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This study aims to clarify the N6-methyladenosine (m6A) modification of LINC01006, which is involved in migration, invasion and proliferation of non-small cell lung cancer (NSCLC). LINC01006 and METTL3 expressions were analyzed in TCGA-LUAD cohort. Colony formation assay, wound-healing assay and transwell assay were performed to evaluate the ability of colony formation, migration and invasion. Q-PCR and western blot analysis determined gene expressions. M6A-RNA immunoprecipitation and m6A quantification assay were used to evaluate m6A modification. qChIP assay was used to validate transcriptional target. Luciferase assay validated the miRNA targets and transcriptional targets. In-situ xenograft model were included to evaluate tumor proliferation in vivo. LINC01006 and METTL3 expressions were elevated in NSCLC cells and tissues. LINC01006 promoted the migration and invasion of NSCLC via epithelial - mesenchymal transition (EMT). The expression of LINC01006 was positively correlated to the expression of METTL3. METTL3 promoted tumor formation and proliferation in the in-situ xenograft model of NSCLC. The expression of LINC01006 was increased by METTL3 via m6A modification. c-MYC directly induced METTL3. Both c-MYC and LINC01006 were commonly targeted by miR-34a/b/c and miR-2682, and thereby c-MYC/METTL3/LINC01006 formed a positive feedback loop through miRNA targets in NSCLC. LINC01006 is an oncogenic lncRNA, which induces migration, invasion and proliferation of NSCLC. METTL3 increases LINC01006 expression through stabilizing LINC01006 mRNA. c-MYC, as a transcription factor, activates METTL3, which results in an elevated level of LINC01006. c-MYC, METTL3 and LINC01006 form a positive feedback loop through multiple miRNA targets in NSCLC.

Background Distant metastasis, which occurs at a rate of 25% in patients with esophageal cancer (EC), has a poor prognosis, with previous studies reporting an overall survival of only 3–10 months. However, few studies have been conducted to predict distant metastasis in EC, owing to a dearth of reliable biomarkers. The purpose of this study was to develop and validate an accurate model for predicting distant metastasis in patients with EC. Methods A total of 299 EC patients were enrolled and randomly assigned to a training cohort ( n  = 207) and a validation cohort ( n  = 92). Logistic univariate and multivariate regression analyses were used to identify clinical independent predictors and create a clinical nomogram. Radiomic features were extracted from contrast-enhanced computed tomography (CT) images taken prior to treatment, and least absolute shrinkage and selection operator (Lasso) regression was used to screen the associated features, which were then used to develop a radiomic signature. Based on the screened features, four machine learning algorithms were used to build radiomics models. The joint nomogram with radiomic signature and clinically independent risk factors was developed using the logical regression algorithm. All models were validated and compared by discrimination, calibration, reclassification, and clinical benefit. Results Multivariable analyses revealed that age, N stage, and degree of pathological differentiation were independent predictors of distant metastasis, and a clinical nomogram incorporating these factors was established. A radiomic signature was developed by a set of sixteen features chosen from 851 radiomic features. The joint nomogram incorporating clinical factors and radiomic signature performed better [AUC(95% CI) 0.827(0.742–0.912)] than the clinical nomogram [AUC(95% CI) 0.731(0.626–0.836)] and radiomics predictive models [AUC(95% CI) 0.754(0.652–0.855), LR algorithms]. Calibration and decision curve analyses revealed that the radiomics–clinical nomogram outperformed the other models. In comparison with the clinical nomogram, the joint nomogram's NRI was 0.114 (95% CI 0.075–0.345), and its IDI was 0.071 (95% CI 0.030–0.112), P  = 0.001. Conclusions We developed and validated the first radiomics–clinical nomogram for distant metastasis in EC which may aid clinicians in identifying patients at high risk of distant metastasis.

The HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus, Tat–TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat–TAR RNA interaction, we used a crystal structure of acetylpromazine bound to the bulge of TAR RNA, to dock compounds from the Enamine database containing over two million individual compounds. The docking procedure identified 173 compounds that were further analyzed for the inhibition of HIV-1 infection. The top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50 = 2.97 μM), T0516-4834 (IC50 = 0.2 μM) and T5628834 (IC50 = 3.46 μM), were further tested for HIV-1 transcription inhibition. Only the T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas the T6780107 compound inhibited equally basal and Tat-induced transcription and the T5628834 compound only inhibited basal HIV-1 transcription. The compounds were tested for the inhibition of translation and showed minimal (<25%) effect. The T0516-4834 compound also showed the strongest inhibition of HIV-1 RNA expression and p24 production in CEM T cells and peripheral blood mononuclear cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound significantly disrupted Tat–TAR RNA interaction. Additionally, of the three tested compounds, T5628834 and, to a lesser extent, T0516-4834 disrupted Tat–CDK9/cyclin T1 interaction. None of the three compounds showed significant inhibition of the cellular CDK9 and cyclin T1 levels. In silico modelling showed that the T0516-4834 compound interacted with TAR RNA by binding to the bulge formed by U23, U25, C39, G26,C39 and U40 residues. Taken together, our study identified a novel benzoxazole compound that disrupted Tat–TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection, suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.

