Acute lung injury (ALI) is a devastating disease characterized by pulmonary edema. Removal of edema from the air spaces is a critical function of the epithelial sodium channel (ENaC) in ALI. The molecular mechanisms behind resolution of pulmonary edema are incompletely understood. MicroRNA’s (miRNA) are crucial gene regulators and are dysregulated in various diseases including ALI. Recent studies suggest that microRNA-16 (miR-16) targets serotonin transporter (SERT) involved in the serotonin (5-HT) transmitter system. Alterations in serotonin levels have been reported in various pulmonary diseases. However, the role of miR-16 on its target SERT, and ENaC, a key ion channel involved in the resolution of pulmonary edema, have not been studied. In the present study, the expression patterns of miR-16, SERT, ENaC and serotonin were investigated in mice exposed to room air and hyperoxia. The effects of miR-16 overexpression on ENaC, SERT, TGF-β and Nedd4 in human alveolar epithelial cells were analyzed. miR-16 and ENaC were downregulated in mice exposed to hyperoxia. miR-16 downregulation in mouse lung was correlated with an increase in SERT expression and pulmonary edema. Overexpression of miR-16 in human alveolar epithelial cells (A549) suppressed SERT and increased ENaCβ levels when compared to control-vector transfected cells. In addition, miR-16 over expression suppressed TGFβ release, a critical inhibitor of ENaC. Interestingly Nedd4, a negative regulator of ENaC remained unaltered in miR-16 over expressed A549 cells when compared to controls. Taken together, our data suggests that miR-16 upregulates ENaC, a major sodium channel involved in resolution of pulmonary edema in ALI.
Background Although patients with acute myeloid leukemia (AML) were shown to have an increased risk of thrombosis, no thrombosis risk assessment scoring system has been developed for AML patients. The Khorana Risk Score (KRS), which has been widely used for thrombosis risk assessment in the clinical setting, was developed on the basis of solid tumor data and has not been validated among AML patients. This study aims to validate the use of the KRS as a thrombosis risk-scoring system among patients with AML. Methods Using data from H. Lee Moffitt Cancer Center and Research Institution’s Total Cancer Care Research Study, we retrospectively identified patients who were histologically confirmed with AML from 2000 to 2018. Clinical and laboratory variables at the time of AML diagnosis were characterized and analyzed. The thrombotic event rate was estimated with the Kaplan-Meier method and compared using the log-rank test. Results A total of 867 AML patients were included in the analysis. The median age at AML diagnosis was 75 years (range, 51–96), and the majority were male (65%, n = 565). A total of 22% ( n = 191), 51% ( n = 445), 24% ( n = 207), and 3% ( n = 24) of patients had a KRS of 0, 1, 2, and 3, respectively. A total of 42 thrombotic events (3% [ n = 6/191] with a KRS of 1; 5% [ n = 23/445] with a KRS of 2; 6.3% [ n = 13/207] with a KRS of 3) were observed, with a median follow-up of 3 months (range, 0.1–307). There was no statistical difference in the risk of thrombosis between these groups ( P = .1949). Conclusions Although there was an increased risk of thrombosis associated with a higher KRS among AML patients with a KRS of 1 to 3, the difference was not statistically significant. Furthermore, only a few patients were found to have a KRS > 3, and this was largely due to pancytopenia, which is commonly associated with AML. These results indicate the need for a better thrombotic risk-scoring system for AML patients.
We tallied the number of possible mutant amino acids in proteins thought to be inactivated early in tumorigenesis and in proteins thought to be inactivated late in tumorigenesis, respectively. Proteins thought to be inactivated early in tumorigenesis, on average, have a greater number of alternative, mutant possibilities, which raises the possibility that the sequential order of mutations associated with cancer development reflects the random chance, throughout life, of a mutagen inactivating a larger versus a smaller target. The hypothesis that the temporal order of genetic changes in cancer reflects mutagen target sizes leads to novel considerations of 1) the mechanisms of the acquisition of cancer hallmarks and 2) cancer screening strategies. Keywordssequential cancer mutations, tumor suppressor proteins, metastasis suppressor proteins Review
Acute lung injury (ALI) is a devastating clinical syndrome manifested by inflammation and decreased lung compliance. Cytokines such as IL‐1b, IL‐6 and IL‐8 have been implicated in the process of inflammation and in chemokine stimulation associated with ALI. Recent studies suggest that circadian clock genes are involved in inflammation disorders; however, the role of these genes in ALI is yet unknown. Therefore, we investigated the role of clock genes on proinflammatory cytokine production in human alveolar epithelial cells (A549). A549 cells were transfected with core clock genes (Bmal1, CLOCK, Cry1/2, Per1, Per2) and subsequently treated with either IL‐1b or hydrogen peroxide. Supernatants were analyzed for the production of IL‐6 and IL‐8. There was a significant decrease in IL‐8 production in cells transfected with core CLOCK genes. However, the level of IL‐6 was unchanged in these cells. Further, A549 cells treated with IL‐1b or hydrogen peroxide after Cry1 and Per2 transfection showed a significant decrease in IL‐6 and IL‐8. Our data suggest that core clock genes may be protective by ameliorating cytokine production thereby offering a potential therapeutic to minimize the clinical severity and mortality of ALI.This work was supported by the AHA 09SDG2260957 and NIH R01 HL105932 grants to N.K.
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