, and the doses that had no significant effects on cell viability were selected) for 24 h. After exposure, the indexes of oxidative stress (SOD and MDA), inflammatory factors (IL-6 and TNF-α), EMT marker proteins (E-cadherin and vimentin), AChE enzymatic activity and mRNA expression levels of different types of acetylcholine receptors (CHRM3, CHRM5, CHRNA5, CHRNA7, CHRNA9 and CHRNB2) were determined. Results: GBW11110K and GBW11126D exposure could lead to the following injury effects: the levels of oxidative stress and inflammatory factors changed to a certain extent (SOD decreased gradually, while MDA, IL-6 and TNF-α increased). The protein level of E-cadherin decreased while the vimentin level increased (P < 0.05), suggesting the occurrence of EMT. The AChE enzymatic activity decreased gradually. The expression of acetylcholine receptor mRNA changed as follows (GBW11110K/GBW11126D: CHRM3 (↑↑), CHRM5 (↓↓), CHRNA5 (↓↓), CHRNA7 (↓↓), CHRNA9 (– ↑), CHRNB2 (– –). The addition of exogenous AChE recombinant protein could antagonize the damage effects caused by the coal particles to a certain extent. Conclusion: The coal particle exposure could induce the change of oxidative stress response, inflammatory response and EMT related markers, down-regulate the AChE enzymatic activity, and interfere the mRNA expression levels of AChRs in A549 cells. The addition of exogenous AChE recombinant protein could reverse the above effects to a certain extent.

BackgroundRotation of the distal fragment often occurs in flexion-type supracondylar humerus fractures (SCHFs), potentially leading to ulnar nerve injury (UNI) and open reduction. We analyzed the correlation between the rotations and UNI or open reduction and then assessed the risk factors associated with these rotations.MethodsData of Wilkins type III lateral flexion SCHFs were collected over a 10-year time period (1 January 2012 to 31 December 2021) in Children's Hospital of Fudan University Anhui Hospital. We defined the rotation of the distal fragment on the coordinate axis as two types, IIIA (X-axis rotation) and IIIB (the rotation of both X- and Y-axes) on X-ray radiography. Demographic data, the incidence of the two-type rotation, odds ratios (ORs) of UNI and open reduction, and risk factors of the rotation of both X- and Y-axes were analyzed.ResultsTotally, 152 patients were found (50 with IIIA vs. 102 IIIB). The UNI rate was 13%, and the open reduction rate was 22%. The UNI rate of the IIIB was five-fold higher than that of the IIIA [OR, 5.143; 95% confidence interval (CI), 1.414–23.125; p = 0.019], and the open reduction rate of the IIIB was nearly five-fold higher than that of the IIIA (OR, 4.729, 95%CI, 1.584–14.495; p = 0.003). In these two types, patients with UNI had a higher risk of open reduction than those without UNI (OR, 9.816; 95%CI, 3.503–27.508; p = 0.001). In the multiple regression analysis, a high level of fracture was identified as a risk factor for the rotation of both X- and Y-axes.ConclusionType IIIB lateral flexion-type SCHFs have higher rates of UNI and open reduction, and a high level of fracture is a risk factor associated with this type.