Asthma has become a global health issue, suffering more than 300 million people in the world, which is a heterogeneous disease, usually characterized by chronic airway inflammation and airway hyperreactivity. Combination of inhaled corticosteroids (ICS) and long acting β-agonists (LABA) can relieve asthma symptoms and reduce the frequency of exacerbations, especially for patients with refractory asthma, but there are limited treatment options for people who do not gain control on combination ICS/LABA. The increase in ICS dose generally provides little additional benefit, and there is an increased risk of side effects. Therefore, therapeutic interventions integrating the use of different agents that focus on different targets are needed to overcome this set of diseases. Some findings suggest autophagy is closely correlated with the severity of asthma through eosinophilic inflammation, and its modulation may provide novel therapeutic approaches for severe allergic asthma. The chinese herbal medicine (CHM) have been demonstrated clinically as potent therapeutic interventions for asthma. Moreover some reports have found that the bioactive components isolated from CHM could modulate autophagy, and exhibit potent Anti-inflammatory activity. These findings have implied the potential for CHMs in asthma or allergic inflammation therapy via the modulation of autophagy. In this review, we discuss the basic pathomechanisms underpinning asthma, and the potential role of CHMs in treating asthma with modulating autophagy.

Aberrant DNA methylation is critical for development and progression of breast cancer. We investigated the association of CpG island methylation in candidate genes and clinicopathological features in 65 African-American (AA) and European-American (EA) breast cancer patients. Quantitative methylation analysis was carried out on bisulfite modified genomic DNA and sequencing (pyrosequencing) for promoter CpG islands of p16, ESR1, RASSF1A, RARβ2, CDH13, HIN1, SFRP1 genes and the LINE1 repetitive element using matched paired non-cancerous and breast tumor specimen (32 AA and 33 EA women). Five of the genes, all known tumor suppressor genes (RASSF1A, RARβ2, CDH13, HIN1 and SFRP1), were found to be frequently hypermethylated in breast tumor tissues but not in the adjacent non-cancerous tissues. Significant differences in the CDH13 methylation status were observed by comparing DNA methylation between AA and EA patients, with more obvious CDH13 methylation differences between the two patient groups in the ER- disease and among young patients (age<50). In addition, we observed associations between CDH13, SFRP1, and RASSF1A methylation and breast cancer subtypes and between SFRP1 methylation and patient's age. Furthermore, tumors that received neoadjuvant therapy tended to have reduced RASSF1A methylation when compared with chemotherapy naïve tumors. Finally, Kaplan Meier survival analysis showed a significant association between methylation at 3 loci (RASSF1A, RARβ2 and CDH13) and reduced overall disease survival. In conclusion, the DNA methylation status of breast tumors was found to be significantly associated with clinicopathological features and race/ethnicity of the patients.

Chlamydia is a zoonotic pathogen that mainly infects poultry and pet birds. This Gram-negative obligate intracellular parasite also causes human psittacosis, the severity of which varies from mild flu-like symptoms to life-threatening severe pneumonia, including sepsis, acute respiratory distress syndrome, and multiple organ failure. Inhalation of aerosols from contaminated bird excreta through the respiratory tract is the main route of transmission to humans. Here, we present a case of pneumonia accompanied by lower extremity atherosclerotic occlusive disease. A 48-year-old man was admitted to the emergency department with a four-day history of cough and dyspnea. A detailed history revealed his contact with domestic pigeons. The results of metagenomic next-generation sequencing of bronchoalveolar lavage fluid suggested infection. Antibacterial agents were switched to targeted doxycycline, but in the next week, skin examination revealed acrocyanosis of both lower extremities, and the remarkable palpable purpura progressively worsened. Re-examination of the lower extremity vascular ultrasound suggested left dorsalis pedis artery occlusion and right peroneal vein thrombosis, which resulted in the amputation of both legs. This case is the first report of pneumonia combined with arterioocclusive sclerosis of both lower extremities.

