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Adenoma detection rate (ADR) is the colonoscopy quality metric with the strongest association to interval or “missed” cancer. Accurate measurement of ADR can be laborious and costly. Our aim was to determine if administrative procedure codes for colonoscopy and text searches of pathology results for adenoma mentions could estimate ADR. We identified US Veterans with a colonoscopy using Current Procedure Terminology (CPT) codes between January 2013 and December 2016 at ten Veterans Affairs sites. We applied simple text searches using Microsoft SQL Server full-text searches to query all pathology notes for “adenoma(s)” or “adenomatous” text mentions to calculate ADRs. To validate our identification of colonoscopy procedures, endoscopists of record, and adenoma detection from the electronic health record, we manually reviewed a random sample of 2000 procedure and pathology notes from the 10 sites. Structured data fields were accurate in identification of colonoscopies being performed (PPV = 0.99; 95% CI 0.99–1.00) and identifying the endoscopist of record (PPV of 0.95; 95% CI 0.94–0.96) for ADR measurement. Simple text searches of pathology notes for adenoma mentions had excellent performance statistics as follows: sensitivity 0.99 (95% CI 0.98–1.00), specificity 0.93 (95% CI 0.92–0.95), NPV 0.99 (95% CI 0.98–1.00), and PPV 0.93 (0.91–0.94) for measurement of ADR. There was no clinically significant difference in the estimates of overall ADR vs. screening ADR (p > 0.05). Measuring ADR using administrative codes and text searches from pathology results is an efficient method to broadly survey colonoscopy quality.

Background: Lung cancer is one of most common malignancies worldwide. We have previously identified retinoic acid-induced gene G (Rig-G) as a tumor suppressor in not only acute promyelocytic leukemia, but as well in other solid tumors. However, the clinical significance of Rig-G and the underlying mechanism(s) for its biological function in lung cancer remain largely unexplored. Methods: We first compared the expression of Rig-G between lung cancer (n=138) and normal tissues (n=23), from public-available datasets and our patient cohort. We further analyzed the correlation of Rig-G expression with key clinico-pathological features and survival outcomes in a multi-site clinical cohort of 300 lung cancer patients. Functional studies for Rig-G were performed in cell lines, and an animal model to support clinical findings. Findings: We found that Rig-G was frequently downregulated in lung cancer tissues and celllines, and correlated with poor prognosis in lung cancer patients. Overexpression of Rig-G led to significantly reduced cell growth and suppressed migrationin A549 and NCI-H1944 cells, accompanied by reduced epithelial-mesenchymal transition. Likewise, restoration of Rig-G in Lewis lung carcinoma cells permitted development of fewer cancer metastases vs. controls in an animal model. Gene expression profiling results identified p53 pathway as a key downstream target of Rig-G, and p53 inhibition by pifithrin-α caused abrogation of tumor-suppressive effects of Rig-G in lung cancer. Interpretation: We for the first time have identified Rig-G as a novel and important tumor suppressor, which may serve as a potential therapeutic target for restoring p53 expression in lung cancer patients. Funding Statement: This work was supported by the National Cancer Institute, NIH (CA72851, CA184792, CA202797 and CA187956), the National Natural Science Foundation of China (81272603, 81472179 and 81873975), the Excellent Academic Leader Training Program of Shanghai Health System (2018BR31), the Clinical Research and Cultivation Project of Shanghai Tongji Hospital grant [ITJ(ZD)1803]. This work was also supported by the National Natural Science Foundation of China (81672826 and 81874179), the Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2017YQ044), the Shanghai Pujiang Talent Plan (18PJD047), the Natural Science Foundation of Shanghai (19ZR1448800), the Medical Guidance Science and Technology Support Project of Shanghai (9411964800) and the National Natural Science Foundation Training Program of Tongji Hospital (GJPY1804). Declaration of Interests: None of the authors have any potential conflicts to disclose. Ethics Approval Statement: A written informed consent was obtained from all patients and the study was approved by ethics committee of Shanghai Tongji Hospital. All animal experiments were approved by the Tongji Hospital of Tongji University Ethics Committee on the Use and Care of Animals.

Background Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear. Methods CRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils. Results Our study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition. Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor-β1 (TGF-β1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF-β1 axis. Conclusion Our study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.

