Clinicopathological, metastatic and prognostic features of stage IV esophageal adenocarcinoma versus squamous cell carcinoma: a SEER database analysis.

BACKGROUND: It is important to note that although the current treatment for advanced esophageal cancer (EC) has made great technological advances, patients' 5-year survival rates do not appear to be encouraging. Therefore, understanding the clinicopathological features and metastasis patterns of the patients with stage IV EC, combined with the prognosis of these patients, can aid in choosing the optimal treatment plan. It is well known that esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two most common pathological types. The aim of this study is to examine and compare the clinicopathological features and metastatic modes of stage IV ESCC and EAC, as well as their prognosis and survival. METHODS: Based on the Surveillance, Epidemiology, and End Results (SEER) database, we assessed the characteristics of ESCCs and EACs associated with prognosis using the Kaplan-Meier survival analysis, and the Cox regression model. Furthermore, the clinical data of 217 patients with stage IV ESCC and EAC in the Department of Gastroenterology of the Second Affiliated Hospital of Nantong University between 2014 and 2016 were reviewed. RESULTS: A total of 3,707 cases treated between 2010 and 2016 were included. The incidence of EAC in the United States is much higher than that of ESCC. Common metastasis patterns were lungs only, liver only, bones only, and lung & liver. The multivariate Cox analysis showed that treatment mode and metastasis patterns were independent risk factors affecting the overall survival (OS) time of patients (stage IV ESCC & EAC). EAC patients with only lung metastases may have a longer survival if chose treatment options that included surgery. In the external cohort, a total of 217 cases were included. The prevalence of ESCC is much higher than that of EAC, and the common metastasis patterns are liver only, lung only, and liver & lung. The multivariate Cox analysis showed that treatment mode was independent risk factor affecting the OS time of patients (stage IV ESCC & EAC). EAC patients treated with surgery combined with chemoradiotherapy may have a better prognosis. CONCLUSIONS: In general, the prognosis of patients with stage IV ESCC and EAC are poor. However, surgery was found to significantly improve the OS time of patients with stage IV EAC in this study.

Euphorbia factor L1 inhibited transport channel and energy metabolism in human colon adenocarcinoma cell line Caco-2.

Euphorbia factor L1 (EFL1) is a kind of lathyrane-type diterpenoid and is isolated from the medical herb Euphorbia lathyris L. (Euphorbiaceae); it has been reported with the toxicity that causes intestinal irritation, but the underlying mechanisms are still obscure. The objective of this study was to assess the EFL1-induced intestinal cytotoxicity in human colon adenocarcinoma Caco-2 cells. The Caco-2 cells were treated with EFL1, and the intracellular calcium ion concentration, mitochondrial membrane potential (MMP), mitochondrial permeability transition pore (mPTP), adenosine 5'-triphosphate (ATP) content, ATPase activities, TGF-ß1 concentration, and transepithelial electrical resistance (TEER) were detected. The interaction between EFL1 and the tight junction proteins Occludin, Claudin-4, Tricellulin, ZO-1, JAM-1, and E-cadherin was simulated by molecular docking. The expression of proteins involved in the energy metabolism, the ion transporters and aquaporins, the tight junction, and the F-actin cytoskeleton were detected by Western blotting and cell immunofluorescence. As a result, EFL1 decreased the intracellular Ca2+, MMP, mPTP, ATP content, and ATPase activities in the Caco-2 cells. The AMPK/SIRT1/PGC-1α signaling pathway, which regulates the energy metabolism, was inhibited. The ion transporters NEH and CFTR, as well as the aquaporins in the Caco-2 cells, were decreased. The tight junction proteins were down-regulated, and the integrity of the intestinal barrier was injured; TGF-ß1 was compensatively increased; so, the intestinal permeability was increased and was characterized by decreased TEER. The morphology of the F-actin cytoskeleton was destroyed. These findings indicated that EFL1 caused cytotoxicity in the human intestinal Caco-2 cells through mitochondrial damage, inhibition of the energy metabolism, and suppression of the ion and water molecule transporters, as well as the down-regulation tight junction and cytoskeleton protiens.