Background The current study aimed to comprehensively analyze the clinical prognostic factors of malignant esophageal fistula (MEF). Furthermore, this study sought to establish and validate prognostic nomograms incorporating radiomics and clinical factors to predict overall survival and median survival after fistula for patients with MEF. Methods The records of 76 patients with MEF were retrospectively analyzed. A stepwise Cox proportional hazards regression model was employed to screen independent prognostic factors and develop clinical nomograms. Radiomic features were extracted from prefistula CT images and post fistula CT images. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression algorithm was used to filter radiomic features and avoid overfitting. Radiomic signature was a linear combination of optimal features and corresponding coefficients. The joint prognostic nomograms was constructed by radiomic signatures and clinical features. All models were validated by Harrell's concordance index (C‐index), caliberation and bootstrap validation. Results For overall survival, age, prealbumin, KPS and interval between diagnosis of esophageal cancer and fistula were identified as independent prognostic factors and incorporated into the clinical nomogram. Age, prealbumin, serum albumin, KPS and neutrophil proportion were selected for the clinical nomogram of post fistula survival. The C‐index of overall survival nomogram was 0.719 (95% CI: 0.645–0.793) and that was 0.722 (95% CI: 0.653–0.791) in the post fistula survival nomogram. The radiomic signature developed by radiomic features of prefistula CT showed a significant correlation with both overall survival and post fistula survival. The C‐index of joint nomogarm for overall survival and post fistula survival was 0.831 (95% CI: 0.757–0.905) and 0.77 (95% CI: 0.686–0.854), respectively. The calibration curve showed the joint nomograms outperformed the clinical ones. Conclusions The study presents nomograms incorporating independent clinical risk factors and radiomic signature to predict the prognosis of MEF. This prognostic classification system has the potential to guide therapeutic decisions for patients with malignant esophageal fistulas. The study presents nomograms incorporating independent clinical risk factors and radiomic signature to predict the prognosis of malignant esophageal fistula. This risk classification system has the potential to guide therapeutic decisions for patients with malignant esophageal fistula.

Androgens are essential for the growth of most prostate cancers (PCa). As a result, androgen ablation is the mainstay of the treatment of PCa. Proteins of the polycomb and trithorax family are master epigenetic regulators of cell type specific gene expression including androgen receptor. We interrogated epigenetic changes of a 24-gene panel corresponding to polycomb and trithorax genes by PCR array and differential gene expression by quantitative real time-PCR on prostate cancer cell line (LNCaP) treated with the synthetic ligand R1881. We observed the highest methylation for CBX2, PCGF6, PHC2, EZH2 and TRIM27 genes and the lowest methylation for CBX8 and PCGF2 (p<0.05), and a modest decrease in the expression of EZH2. Differential methylation profiles of polycomb and trithorax genes may contribute to the dynamics of prostate carcinogenesis.

Purpose Lung cancer (LC) is the most common malignancy in the world. It is well that hypoxia is common in lung cancer, which contributes to lung cancer progression and metastasis [ 1 ]. miRNA-27a as a repressor factor is a lowly expression within non-small cell lung cancer (NSCLC). However, the molecular mechanism between miR-27a and hypoxia in lung cancer progression remains poorly understood. This study aims to explore hypoxia promotes epithelial-mesenchymal transition in lung cancer cells via regulating the NRF2/miR‑27a/ BUB1 pathway. Methods We detect the expression of miR-27a after exposure to hypoxia conditions in lung cancer cells via qPCR. Using MTT assay and colony assay to assess the ability of proliferation in lung cancer cells under hypoxia or transfect miR-27a mimics. The capability of migration and invasion was evaluated by wound healing assay and Boyden-chamber assay. The mRNA and protein expression of EMT markers was respectively detected by qPCR and western blot. We detected NRF2 occupancy at the miR-27a promoter by ChIP-Seq analysis. Meanwhile, the luciferase assay verified BUB1 as a direct target of miR-27a. Results We found hypoxia promotes lung cancer cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process by inhibiting the miR-27a expression. miR-27a mimics significantly reduced the promotion effect of hypoxia on the invasion and proliferation of lung cancer cells. NRF2 as regulating the oxidation/anti-oxidation factor was activated under hypoxia conditions. The activation of NRF2 repressed miR-27a expression. On the contrary, the inhibitory effect of hypoxia on miR-27a was reversed when the NFE2L2 gene was silenced. Ectopic expression of NRF2 inhibited miR-27a expression under normoxia. We further validated BUB1 as a direct target of the miR-27a by luciferase assay. Conclusion Hypoxia promotes invasion and epithelial-mesenchymal transition of Lung cancer cells by regulating the NRF2/miR-27a/ BUB1 axis.

We hypothesized that ancestry-mediated methylated DNA changes may drive racial and ethnic disparity in prostate cancer (PCa). To test this hypothesis, we analyzed genetic ancestry and association with DNA methylation changes in PCa disparity. Pyrosequencing and ancestry informative markers were used for DNA methylation and genetic ancestry testing, respectively. Using Spearman rho rank correlation test, the data demonstrated significant (p<0.05) and variable association between African-American ancestry and DNA methylation for all genes investigated in prostate tissues. Genetic ancestry influences DNA methylation and this modifying factor must be considered in epigenetic association studies in populations of admixed patients.