Rationale: Antimicrobial peptides, such as cathelicidin LL-37/hCAP-18, are important effectors of the innate immune system with direct antibacterial activity. In addition, LL-37 is involved in the regulation of tumor cell growth. However, the molecular mechanisms underlying the functions of LL-37 in promoting lung cancer are not fully understood. Methods: The expression of LL-37 in the tissues and sera of patients with non-small cell lung cancer was determined through immunohistological, immunofluorescence analysis, and enzyme-linked immunosorbent assay. The animal model of wild-type and Cramp knockout mice was employed to evaluate the tumorigenic effect of LL-37 in non-small cell lung cancer. The mechanism of LL-37 involving in the promotion of lung tumor growth was evaluated via microarray analyses, recombinant protein treatment approaches in vitro, tumor immunohistochemical assays, and intervention studies in vivo. Results: LL-37 produced by myeloid cells was frequently upregulated in primary human lung cancer tissues. Moreover, its expression level correlated with poor clinical outcome. LL-37 activated Wnt/β-catenin signaling by inducing the phosphorylation of protein kinase B and subsequent phosphorylation of glycogen synthase kinase 3β mediated by the toll-like receptor-4 expressed in lung tumor cells. LL-37 treatment of tumor cells also decreased the levels of Axin2. In contrast, it elevated those of an RNA-binding protein (tristetraprolin), which may be involved in the mechanism through which LL-37 induces activation of Wnt/β-catenin. Conclusion: LL-37 may be a critical molecular link between tumor-supportive immune cells and tumors, facilitating the progression of lung cancer.

Background Ginkgolide B (GKB) is a major active component of the extracts of Ginkgo biloba leaves, and it has been used as an anti-cancer agent. However, it is unknown whether GKB has the therapeutic effects on lung cancer. Here, we studied the effects of GKB on lung cancer cells. Methods The effects of GKB on lung cancer cell proliferation and invasion were analyzed by cell counting kit (CCK-8) and cell invasion assays, respectively. Apoptosis was detected by flow cytometry. Western blot analysis was used to confirm the expression of autophagy-associated proteins in GKB-treated cells. Immunofluorescence analysis was used to analyze the level of light chain 3B (LC3B). Results Treatment with GKB time-dependently inhibited the proliferation and decreased the invasive capacity of A549 and H1975 cells. GKB induced apoptosis of these cells, but there was no significant effect on apoptosis compared to the control treatment. GKB-induced inhibition of cell proliferation and GKB-induced cell death were due to autophagy rather than apoptosis. GKB-induced autophagy of lung cancer cells was dependent on beclin-1, and autophagy-induced inhibition of the NLRP3 inflammasome contributed to the anti-tumor effect of GKB. Conclusions GKB-mediated autophagy of lung cancer cells is beclin-1-dependent and results in inhibition of the NLRP3 inflammasome. Therefore, GKB might be a potential therapeutic candidate for the treatment of lung cancer.

Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are associated with acute and chronic bacterial infections of the lung. Excessive differentiation of basal cells to mucus-producing goblet cells can result in mucus hyperproduction and loss of mucociliary clearance in the airways of CF and COPD patients. Here, we aimed to investigate the effect of pathogen-associated molecular patterns (PAMPs) on the differentiation of human 3D bronchospheres. Primary human bronchial epithelial cells (HBECs) were differentiated to bronchospheres in the presence of bacterial flagellin and LPS and the synthetic Toll-like receptor (TLR) ligands Pam3CSK4 (TLR-2) and polyinosinic:polycytidylic acid (pIC, TLR-3). Electron and fluorescence microscopy showed that the differentiation of bronchospheres associated with the formation of lumina and appearance of cilia within 30 days after seeding. Incubation with flagellin resulted in a decreased formation of lumina and loss of cilia formation. Incubation with Pam3CSK, pIC, and LPS did not significantly affect formation of lumina and ciliation. Mucus production was strongly increased in response to flagellin and, to a lesser degree, in response to Pam3CSK4. Our results indicate that bacterial factors, such as flagellin, drive the differentiation of the respiratory epithelium towards mucus hyperproduction.