[Risk factors for the development of airway hyperresponsiveness in patients with allergic rhinitis].

Allergic rhinitis（AR） is an independent risk factor for allergic asthma. Some AR patients may have developed airway hyperresponsiveness（AHR） in the absence of asthma symptoms. In this stage, AHR is often neglected due to the absence of typical asthma symptoms. Exploring the clinically relevant risk factors for AHR in patients with AR, as well as the clinical indicators and biomarkers to predict AHR in patients with AR, is of great significance to the prevention of the occurrence of AHR and asthma. This review summarized the risk factors for the development of AHR in AR patients, and gave hints to the prevention of AHR in AR patients.

Intermittent fasting protects against food allergy in a murine model via regulating gut microbiota.

Background: The prevalence of food allergy (FA) is increasing. Decreases in the diversity of gut microbiota may contribute to the pathogenesis of FA by regulating IgE production of B cells. Intermittent fasting (IF) is a popular diet with the potential to regulate glucose metabolism, boosting immune memory and optimizing gut microbiota. The potential effect of long-term IF on the prevention and treatment of FA is still unknown. Methods: Two IF protocols (16 h fasting/8 h feeding and 24 h fasting/24 h feeding) were conducted on mice for 56 days, while the control mice were free to intake food (free diet group, FrD). To construct the FA model, all mice were sensitized and intragastrical challenged with ovalbumin (OVA) during the second half of IF (day 28 to day 56). Rectal temperature reduction and diarrhea were recorded to evaluate the symptoms of FA. Levels of serum IgE, IgG1, Th1/Th2 cytokines, mRNA expression of spleen T cell related transcriptional factors, and cytokines were examined. H&E, immunofluorescence, and toluidine blue staining were used to assess the structural changes of ileum villi. The composition and abundance of gut microbiota were analyzed by 16srRNA sequencing in cecum feces. Results: The diarrhea score and rectal temperature reduction were lower in the two fasting groups compared to the FrD groups. Fasting was associated with lower levels of serum OVA-sIgE, OVA-sIgG1, interleukin (IL)-4 and IL-5, and mRNA expression of IL-4, IL-5, and IL-10 in the spleen. While no significant association was observed in interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-6, IL-2 levels. Less mast cell infiltration in ileum was observed in the 16h/8h fasting group compared to the FrD group. ZO-1 expression in the ileum of the two fasting groups was higher in IF mice. The 24h/24h fasting reshaped the gut microbiota, with a higher abundance of Alistipes and Rikenellaceae strains compared to the other groups. Conclusion: In an OVA-induced mice FA model, long-term IF may attenuate FA by reducing Th2 inflammation, maintaining the integrity of the intestinal epithelial barrier, and preventing gut dysbiosis.

Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes.

Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role.

Integrated Analysis of Transcriptome and microRNA Profile Reveals the Toxicity of Euphorbia Factors toward Human Colon Adenocarcinoma Cell Line Caco-2.

Euphorbia factors, lathyrane-type diterpenoids isolated from the medical herb Euphorbia lathyris L. (Euphorbiaceae), have been associated with intestinal irritation toxicity, but the mechanisms underlying this phenomenon are still unknown. The objective of this study was to evaluate the transcriptome and miRNA profiles of human colon adenocarcinoma Caco-2 cells in response to Euphorbia factors L1 (EFL1) and EFL2. Whole transcriptomes of mRNA and microRNA (miRNA) were obtained using second generation high-throughput sequencing technology in response to 200 µM EFL treatment for 72 h, and the differentially expressed genes and metabolism pathway were enriched. Gene structure changes were analyzed by comparing them with reference genome sequences. After 72 h of treatment, 16 miRNAs and 154 mRNAs were differently expressed between the EFL1 group and the control group, and 47 miRNAs and 1101 mRNAs were differentially expressed between the EFL2 group and the control. Using clusters of orthologous protein enrichment, the sequenced mRNAs were shown to be mainly involved in transcription, post-translational modification, protein turnover, chaperones, signal transduction mechanisms, intracellular trafficking, secretion, vesicular transport, and the cytoskeleton. The differentially expressed mRNA functions and pathways were enriched in transmembrane transport, T cell extravasation, the IL-17 signaling pathway, apoptosis, and the cell cycle. The differentially expressed miRNA EFLs caused changes in the structure of the gene, including alternative splicing, insertion and deletion, and single nucleotide polymorphisms. This study reveals the underlying mechanism responsible for the toxicity of EFLs in intestinal cells based on transcriptome and miRNA profiles of gene expression and structure.