Abstract Background Gastric cancer (GC) is one of the most common cancer worldwide. It is essential to identify non-invasive diagnostic and prognostic biomarkers of GC. The aim of the present study was to screen candidate biomarkers associated with the pathogenesis and prognosis of GC by a novel strategy. Methods The expression level of gene higher in cancer than in adjacent non-cancer tissue was defined as “positive”, and the top 5% genes with “positive rate” were filtered out as candidate diagnostic biomarkers in three Gene Expression Omnibus (GEO) datasets. Further, a prognostic risk model was constructed by multivariate Cox regression analysis in GEO dataset and validated in The Cancer Genome Atlas (TCGA). The expression level of candidate biomarkers was determined in serum and serum-derived exosomes of GC patients. Moreover, the effect of biomarkers in exosomes on migration of GC cells was analyzed by transwell assay. Results Ten candidate biomarkers (AGT, SERPINH1, WNT2, LIPG, PLAU, COL1A1, MMP7, MXRA5, CXCL1 and COL11A1) were identified with efficient diagnostic value in GC. A prognostic gene signature consisted of AGT, SERPINH1 and MMP7 was constructed and showed a good performance in predicting overall survivals in TCGA. Consistently, serum levels of the three biomarkers also showed high sensitivity and specificity in distinguishing GC patients from controls. In addition, the expression level of the three biomarkers were associated with malignant degree and decreased after surgery in GC patients. Moreover, the expression level of AGT and MMP7 in exosomes correlated positively with serum level. The exosomes derived from serum of GC patients can promote migration of SGC‐7901 cells. After neutralized the expression level of three proteins in exosomes with antibodies, the migration of GC cells was obviously suppressed. Conclusions Our findings provided a novel strategy to identify diagnostic biomarkers based on public datasets, and suggested that the three-gene signature was a candidate diagnostic and prognostic biomarker for patients with GC.

Objectives This study aims to explore a novel intraoperative trajectory‐determined strategy of grouped patient‐specific drill templates (PDTs) for transoral C2 pedicle screw insertion (C2TOPI) for atlantoaxial dislocation (AAD) with incomplete reduction and to evaluate its efficiency and accuracy. Methods Ten cadaveric C2 specimens were scanned by computed tomography (CT) and randomly divided into two groups (the PDT and freehand groups). A novel intraoperative trajectory‐determined strategy of grouped PDTs was created for AAD with incomplete reduction. C2TOPI was performed by use of the PDT technique and the fluoroscopy‐guided freehand technique. After surgery, the screw deviations from the centroid of the cross‐section at the midpoint of the pedicle and screw position grades were assessed in both groups. Results Compared to the freehand group, the PDT group had a significantly shorter surgery time than the freehand group (47.7 vs 61.9 min, P 0.05). Conclusion The novel intraoperative trajectory‐determined strategy of grouped PDTs can be used as an accurate and feasible method for C2TOPI for AAD with incomplete reduction.

Background: The progression from chronic gastroesophageal reflux disease (GERD) to Barrett esophagus (BE) and esophageal adenocarcinoma (EAC) is an inflammatory-driven neoplastic change. Interleukin-33 (IL-33) has identified as a crucial factor in several inflammatory disorders and malignancies.Methods: The high-density tissue microarray of the human EAC was analyzed with IL-33 immunohistochemistry staining (IHC). By anastomosing the jejunum with the esophagus, the rat model of EAC with mixed gastroduodenal reflux was established. The expression of IL-33 was determined using quantitative real-time polymerase chain reaction (RT-qPCR), western blot (WB), IHC and enzyme-linked immunosorbent assay (ELISA). Esophageal adenocarcinoma cells (OE19 and OE33) and human esophageal epithelial cells (HEECs) were used.Results: In the cytoplasm of human EAC tissue, IL-33 expression was substantially greater than in adjacent normal tissue. In rat model, the expression of IL-33 in the EAC group was considerably greater than in the control group, and this expression increased with the upgrade of pathological stage. In in vitro experiment, the mRNA and protein levels of IL-33 were considerably greater in OE19 and OE33 than in HEECs. The stimulation of IL-33 enhanced the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of OE19 and OE33, but soluble ST2 (sST2) inhibited these effects. IL-33 stimulated the release of IL-6 by OE19 and OE33 cells.Conclusion: This study demonstrated the overexpression of IL-33 in the transition from GERD to EAC and that IL-33 promoted carcinogenesis in EAC cells through ST2. IL-33 might be a possible preventive target for EAC.

