Rationale: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized.Objectives: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD.Methods: Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. Measurements and Main Results:A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD.Conclusions: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.Keywords: interstitial lung disease; rheumatoid arthritis; subclinical; biomarkers; risk prediction
Epithelial ovarian cancer (EOC) is a highly lethal gynaecological malignancy. Cisplatin is the basal chemotherapeutic agent used to treat EOC, but resistance to cisplatin leads to chemotherapy failure. MicroRNAs are a novel class of regulators that function by controlling gene expression at the post-transcriptional level. Several recent reports have identified some microRNAs that are related to chemotherapy sensitivity. In this study, we found two microRNAs miR-152 and miR-185 that were significantly downregulated in the cisplatin-resistant ovarian cell lines SKOV3/DDP and A2780/DDP, compared with their sensitive parent line SKOV3 and A2780, respectively. Subsequently, the roles of miR-152 and miR-185 were evaluated in vitro and in vivo. The overexpression of miR-152 or miR-185 increased cisplatin sensitivity of SKOV3/DDP and A2780/DDP cells by inhibiting proliferation and promoting apoptosis, then we further confirmed that these miRNAs functioned through suppressing DNA methyltransferase 1 (DNMT1) directly. Concordantly, CD-1/CD-1 nude mice that were injected intraperitoneally with SKOV3/DDP cells transfected with miR-152 mimics exhibited upregulated cisplatin sensitivity in vivo. Interestingly, we found that there were no significant changes in the expression of these two microRNAs after treatment with decitabine (DAC), a traditional epigenetic therapeutic agent, suggesting these miRNAs represented two new regulators independent of DAC. Finally, the survival assay in A549 and HepG2 cells revealed that the two microRNAs involved in cisplatin sensitivity were related to cell types. Our results indicated that miR-152 and miR-185 were involved in ovarian cancer cisplatin resistance in vitro and in vivo by targeting DNMT1 directly. These molecules may serve as potential epigenetic therapeutic targets in other cancers.
Summary Lung cancer is an extremely heterogeneous disease, and its treatment remains one of the most challenging tasks in medicine. Few existing laboratory lung cancer models can faithfully recapitulate the diversity of the disease and predict therapy response. Here, we establish 12 patient-derived organoids from the most common lung cancer subtype, lung adenocarcinoma (LADC). Extensive gene and histopathology profiling show that the tumor organoids retain the histological architectures, genomic landscapes, and gene expression profiles of their parental tumors. Patient-derived lung cancer organoids are amenable for biomarker identification and high-throughput drug screening in vitro . This study should enable the generation of patient-derived lung cancer organoid lines, which can be used to further the understanding of lung cancer pathophysiology and to assess drug response in personalized medicine.
Heme oxygenase-1 (HO-1) has been implicated in cardiac dysfunction, oxidative stress, inflammation, apoptosis and autophagy associated with heart failure, and atherosclerosis, in addition to its recognized role in metabolic syndrome and diabetes. Numerous studies have presented contradictory findings about the role of HO-1 in diabetic cardiomyopathy (DCM). In this study, we explored the role of HO-1 in myocardial dysfunction, myofibril structure, oxidative stress, inflammation, apoptosis and autophagy using a streptozotocin (STZ)-induced diabetes model in mice systemically overexpressing HO-1 (Tg-HO-1) or mutant HO-1 (Tg-mutHO-1). The diabetic mouse model was induced by multiple peritoneal injections of STZ. Two months after injection, left ventricular (LV) function was measured by echocardiography. In addition, molecular biomarkers related to oxidative stress, inflammation, apoptosis and autophagy were evaluated using classical molecular biological/biochemical techniques. Mice with DCM exhibited severe LV dysfunction, myofibril structure disarray, aberrant cardiac oxidative stress, inflammation, apoptosis, autophagy and increased levels of HO-1. In addition, we determined that systemic overexpression of HO-1 ameliorated left ventricular dysfunction, myofibril structure disarray, oxidative stress, inflammation, apoptosis and autophagy in DCM mice. Furthermore, serine/threonine-specific protein kinase (Akt) and AMP-activated protein kinase (AMPK) phosphorylation is normally inhibited in DCM, but overexpression of the HO-1 gene restored the phosphorylation of these kinases to normal levels. In contrast, the functions of HO-1 in DCM were significantly reversed by overexpression of mutant HO-1. This study underlines the unique roles of HO-1, including the inhibition of oxidative stress, inflammation and apoptosis and the enhancement of autophagy, in the pathogenesis of DCM.