EST12 regulates Myc expression and enhances anti-mycobacterial inflammatory response via RACK1-JNK-AP1-Myc immune pathway.

c-Myc (Myc) is a well-known transcription factor that regulates many essential cellular processes. Myc has been implicated in regulating anti-mycobacterial responses. However, its precise mechanism in modulating mycobacterial immunity remains elusive. Here, we found that a secreted Rv1579c (early secreted target with molecular weight 12 kDa, named EST12) protein, encoded by virulent Mycobacterium tuberculosis (M.tb) H37Rv region of deletion (RD)3, induces early expression and late degradation of Myc protein. Interestingly, EST12-induced Myc was further processed by K48 ubiquitin proteasome degradation in E3 ubiquitin ligase FBW7 dependent manner. EST12 protein activates JNK-AP1-Myc signaling pathway, promotes Myc binding to the promoters of IL-6, TNF-α and iNOS, then induces the expression of pro-inflammatory cytokines (IL-6 and TNF-α)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) to increase mycobacterial clearance in a RACK1 dependent manner, and these effects are impaired by both Myc and JNK inhibitors. Macrophages infected with EST12-deficiency strain (H37RvΔEST12) displayed less production of iNOS, IL-6 and TNF-α. In conclusion, EST12 regulates Myc expression and enhances anti-mycobacterial inflammatory response via RACK1-JNK-AP1-Myc immune pathway. Our finding provides new insights into M.tb-induced immunity through Myc.

Involvement and therapeutic implications of airway epithelial barrier dysfunction in type 2 inflammation of asthma.

ABSTRACT: Type 2 inflammation is a complex immune response and primary mechanism for several common allergic diseases including allergic rhinitis, allergic asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps. It is the predominant type of immune response against helminths to prevent their tissue infiltration and induce their expulsion. Recent studies suggest that epithelial barrier dysfunction contributes to the development of type 2 inflammation in asthma, which may partly explain the increasing prevalence of asthma in China and around the globe. The epithelial barrier hypothesis has recently been proposed and has received great interest from the scientific community. The development of leaky epithelial barriers leads to microbial dysbiosis and the translocation of bacteria to inter- and sub-epithelial areas and the development of epithelial tissue inflammation. Accordingly, preventing the impairment and promoting the restoration of a deteriorated airway epithelial barrier represents a promising strategy for the treatment of asthma. This review introduces the interaction between type 2 inflammation and the airway epithelial barrier in asthma, the structure and molecular composition of the airway epithelial barrier, and the assessment of epithelial barrier integrity. The role of airway epithelial barrier disruption in the pathogenesis of asthma will be discussed. In addition, the possible mechanisms underlying the airway epithelial barrier dysfunction induced by allergens and environmental pollutants, and current treatments to restore the airway epithelial barrier are reviewed.

Secondary primary lung cancer after esophageal cancer: a population-based study of 44,172 patients.

BACKGROUND: The present study aimed to assess the survival, incidence, and characteristics of secondary primary lung cancer (SPLC) after esophageal cancer (EC-LC). METHODS: The patients with esophageal cancer (EC) who developed SPLC and patients with first primary lung cancer (LC-1) were retrospectively reviewed in the Surveillance, Epidemiology, and End Results 18 registries covering 2000-2016. Overall survival and characteristics were compared between patients with EC-LC and patients with LC-1. The independent relation between a history of EC and death was evaluated by calculating hazard ratios in multivariate Cox regression analysis propensity score-matching analysis, and multiple imputation for cases with missing information. RESULTS: In comparison with the general population, the patients with EC had a higher risk for developing secondary primary lung cancer (SIR =1.86, 95% confidence interval (CI): 1.69-2.05). A history of EC was found to be an independent risk factor of death for lung squamous carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients in localized stage based on multivariate Cox regression analysis, propensity score-matching analysis and multiple imputation. CONCLUSIONS: There is a significantly increased risk of secondary primary lung cancer in EC survivors and a history of EC adversely affects overall survival in individuals who subsequently develop localized LUSC and LUAD. Clinicians should moderately strengthen lung tissue protection during the management of EC patients.

Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is the most prevalent renal malignancy. The pathogenesis of the disease is currently poorly understood, and the prognosis is poor. Therefore, in this study, we focused on exploring and identifying genes and signal transduction pathways that are closely related to ccRCC. Differentially expressed genes (DEGs) were analyzed using the renal cell oncogene expression profiles GSE100666 and GSE68417. DAVID evaluation of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses was used. We constructed a protein-protein interaction (PPI) network of DEGS using Cytoscape software and analyzed the submodules with the CytoHubba plugin. Finally, we performed western blot, immunohistochemistry, and PCR validation by collecting tissues, and also utilized cells for in vitro functional analysis of ceruloplasmin (CP). In total, 202 DEGs (52 upregulated and 150 downregulated genes) were identified. Upregulated DEGs are significantly rich in angiogenesis, cell adhesion, and response to hypoxia, whereas downregulated DEGs are involved in intracellular pH regulation, excretion, coagulation, and chloride transmembrane transport. We selected the interactions of the top 20 hub genes provided by the PPI network, all of which are involved in important physiological pathways in vivo, such as complement and coagulation cascades. Tissue protein assays demonstrated that renal cancer highly expressed CP, while in vitro experiments showed that CP could promote the invasion of renal cancer cells. Our study suggests that ALB, C3, LOX, HRG, CXCR4, GPC3, SLC12A3, CP, and CASR may be involved in the development of ccRCC, and is expected to provide theoretical support for future studies on the diagnosis and targeted therapy of ccRCC.

Clinical, radiological, and laboratory characteristics and risk factors for severity and mortality of 289 hospitalized COVID-19 patients.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has become a global pandemic, with 10%-20% of severe cases and over 508 000 deaths worldwide. OBJECTIVE: This study aims to address the risk factors associated with the severity of COVID-19 patients and the mortality of severe patients. METHODS: 289 hospitalized laboratory-confirmed COVID-19 patients were included in this study. Electronic medical records, including patient demographics, clinical manifestation, comorbidities, laboratory tests results, and radiological materials, were collected and analyzed. According to the severity and outcomes of the patients, they were divided into three groups: nonsurvived (n = 49), survived severe (n = 78), and nonsevere (n = 162) groups. Clinical, laboratory, and radiological data were compared among these groups. Principal component analysis (PCA) was applied to reduce the dimensionality and visualize the patients on a low-dimensional space. Correlations between clinical, radiological, and laboratory parameters were investigated. Univariate and multivariate logistic regression methods were used to determine the risk factors associated with mortality in severe patients. Longitudinal changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay were also collected. RESULTS: Of the 289 patients, the median age was 57 years (range, 22-88) and 155 (53.4%) patients were male. As of the final follow-up date of this study, 240 (83.0%) patients were discharged from the hospital and 49 (17.0%) patients died. Elder age, underlying comorbidities, and increased laboratory variables, such as leukocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), procalcitonin (PCT), D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) on admission, were found in survived severe cases compared to nonsevere cases. According to the multivariate logistic regression analysis, elder age, a higher number of affected lobes, elevated CRP levels on admission, increased prevalence of chest tightness/dyspnea, and smoking history were independent risk factors for death of severe patients. A trajectory in PCA was observed from "nonsevere" toward "nonsurvived" via "severe and survived" patients. Strong correlations between the age of patients, the affected lobe numbers, and laboratory variables were identified. Dynamic changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay showed that continuing increase of leukocytes and neutrophil count, sustained lymphopenia and eosinopenia, progressing decrease in platelet count, as well as high levels of NLR, CRP, PCT, AST, BUN, and serum creatinine were associated with in-hospital death. CONCLUSIONS: Survived severe and nonsurvived COVID-19 patients had distinct clinical and laboratory characteristics, which were separated by principle component analysis. Elder age, increased number of affected lobes, higher levels of serum CRP, chest tightness/dyspnea, and smoking history were risk factors for mortality of severe COVID-19 patients. Longitudinal changes of laboratory findings may be helpful in predicting disease progression and clinical outcome of severe patients.