Aims: This study aims to screen the potential targets of tetrandrine (Tet) against pulmonary fibrosis (PF) based on network pharmacological analysis, molecular docking and experimental verification. Main methods: The network pharmacology methods were employed to predict targets, construct Tet-PF-intersection target-pathway networks, and screen the candidate targets. The molecular docking was performed using AutoDockTools1.5.6. TGF-β1-induced human lung adenocarcinoma A549 cells were used as an in vitro experimental verification model, taking dexamethasone (Dex) as the positive control, to verify the effects of Tet on the mRNA expression of the candidate targets. Key findings: Six candidate targets were predicted based on network pharmacology and molecular docking, namely PIK3CA, PDPK1, RAC1, PTK2, KDR, and RPS6KB1. The experimental verification results showed that Dex and Tet presented quite different pharmacological effects. Specifically, compared with the model group, both Dex and Tet (5 μΜ) significantly increased the mRNA expression of PIK3CA and KDR (P < 0.001). Dex up-regulated the mRNA expression of PDPK1 and RAC1, while Tet (1.25 μΜ) down-regulated (P < 0.001). Dex up-regulated the mRNA expression of PTK2, but Tet had no effect. Dex down-regulated RPS6KB1 mRNA expression, while Tet (5 μΜ) up-regulated (P < 0.01). Significance: Combined with the results of theoretical calculation and experimental verification, and considering the roles of these targets in the pathogenesis of PF, Tet might antagonize PF by acting on PDPK1 and RAC1. The results of this study will provide scientific reference for the prevention and clinical diagnosis and treatment of PF.

Abstract Background Sentinel lymph node biopsy (SLNB) plays a vital role in breast cancer surgery, and the identified number of sentinel nodes determines its accuracy for representing the status of the axillae. There are two types of tumor biopsies in breast cancer: preoperative and intraoperative biopsies. We compared the effects of the two different biopsies on the results of SLNB. Methods Patients with clinical stages T1–3, N0 (cT1-3 N0) tumors were enrolled in this study. A total of 53% of patients received preoperative tumor biopsy, and 47% received intraoperative excisional biopsy. To identify the sentinel lymph nodes, patients received dual tracer injection. The number of SLNs detected and the false-negative rate were compared between groups. Results A total of 204 patients were enrolled, 108 received preoperative tumor biopsy, and 96 received intraoperative excisional biopsy. Among all the patients, 160 received axillary lymph node dissection (ALND) following SLNB. Preoperative tumor biopsy detected more SLNs than intraoperative biopsy (mean rank 113.87 vs. 90.9, p = 0.004). The false-negative rates in the preoperative and intraoperative tumor biopsy groups were 3% and 18%, respectively. Conclusions Patients in the preoperative tumor biopsy group had more SLNs identified than intraoperative biopsy patients. The false-negative rate was also lower in the preoperative biopsy group.

Background: Split-dose (SPD) regimen has been proved more effective than a single-dose (SID) regimen for various drug preparations; however, limited data have focused on morning colonoscopy. We implemented this study to compare the bowel cleanliness and tolerability of a same-day SID versus SPD 2 L polyethylene glycol electrolyte solution (PEG) for morning colonoscopy. Methods: Patients undergoing morning colonoscopy were randomized into two groups, SID or SPD. In the SID group, patients had to complete 2 L PEG between 4 and 6 am on the day of colonoscopy. In the SPD group, patients had to complete 1 L PEG between 8 and 9 pm on the day before followed by another 1 L PEG between 5 and 6 am on the day of colonoscopy. Colonoscopy was performed between 8 and 12 am under anesthesia. Investigators and endoscopists were blinded to the allocation. The primary end point was the effectiveness of bowel cleansing according to the Boston Bowel Preparation Scale (BBPS). The secondary outcomes were polyp detection rate, compliance, tolerability, and patient satisfaction. Results: Overall, there were 147 and 148 patients in the SID and SPD group, respectively. The SPD group had a better quality of bowel preparation than the SID group with a total BBPS score of 7.25 ± 1.53 versus 6.71 ± 1.65 (P = 0.005). No difference in the polyp detection rate was noted, although more polyps were detected in the SPD group. More patients felt acceptable with the bowel preparation regimen in the SPD group compared to the SID group (76% vs. 65%, P = 0.03). The adverse events were more commonly observed in the SID group, presented as nausea and vomiting. Conclusion: For morning colonoscopy, split-dose 2 L PEG is superior to single-dose 2 L PEG by improved bowel preparation, better tolerability, and patient satisfaction.