Background Globus pharyngeus is common and has a low cure rate. Its etiology is complex and reported to be associated with laryngopharyngeal reflux (LPR). However, some patients with globus do not exhibit any reflux symptoms or respond to proton pump inhibitors (PPIs) treatments. The purpose of this study was to clarify the related risk factors of these patients with a final objective of improving the curative effect. Methods Forty two patients afflicted with globus pharyngeus (G group) and 38 patients without globus pharyngeus (NG group) were included in this study. According to the laryngopharyngeal Reflux Symptom Index and the response to PPIs treatments, the patients were further divided into reflux groups (G-R, NG-R) and non-reflux groups (G-NR, NG-NR). High Resolution Manometry (HRM) was performed to assess esophageal motility. Questionnaires, including categories such as life exposure factors, were conducted. Results a) The average resting and residual pressures of the upper esophageal sphincter (UES) in the G-NR group was higher than in the NG-NR and NG-R groups (P 0.05). c) The esophageal distal contractile integral score of the G-NR group was not different from the NG-NR group (P > 0.05). d) Compared to the NG-NR group, the G-NR group showed higher incidence of stress, smoking, drinking, high salt and anxiety (P

Background and Purpose PGE2 inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE2 has not been defined. The aim of this study was to identify the EP receptor by which PGE2 inhibits cytokine generation from human lung macrophages. This was determined by using recently developed EP receptor ligands. Experimental Approach The effects of PGE2 and EP-selective agonists on LPS-induced generation of TNF-α and IL-6 from macrophages were evaluated. The effects of EP2-selective (PF-04852946, PF-04418948) and EP4-selective (L-161,982, CJ-042794) receptor antagonists on PGE2 responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT-PCR. Key Results PGE2 inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP2 and EP4 receptors. L-902,688 (EP4 receptor-selective agonist) was considerably more potent than butaprost (EP2 receptor-selective agonist) as an inhibitor of TNF-α generation from macrophages. EP2 receptor-selective antagonists had marginal effects on the PGE2 inhibition of TNF-α generation, whereas EP4 receptor-selective antagonists caused rightward shifts in the PGE2 concentration–response curves. Conclusions and Implications These studies demonstrate that the EP4 receptor is the principal receptor that mediates the anti-inflammatory effects of PGE2 on human lung macrophages. This suggests that EP4 receptor agonists could be effective anti-inflammatory agents in human lung disease.

// Dong Li 1, * , Junjun Sun 1, * , Wenfang Liu 2, * , Xuan Wang 3 , Robert Bals 4 , Junlu Wu 1 , Wenqiang Quan 1 , Yiwen Yao 1 , Yu Zhang 1 , Hong Zhou 1 , Kaiyin Wu 5 1 Department of Clinical Laboratory, Shanghai Tongji Hospital, Tongji University School of Medicine, 200065 Shanghai, China 2 Department of General Surgery, Shanghai Tongji Hospital, Tongji University School of Medicine, 200065 Shanghai, China 3 Department of Pharmacy, Putuo People’s Hospital, 200060 Shanghai, China 4 Department of Internal Medicine V – Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, 66424 Homburg, Germany 5 Institute of Pathology, Charite Medical University, 10117 Berlin, Germany * These authors contributed equally as first authors Correspondence to: Dong Li, email: 186ld@163.com Keywords: Rig-G, lung cancer, growth inhibition, NF-κB, STAT3 Received: February 25, 2016 Accepted: August 24, 2016 Published: September 01, 2016 ABSTRACT The expression of the retinoic acid-induced G (Rig-G) gene, an all trans retinoic acid (ATRA)-inducible gene, was observed in multiple cancer cells, including lung cancer cells. However, whether Rig-G is a tumor suppressor in lung cancer is unknown. Here, we found that ectopic expression of Rig-G can lead to a significant decrease in proliferation of lung cancer cells, resulting in an inhibition of tumor growth. Rig-G knockdown results in a modest increase in cell proliferation, as well as confers an increase in colony formation. Furthermore, transcriptome and pathway analyses of cancer cells revealed a fundamental impact of Rig-G on various growth signaling pathways, including the NF-κB pathway. Rig-G inhibits NF-κB activity by suppressing STAT3 in lung cancer cells. The downregulation of miR21 and miR181b-1 and subsequent activation of PTEN/Akt and CYLD/IκB signaling axis leading to decreased NF-κB activity required to maintain the tumor-inhibiting effect of Rig-G.. Our findings contribute to a better understanding of the antitumor effect mechanism of Rig-G, as well as offer a novel strategy for lung cancer therapy.