Risk factors for severe and critically ill COVID-19 patients: A review.

The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and high numbers of deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1ß, Krebs von den Lungen-6 (KL-6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID-19.

Acute toxicity and health effect of perfluoroisobutyronitrile on mice: a promising substitute gas-insulating medium to SF6.

Perfluoroisobutyronitrile (C4F7N) is a new eco-friendly gas insulation medium that has potential to replace the most greenhouse gas sulfur hexafluoride (SF6) used in power industry. In order to ensure the engineering application safety, an in-depth assessment of the acute inhalation toxicity of C4F7N gas mixture is required. This article revealed gender differences in male and female mice after exposure to C4F7N and the physiological recovery characteristics of surviving mice by means of 4 h acute inhalation toxicity tests, hematological determinations and histopathological examination. Comparative analysis on the toxicity of C4F7N on mice and rats is also evaluated. We find that the LC50 of C4F7N for male and female mice is 1175 ppm (4 h), 1380 ppm (4 h) and female ones are more tolerant to C4F7N. Mice that exposed to 1000 ppm C4F7N for 4 h could survive and return to their normal state after the 14-day observation period without irreversible damage. The toxic effect duration of C4F7N on rats is longer than that of mice. Relevant results revealed the acute inhalation toxicity of C4F7N systematically and provided fundamental reference for inhalation safety protection and engineering application.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: An evidence-based clinical practice guideline (updated version).

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID-19 patients.

Identification of MicroRNA-Target Gene-Transcription Factor Regulatory Networks in Colorectal Adenoma Using Microarray Expression Data.

OBJECTIVE: The aim of the study was to find the key genes, microRNAs (miRNAs) and transcription factors (TFs) and construct miRNA-target gene-TF regulatory networks to investigate the underlying molecular mechanism in colorectal adenoma (CRA). METHODS: Four mRNA expression datasets and one miRNA expression dataset were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were identified between CRA and normal samples. Moreover, functional enrichment analysis for DEGs was carried out utilizing the Cytoscape-plugin, known as ClueGO. These DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, a miRNA-target gene regulatory network was established to screen key DEMs. In addition, similar workflow of the analyses were also performed comparing the CRC samples with CRA ones to screen key DEMs. Finally, miRNA-target gene-TF regulatory networks were constructed for these key DEMs using iRegulon plug-in in Cytoscape. RESULTS: We identified 514 DEGs and 167 DEMs in CRA samples compared to healthy samples. Functional enrichment analysis revealed that these DEGs were significantly enriched in several terms and pathways, such as regulation of cell migration and bile secretion pathway. A PPI network was constructed including 325 nodes as well as 890 edges. A total of 59 DEGs and 65 DEMs were identified in CRC samples compared to CRA ones. In addition, Two key DEMs in CRA samples compared to healthy samples were identified, such as hsa-miR-34a and hsa-miR-96. One key DEM, hsa-miR-29c, which was identified when we compared the differentially expressed molecules found in the comparison CRA versus normal samples to the ones obtained in the comparison CRC versus CRA, was also identified in CRC samples compared to CRA ones. The miRNA-target gene-TF regulatory networks for these key miRNAs included two TFs, one TF and five TFs, respectively. CONCLUSION: These identified key genes, miRNA, TFs and miRNA-target gene-TF regulatory networks associated with CRA, to a certain degree, may provide some hints to enable us to better understand the underlying pathogenesis of CRA.

Exchange protein directly activated by cAMP (Epac) protects against airway inflammation and airway remodeling in asthmatic mice.