Next-generation sequencing of circulating tumor DNA presents a promising approach to cancer diagnostics, complementing conventional tissue-based diagnostic testing by enabling minimally invasive serial testing and broad genomic coverage through a simple blood draw to maximize therapeutic benefit to patients. LiquidHALLMARK® is an amplicon-based next-generation sequencing assay developed for the genomic profiling of plasma-derived cell-free DNA (cfDNA). The comprehensive 80-gene panel profiles point mutations, insertions/deletions, copy number alterations, and gene fusions, and further detects oncogenic viruses (Epstein-Barr virus (EBV) and hepatitis B virus (HBV)) and microsatellite instability (MSI). Here, the analytical and clinical validation of the assay is reported. Analytical validation using reference genetic materials demonstrated a sensitivity of 99.38% for point mutations and 95.83% for insertions/deletions at 0.1% variant allele frequency (VAF), and a sensitivity of 91.67% for gene fusions at 0.5% VAF. In non-cancer samples, a high specificity (≥99.9999% per-base) was observed. The limit of detection for copy number alterations, EBV, HBV, and MSI were also empirically determined. Orthogonal comparison of epidermal growth factor receptor (EGFR) variant calls made by LiquidHALLMARK and a reference allele-specific polymerase chain reaction (AS-PCR) method for 355 lung cancer specimens revealed an overall concordance of 93.80%, while external validation with cobas® EGFR Mutation Test v2 for 50 lung cancer specimens demonstrated an overall concordance of 84.00%, with a 100% concordance rate for EGFR variants above 0.4% VAF. Clinical application of LiquidHALLMARK in 1,592 consecutive patients demonstrated a high detection rate (74.8% circulating tumor DNA (ctDNA)-positive in cancer samples) and broad actionability (50.0% of cancer samples harboring alterations with biological evidence for actionability). Among ctDNA-positive lung cancers, 72.5% harbored at least one biomarker with a guideline-approved drug indication. These results establish the high sensitivity, specificity, accuracy, and precision of the LiquidHALLMARK assay and supports its clinical application for blood-based genomic testing.

Endometriosis is the most common cause of infertility. Endometrial receptivity has been suggested to contribute to infertility and poor reproductive outcomes in affected women. Even though experimental and clinical data suggest that the endometrium differs in women with endometriosis, the pathogenesis of impaired endometrial receptivity remains incomplete. Therefore, this review summarizes the potential mechanisms that affect endometrial function and contribute to implantation failure. Contemporary data regarding hormone imbalance, inflammation, and immunoregulatory dysfunction will be reviewed here. In addition, genetic, epigenetic, glycosylation, metabolism and microRNA in endometriosis-related infertility/subfertility will be summarized. We provide a brief discussion and perspectives on their future clinical implications in the diagnosis and therapy to improve endometrial function in affected women.

Mast cell (MC) plays a central role in intestinal permeability; however, few MC-targeting drugs are currently available for protection of the intestinal barrier in clinical practice. A nonfluorinated Lidocaine analog 2-diethylamino-N-2,5-dimethylphenyl acetamide (JM25-1) displays anti-allergic effect, but its impact on MC remains elusive. In this study, we explored whether JM25-1 has therapeutic potential on intestinal barrier defect through stabilizing MC. JM25-1 alleviated release of β-hexosaminidase and cytokine production of MC. The paracellular permeability was redressed by JM25-1 in intestinal epithelial cell monolayers co-cultured with activated MC. In vivo, JM25-1 diminished intestinal mucosal MC amount and cytokine production, especially downregulating the expression of CRHR1, accompanied by an increase of CRHR2. Protective effects appeared in JM25-1-treated stress rats with a recovery of weight and intestinal barrier integrity. Through network pharmacology analysis, JM25-1 showed a therapeutic possibility for irritable bowel syndrome (IBS) with predictive targeting on PI3K/AKT/mTOR signaling. As expected, JM25-1 reinforced p-PI3K, p-AKT, p-mTOR signaling in MC, while the mTOR inhibitor Rapamycin reversed the action of JM25-1 on the expression of CRHR1 and CRHR2. Moreover, JM25-1 successfully remedied intestinal defect and declined MC and CRHR1 expression in rat colon caused by colonic mucus of IBS patients. Our data implied that JM25-1 possessed therapeutic capacity against intestinal barrier defects by targeting the CRH receptors of MC through PI3K/AKT/mTOR signaling.