Placenta-specific 8 (PLAC8) is closely associated with the proliferation, apoptosis and autophagy of several tumor cells. However, the expression and function of PLAC8 in oral squamous cell carcinoma (OSCC) remain unknown. Therefore, the present study investigated the function and mechanism of PLAC8 in OSCC. Reverse transcription-quantitative PCR and western blot analyses were performed to quantify the expression of PLAC8 in OSCC cell lines. The function of PLAC8 in OSCC was investigated via transfection, the Transwell and Cell Counting Kit-8 assays, immunofluorescence staining and western blotting. The results demonstrated that PLAC8 exspression was downregulated in OSCC cell lines. PLAC8 inhibited the cell proliferation in OSCC. In addition, PLAC8 restrained invasion and epithelial-mesenchymal transition of OSCC cells. Furthermore, β-catenin helped to repress PLAC8 expression by regulating the Wnt/β-catenin and PI3K/Akt/GSK3β signaling pathways in OSCC cells. Collectively, the results of the present study suggest that PLAC8 acts as a tumor suppressor in OSCC by downregulating β-catenin.

Background We report VA-wide trends over time in acute respiratory infection (ARI) antibiotic prescribing, and early assessment of an intervention to improve ARI management. Methods We created a retrospective cohort of ARI (sinusitis, pharyngitis, bronchitis, and URI-NOS) visits between 2009 and April 2018. Patients with complicating conditions were excluded. Antibiotic prescribing rates were calculated. A provider-directed VA-wide ARI campaign was initiated in October 2017. The Campaign was implemented locally by antibiotic stewards or regional personnel trained in academic detailing (AD). Campaign components: dashboards for tracking provider and facility prescribing metrics, printable feedback reports, and AD educational materials. Metrics include: ARI antibiotic prescribing rates, bronchitis/URI-NOS antibiotic prescribing rates, guideline-concordant antibiotic selection for sinusitis or pharyngitis, and proportion of ARI visits with a sinusitis diagnosis. A Logistic generalized estimating equation model assessed metrics over time pre-/postintervention and χ2 tests compared guideline concordant antibiotic proportions pre-/postintervention. Results There were 1,580,612 and 137,421 ARI visits pre-/postintervention, respectively. Antibiotic prescribing decreased from 2009, annual odds ratio (OR) 0.94 [95% CI 0.93, 0.96; P < 0.001]. An additional effect was observed postintervention [OR 0.88, (0.84, 0.88), P < 0.001]. Bronchitis/URI-NOS prescribing rates decreased from 2009 [annual OR 0.94 (CI 0.93, 0.95), P < 0.001]. Additional effect was observed postintervention [OR 0.86, (0.81, 0.91), P < 0.001]. Overall, the proportion of ARI visits diagnosed with sinusitis increased [annual OR 1.09 (1.08, 1.10), P < 0.01], but the proportion of sinusitis diagnoses decreased [OR 0.72 (0.69, 0.75), P < 0.001] postintervention. Guideline-concordant antibiotic selection was 61.5% vs. 71.2% for sinusitis and 63.3% vs. 67.8% for pharyngitis pre-/postintervention, respectively (both P < 0.001). Conclusion Antibiotic prescribing rates for ARIs within the VA have steadily declined since 2010. Additional decline in antibiotic prescribing was associated with the launch of a national campaign to improve ARI management. Disclosures All authors: No reported disclosures.

Ring finger protein 135 (RNF135), located on chromosome 17q11.2, is a RING finger domain-containing E3 ubiquitin ligase that was identified as a bio-marker and therapy target of glioblastoma. In our study, we confirmed that RNF135 was up-regulated in glioblastoma tissues compared with normal brain (NB) tissues, and that RNF135 knockdown inhibited proliferation and migration and led to cell cycle arrest in the G0/G1 phase in vivo. By lowering RNF135 expression, phosphorylated Erk and cell cycle protein CDK4 were down-regulated, while p27Kip1 and p21Waf1/Cip1 were up-regulated in U87 and U251 cells in vitro. In addition, using the immunofluorescence double labelling method, we found that RNF135 and P-Erk were co-localized in the cytoplasm and were highly expressed in glioblastoma samples compared with NB tissues. Moreover, the growth of U87 cell-transplanted tumours in nude mice was inhibited while transduced with Lv-shRNF135. Taken together, our findings demonstrate the biological effects of RNF135 in glioblastoma cell proliferation, migration and cell cycle, and its role in the progression of glioblastoma may be associated with the ERK signal transduction pathway.