BACKGROUND: ß2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in asthmatic airway inflammation and airway remodeling is unclear. METHODS: We established OVA-sensitized and -challenged acute and chronic asthma mice models to explore the expression of Epac at first. Then, airway inflammation and airway hyperresponsiveness in acute asthma mice model and airway remodeling in chronic asthma mice model were observed respectively after treatment with Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP (8pCPT) and Epac inhibitor ESI-09. Next, the effects of 8pCPT and ESI-09 on the proliferation and apoptosis of in vitro cultured mouse airway smooth muscle cells (ASMCs) were detected with CCK-8 assays and Annexin-V staining. Lastly, the effects of 8pCPT and ESI-09 on store-operated Ca2+ entry (SOCE) of ASMCs were examined by confocal Ca2+ fluorescence measurement. RESULTS: We found that in lung tissues of acute and chronic asthma mice models, both mRNA and protein expression of Epac1 and Epac2, two isoforms of Epac, were lower than that of control mice. In acute asthma mice model, the airway inflammatory cell infiltration, Th2 cytokines secretion and airway hyperresponsiveness were significantly attenuated by 8pCPT and aggravated by ESI-09. In chronic asthma mice model, 8pCPT decreased airway inflammatory cell infiltration and airway remodeling indexes such as collagen deposition and airway smooth muscle cell proliferation, while ESI-09 increased airway inflammation and airway remodeling. In vitro cultured mice ASMCs, 8pCPT dose-dependently inhibited, whereas ESI-09 promoted ASMCs proliferation. Interestingly, 8pCPT promoted the apoptosis of ASMCs, whereas ESI-09 had no effect on ASMCs apoptosis. Lastly, confocal Ca2+ fluorescence examination found that 8pCPT could inhibit SOCE in ASMCs at 100 µM, and ESI-09 promoted SOCE of ASMCs at 10 µM and 100 µM. In addition, the promoting effect of ESI-09 on ASMCs proliferation was inhibited by store-operated Ca2+ channel blocker, SKF-96365. CONCLUSIONS: Our results suggest that Epac has a protecting effect on asthmatic airway inflammation and airway remodeling, and Epac reduces ASMCs proliferation by inhibiting SOCE in part.

Assessment on the toxicity and application risk of C4F7N: A new SF6 alternative gas.

C4F7N (fluorinated nitrile) gas mixture has been utilized as the gas insulating medium to replace the most greenhouse gas SF6 (sulphur hexafluoride). Nowadays, there are few reports on the toxicity mechanism of C4F7N and studies on the application risk of C4F7N is insufficient. In this paper, we carried out acute toxicity tests for C4F7N gas systematically. The changes of vital signs of rats after exposure to C4F7N were analyzed and the influence of C4F7N on the main organs of rats was revealed for the first time. It was found that rats developed symptoms of respiratory rate decrease, respiratory mucosa damage, movement systems impairment and abnormal blood cell count after exposure to C4F7N. Pathological section results showed that 1.5% C4F7N could damage the lung, kidney, intestine and brain tissues of rats to a certain extent, but has little influence to the eye, skin, heart and liver. The LC50 (rat, 4 h) of C4F7N gas is in the range of 15,000 ppm (1.5%) and 20,000 ppm (2%). Relevant research results not only reveal the acute toxicity mechanism of C4F7N, but also provide important reference for the safety protection of scientific researcher, equipment production, engineering operation and maintenance personnel.

Comparison of diagnostic efficacy between CLE, tissue sampling, and CLE combined with tissue sampling for undetermined pancreaticobiliary strictures: a meta-analysis.