Text classification is one of the most important and typical tasks in Natural Language Processing (NLP) which can be applied for many applications. Recently, deep learning approaches has shown their advantages in solving text classification problem, in which Convolutional Neural Network (CNN) is one of the most successful model in the field. In this paper, we propose a novel deep learning approach for categorizing text documents by using scope-based convolutional neural network. Different from window-based CNN, scope does not require the words that construct a local feature have to be contiguous. It can represent deeper local information of text data. We propose a large-scale scope-based convolutional neural network (LSS-CNN), which is based on scope convolution, aggregation optimization, and max pooling operation. Based on these techniques, we can gradually extract the most valuable local information of the text document. This paper also discusses how to effectively calculate the scope-based information and parallel training for large-scale datasets. Extensive experiments have been conducted on real datasets to compare our model with several state-of-the-art approaches. The experimental results show that LSS-CNN can achieve both effectiveness and good scalability on big text data.

ObjectivesThe NCCN guidelines recommend that the addition of bevacizumab should be considered in metastatic breast cancers in some circumstances, but there are no recommendations for the similar antiangiogenic drug apatinib. The aim of this study was to evaluate the safety and efficacy of apatinib in metastatic breast cancer patients pretreated with multiline treatment in a real-world setting.Materials and MethodsMetastatic breast cancer patients pretreated with multiline treatment who had apatinib treatment initiated from September 2015 to August 2019 at Shandong Cancer Hospital and Institute were included. The primary endpoints included PFS and OS, and the secondary endpoint was treatment-related toxicity.ResultsA total of 66 patients with metastatic breast cancer received apatinib treatment after failure of multiline chemotherapy in this study. The median PFS and OS of all 66 patients were 6.0 months and 10.0 months, respectively. The clinical beneficial rate was 40.9%. All patients tolerated treatment well, and no patients died of toxicity. The common toxicities of apatinib were hand and foot syndrome, secondary hypertension and fatigue events. The number of prior chemotherapy regimens was significantly associated with DFS and OS. Capecitabine may be a better choice for combination with a longer median OS of 19 months, while apatinib combined with other drugs was 9 months, and the apatinib monotherapy was 10 months.ConclusionApatinib produced moderate efficacy in metastatic breast cancer patients pretreated with multiline treatment with no significant treatment-related adverse events. Apatinib might be a choice for women as a maintenance salvage therapy following multiline chemotherapy failure.

Objective. This study aimed at investigating the therapeutic effect and mechanism of pioglitazone metformin complex preparation (PM) in polycystic ovary syndrome (PCOS) comorbid psychological distress. Methods. Seventy-five patients with PCOS comorbid psychological distress were randomly allocated into the PM, metformin, and placebo groups. The primary efficacy measure was the change from baseline to week 12 on the Symptom Checklist 90-R (SCL-90-R) scores. NLRP3 inflammasome, IL-1β, IL-6, TNF-α, and biochemical parameters were determined at baseline and at week 12. The participants were required to meet the criteria for PCOS (Rotterdam, NIH) and psychological distress (any factor scores of SCL−90−R>2). Results. The participants had significantly high scores on the SCL-90-R scales of anxiety and depression. PM significantly decreased anxiety and depression symptom severity (from 2.31±0.75 to 1.65±0.38, p

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.