The transition from liver fibrosis to hepatocellular carcinoma (HCC) has been suggested to be a continuous and developmental pathological process. MicroRNAs (miRNAs) are recently discovered molecules that regulate the expression of genes involved in liver disease. Many reports demonstrate that miR-483-5p and miR-483-3p, which originate from miR-483, are up-regulated in HCC, and their oncogenic targets have been identified. However, recent studies have suggested that miR-483-5p/3p is partially down-regulated in HCC samples and is down-regulated in rat liver fibrosis. Therefore, the aberrant expression and function of miR-483 in liver fibrosis remains elusive. In this study, we demonstrate that overexpression of miR-483 in vivo inhibits mouse liver fibrosis induced by CCl4. We demonstrate that miR-483-5p/3p acts together to target two pro-fibrosis factors, platelet-derived growth factor-β and tissue inhibitor of metalloproteinase 2, which suppress the activation of hepatic stellate cells (HSC) LX-2. Our work identifies the pathway that regulates liver fibrosis by inhibiting the activation of HSCs.
Electronic cigarettes are the most commonly used nicotine containing product among teenagers. The oral epithelium is the first site of exposure and our recent work revealed considerable diversity among e-liquids for composition and level of chemical constituents that impact nicotine deposition in a human oral-trachea cast and affect the formation of reactive carbonyls. Here we evaluate the dose response for cytotoxicity and genotoxicity of e-cigarette-generated aerosols from ten diverse flavored e-liquid products with and without nicotine compared to unflavored in three immortalized oral epithelial cell lines. Three e-liquids, Blue Pucker, Love Potion, and Jamestown caused ≥20% cell toxicity assessed by the neutral red uptake assay. Nine products induced significant levels of oxidative stress up to 2.4-fold quantified by the ROS-Glo assay in at least one cell line, with dose response seen for Love Potion with and without nicotine across all cell lines. Lipid peroxidation detected by the TBARs assay was less common among products; however, dose response increases up to 12-fold were seen for individual cell lines. Micronuclei formation indicative of genotoxicity was increased up to 5-fold for some products. Blue Pucker was the most genotoxic e-liquid, inducing micronuclei across all cell lines irrespective of nicotine status. A potency score derived from all assays identified Blue Pucker and Love Potion as the most hazardous e-liquids. These in vitro acute exposure studies provide new insight about the potential for some flavored vaping products to induce significant levels of oxidative stress and genotoxicity.
The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p<0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2′-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45% (118/262) lung tumors and 55% (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51%) compared to squamous cell carcinoma (17/62, 27%), p<0.001; HR=3.513 (CI: 1.818–6.788); and in smokers (73/128, 57%) than never-smokers (28/72, 39%), p=0.014; HR=2.086 (CI: 1.157–3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients’ smoking history, and contributes to miR-486-5p repression.
Background COPD is the third leading cause of death in the United States. Cigarette smoking accelerates the age-related forced expiratory volume in 1 s (FEV 1 ) decline, an important determinant for the genesis of COPD. Hispanic smokers have lower COPD prevalence and FEV 1 decline than non-Hispanic whites (NHWs). Patients and methods A nutritional epidemiological study was conducted in the Lovelace Smokers cohort (LSC; n=1,829) and the Veterans Smokers cohort (n=508) to identify dietary nutrients (n=139) associated with average FEV 1 and its decline and to assess whether nutrient intakes could explain ethnic disparity in FEV 1 decline between Hispanics and NHW smokers. Results Nutrients discovered and replicated to be significantly associated with better average FEV 1 included magnesium, folate, niacin, vitamins A and D, eicosenoic fatty acid (20:1n9), eicosapentaenoic acid (20:5n3), docosapentaenoic acid (DPA; 22:5n3), docosahexaenoic acid (22:6n3), and fiber. In addition, greater intakes of eicosenoic fatty acid and DPA were associated with slower FEV 1 decline in the LSC. Among omega 3 polyunsaturated fatty acids, DPA is the most potent nutrient associated with better average FEV 1 and slower FEV 1 decline. Adverse effect of continuous current smoking on FEV 1 decline was completely negated in LSC members with high DPA intake (>20 mg/day). Slower FEV 1 decline in Hispanics compared to NHWs may be due to the greater protection of eicosenoic fatty acid and DPA for FEV 1 decline rather than greater intake of protective nutrients in this ethnic group. Conclusion The protective nutrients for the preservation of FEV 1 in ever smokers could lay foundation for designing individualized nutritional intervention targeting “optimal physiological levels” in human to improve lung function in ever smokers. Ethnic disparity in FEV 1 decline may be explained by difference in magnitude of protection of dietary intakes of eicosenoic fatty acid and DPA between Hispanics and NHWs.
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