OBJECTIVE: The accurate diagnosis of undetermined pancreaticobiliary strictures remains challenging. Current ERCP-guided tissue sampling methods are of low sensitivity. Confocal laser endomicroscopy (CLE) is a new procedure and allows real optical biopsies that may improve the diagnosis of undetermined pancreaticobiliary strictures. The aim of this meta-analysis was to determine the diagnostic yield of CLE, tissue sampling, and CLE combined with tissue sampling for undetermined pancreaticobiliary strictures. METHOD: Pubmed, Embase, and the Cochrane Library database were reviewed for relevant studies. Pooled estimates of sensitivity and specificity with 95% confidence intervals (CIs) were calculated using the random-effects meta-analysis model. The summary receiver-operating characteristic (SROC) curve was constructed, and the area under the receiver operating characteristic curve (AUC) was calculated. RESULTS: Twelve studies involving 591 patients were enrolled in our analysis. The overall sensitivity and the specificity estimate of CLE for discriminating benign and malignant pancreaticobiliary strictures were 87% (95%CI, 83-91%) and 76% (95%CI, 70-81%), respectively. The AUC to assess the diagnostic efficacy was 0.8705. For tissue sampling, the overall sensitivity and the specificity estimate were 64% (95%CI, 57-70%) and 94% (95%CI, 90-97%), respectively. The AUC to assess the diagnostic efficacy was 0.8040. A combination of both methods increased the sensitivity (93%; 95%CI, 88-96%) with a specificity of 82% (95%CI, 74-89%). The AUC to assess the diagnostic efficacy was 0.9377. There was no publication bias by Deeks' Funnel Plot with p = .936. CONCLUSIONS: Compared with tissue sampling, CLE may increase the sensitivity for the diagnosis of malignant pancreaticobiliary strictures. A combination of both can effectively diagnose malignant pancreaticobiliary strictures.

IL-4 and serum amyloid P inversely regulate fibrocyte differentiation by targeting store-operated Ca2+ channels.

BACKGROUND: Circulating fibrocytes (CFs) have been shown to participate in subepithelial fibrosis of asthma with chronic airflow limitation by acting as an important source of fibroblasts deposited beneath airway epithelia. Serum amyloid P (SAP) is an innate inhibitor of fibrocytes differentiation. Store-operated Ca2+ entry (SOCE) is the major Ca2+ influx of non-excitable cells. In this study, the role of SOCE in the regulation of fibrocytes differentiation and the effects of Th2 cytokine IL-4 and SAP on SOCE of fibrocytes were investigated. METHODS: Peripheral blood mononuclear cells or monocytes were cultured in serum-free medium for 7days to differentiate into fibrocytes; the expression of SOC channels was determined with PCR, SOCE was measured with Ca2+ fluorescence imaging. RESULTS: IL-4 significantly promoted monocyte derived fibrocytes differentiation in vitro. It also increased both SOCE which was induced by thapsigargin or UTP and molecules STIM1 and Orai1 which were related to expression of SOC channels in fibrocytes. Fibrocytes differentiation induced by IL-4 and SOC channels activity could be inhibited by SOC channel blocker SKF-96365. As expected, SAP significantly inhibited IL-4-induced differentiation of fibrocytes, the activity of SOCE and the expression of STIM1 and Orai1 in IL-4-treated fibrocytes. CONCLUSION: IL-4 and SAP reversely regulates cultured fibrocytes differentiation in vitro by respectively promoting or inhibiting the expression and activity of SOC channels in fibrocytes.

Endobronchial one-way valves for treatment of persistent air leaks: a systematic review.

Persistent air leak (PAL) is associated with significant morbidity and mortality, prolonged hospitalization and increased health-care costs. It can arise from a number of conditions, including pneumothorax, necrotizing infection, trauma, malignancies, procedural interventions and complications after thoracic surgery. Numerous therapeutic options, including noninvasive and invasive techniques, are available to treat PALs. Recently, endobronchial one-way valves have been used to treat PAL. We conducted a systematic review based on studies retrieved from PubMed, EMbase and Cochrane library. We also did a hand-search in the bibliographies of relevant articles for additional studies. 34 case reports and 10 case series comprising 208 patients were included in our review. Only 4 patients were children, most of the patients were males. The most common underlying disease was COPD, emphysema and cancer. The most remarkable cause was pneumothorax. The upper lobes were the most frequent locations of air leaks. Complete resolution was gained within less than 24 h in majority of patients. Complications were migration or expectoration of valves, moderate oxygen desaturation and infection of related lung. No death related to endobronchial one-way valves implantation has been found. The use of endobronchial one-way valve adds to the armamentarium for non-invasive treatments of challenging PAL, especially those with difficulties of anesthesia, poor condition and high morbidity. Nevertheless, prospective randomized control trials with large sample should be needed to further evaluate the effects and safety of endobronchial one-way valve implantation in the treatment of PAL.