This article takes into account the form of mixed data as well as the peak and thick tail characteristics contained in the data characteristics, expands the GARCH-MIDAS (Generalized Autoregressive Conditional Heteroskedasticity-Mixed Data Sampling) model, establishes a new GARCH-MIDAS model with the residual term of the skewed-t distribution, and analyzes the influence factors of crude oil futures price volatility, which can better explain the changing laws of crude oil price volatility. The results show the following: First, the low-frequency factors include crude oil production, consumption, inventory, and natural gas spot price, and the high-frequency factors include on-market trading volume and off-market spot price, which can significantly explain the volatility of oil price. Second, low-frequency factors include crude oil inventory, consumption, crude oil production, and speculative factors, and high-frequency factors include crude oil spot price and substitute prices. The increase in the volatility of trading volume is significantly positively correlated with oil price volatility, and the overall volatility model outperforms the horizontal effect model. Third, from the perspective of the combined effect of a single factor level and volatility, we find that supply and demand are the low-frequency factors; the trading volume of on-market factors, natural gas price, and crude oil spot price of off-market factors, among the high-frequency factors, are the most important factors affecting oil price volatility. Fourth, from the perspective of high-frequency and low-frequency effects combined, there is no significant difference between the various factor models, which shows that the mixed effect model of high and low frequency models has advantages in terms of the stability of the estimation results.

Malaria eradication is a major goal in public health but is challenged by relapsing malaria species, expanding drug resistance, and the influence of host genetics on antimalarial drug efficacy. To overcome these hurdles, it is imperative to establish in vitro assays of liver-stage malaria for drug testing. Induced pluripotent stem cells (iPSC) potentially allow the assessment of donor-specific drug responses, and iPSC-derived hepatocyte-like cells (iHLCs) can facilitate the study of host genetics on host-pathogen interactions and the discovery of novel targets for antimalarial drug development. We establish in vitro liver-stage malaria infections in iHLCs using P. berghei, P. yoelii, P. falciparum, and P. vivax and show that differentiating cells acquire permissiveness to malaria infection at the hepatoblast stage. We also characterize antimalarial drug metabolism capabilities of iHLCs using prototypical antimalarial drugs and demonstrate that chemical maturation of iHLCs can improve their potential for antimalarial drug testing applications.

BACKGROUND:Esophageal epithelial cells are an initiating cell type in esophageal inflammation, playing an essential role in the pathogenesis of gastroesophageal reflux disease (GERD). A new tissue-derived cytokine, interleukin-33 (IL-33), has been shown to be upregulated in esophageal epithelial cell nuclei in GERD, taking part in mucosal inflammation. Here, inflammatory cytokines secreted by esophageal epithelial cells, and their regulation by IL-33, were investigated. METHODS:In an in vitro stratified squamous epithelial model, IL-33 expression was examined using quantitative RT-PCR, western blot, ELISA, and immunofluorescence. Epithelial cell secreted inflammatory cytokines were examined using multiplex flow immunoassay. IL-33 was knocked down with small interfering RNA (siRNA) in normal human esophageal epithelial cells (HEECs). Pharmacological inhibitors and signal transducers and activators of transcription 1 (STAT1) siRNA were used to explore the signaling pathways. RESULTS:Interferon (IFN)γ treatment upregulated nuclear IL-33 in HEECs. Furthermore, HEECs can produce various inflammatory cytokines, such as IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), regulated on activation normal T-cell expressed and presumably secreted (RANTES), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to IFNγ. Nuclear, but not exogenous IL-33, amplified IFN induction of these cytokines. P38 mitogen-activated protein kinase (MAPK) and janus protein tyrosine kinases (JAK)/STAT1 were the common signaling pathways of IFNγ-mediated induction of IL-33 and other cytokines. CONCLUSIONS:Esophageal epithelial cells can actively participate in GERD pathogenesis through the production of various cytokines, and epithelial-derived IL-33 might play a central role in the production of these cytokines.

[This corrects the article DOI: 10.1371/journal.pone.0154234.].

Interleukin-33 (IL-33) is a tissue-derived cytokine that is constitutively expressed in epithelial cells of tissues exposed to the environment and plays a role in sensing damage caused by inflammatory diseases. IL-33 acts as both a traditional cytokine and as a chromatin-associated nuclear factor in both innate and adaptive immunity. We recently showed that IL-33 in esophageal mucosa is upregulated in reflux esophagitis. However, IL-33 expression in patients with heartburn without mucosal injury and its relationship with intercellular space (ICS) have never been examined. We therefore examined the expression of cytokines and ICS in patients with heartburn.The expression of IL-33 in the middle and distal esophageal mucosa of patients with heartburn without mucosal break and control samples was examined using real-time RT-PCR and immunofluorescence. The mRNA expression of IL-6, IL-8, MCP-1, and RANTES, and ICS was also analyzed.IL-33 expression and the mean ICS were significantly increased in the mucosa of patients with heartburn compared to that of the control. IL-33 and ICS were not different between the patients who were taking a PPI and those who were not. The upregulated IL-33 expression in the heartburn group was located in the nuclei of the basal cell layer. Although IL-6, IL-8, MCP-1 and RANTES levels were not different between control and patients with heartburn samples, IL-33 mRNA levels were still significantly correlated with IL-6, IL-8, or MCP-1 mRNA levels.Nuclear IL-33 is upregulated in patients with heartburn. Upregulated IL-33 in heartburn patients is related to the symptoms.

ABCA7 is homologous to ABCA1 and has recently been shown in cell culture to bind apolipoprotein A-I (apoA-I) and to promote the efflux of phospholipids. However, it is not known if ABCA7 promotes lipid efflux in vivo. When expressed in HEK293 cells, both human and mouse ABCA7 promoted phospholipid efflux to apoA-I but no detectable cholesterol efflux. However, genetic knockdown of ABCA7 in mouse peritoneal macrophages did not affect phospholipid or cholesterol efflux to apoA-I. Moreover, in ABCA1-knockout macrophages, there was no detectable apoA-I-stimulated phospholipid efflux, inconsistent with a residual role of ABCA7. In contrast to plasma membrane localization of ABCA7 in transfected embryonic kidney cells, immunofluorescence microscopy of endogenous ABCA7 in macrophages showed a predominantly intracellular localization of the protein. Strikingly, immunofluorescence studies of adult mouse kidney revealed an apical brush border membrane localization of ABCA7 in the proximal tubule, suggesting that ABCA7 may come in contact with apoA-I in the glomerular filtrate.Although ABCA7 does not contribute to apolipoprotein-mediated lipid efflux in resting macrophages, its cell surface location in the kidney suggests that it could serve such a role in tissue microenvironments.

We determined the role of N-linked glycosylation of apolipoprotein B (apoB) in the assembly and secretion of lipoproteins using transfected rat hepatoma McA-RH7777 cells expressing human apoB-17, apoB-37, and apoB-50, three apoB variants with different ability to recruit neutral lipids. Substituting Asn residue with Gln at the single glycosylation site within apoB-17 (N158) decreased its secretion efficiency to a level equivalent to that of wild-type apoB-17 treated with tunicamycin, but had little effect on its synthesis or intracellular distribution. When selective N-to-Q substitution was introduced at one or more of the five N-linked glycosylation sites within apoB-37 (N158, N956, N1341, N1350, and N1496), secretion efficiency of apoB-37 from transiently transfected cells was variably affected. When all five N-linked glycosylation sites were mutated within apoB-37, the secretion efficiency and association with lipoproteins were decreased by >50% as compared with wild-type apoB-37. Similarly, mutant apoB-50 with all of its N-linked glycosylation sites mutagenized showed decreased secretion efficiency and decreased lipoprotein association in both d < 1.02 and d > 1.02 g/ml fractions. The inability of mutant apoB-37 and apoB-50 to associate with very low-density lipoproteins was attributable to impaired assembly and was not due to the limitation of lipid availability. The decreased secretion of mutant apoB-17 and apoB-37 was not accompanied by accumulation within the cells, suggesting that the proportion of mutant apoB not secreted was rapidly degraded. However unlike apoB-17 or apoB-37, accumulation of mutant apoB-50 was observed within the endoplasmic reticulum and Golgi compartments.These data imply that the N-glycans at the amino terminus of apoB play an important role in the assembly and secretion of lipoproteins containing the carboxyl terminally truncated apoB.