MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs that posttranscriptionally repress expression of target genes through imperfect base pairing with the 3 ¶ untranslated region. We previously reported amplification and overexpression of the miR-17-92 miRNA cluster at 13q31.3 in lung cancers, as well as growth inhibition by treatment with antisense oligonucleotides against miR-17-5p and miR-20a, constituents of miR-17-92, specifically in miR-17-92-overexpressing lung cancer cell lines. Although these findings clearly suggested important roles of miR-17-92 overexpression in lung cancers, only a few targets for the miR-17-92 cluster have been identified thus far. In this study, we identified hypoxiainducible factor (HIF)-1A as a novel direct target for miR-17-92 through global expression profiling by mass spectrometric analysis using an isobaric tagging reagent, iTRAQ, combined with bioinformatic target prediction. This is the first report to describe negative regulation of HIF-1A by miRNA, which seemed to occur without disrupting the induction of HIF-1A for cellular adaptation to hypoxia. In addition, overexpression of c-myc led to down-regulation of HIF-1A and induction of miR-17-92, the latter of which was previously reported to be a transcriptional activation activity, suggesting that the induction of miR-17-92 may play a role at least in part in c-myc-mediated repression of HIF-1A. Together with previous reports on the functional negative regulation of c-myc by HIF-1A, our findings suggest the possible existence of an intricate and finely tuned circuit involving c-myc, miR-17-92, and HIF-1A that may play a role in cancer cell proliferation under normoxia in a cellular context-dependent manner.

IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA.

Background Duodenal endoscopic submucosal dissection (ESD) remains technically challenging, with a high risk of severe adverse events. Because exposure of the duodenal post-ESD mucosal defect to pancreatic juice and bile acid reportedly induces delayed perforation and bleeding, we examined whether defect closure using an over-the-scope clip (OTSC) system was useful for preventing postoperative adverse events. Methods From April 2016 to February 2017, a total of 50 consecutive patients with superficial non-ampullary duodenal epithelial tumors (SNADETs) larger than 10 mm, with no more than semi-circumferential spread, were prospectively enrolled in this study. All of the lesions were treated by experienced ESD operators and the post-ESD mucosal defect was closed using OTSCs. Results All of the SNADETs were completely removed by ESD, with an R0 resection rate of 88.0 %. The mean procedure and closure times were 67.3 ± 58.8 minutes and 9.8 ± 7.2 minutes, respectively. Although complete defect closure was achieved in 94.0 % of the patients (47/50), two patients required surgical conversion. Delayed perforation occurred in only one patient (2.1 %), who did not have successful closure of the defect, as misplacement of the OTSC exposed the muscle layer. Meanwhile, delayed bleeding occurred in three patients (6.3 %); however, the bleeding was easily controlled using endoscopic coagulation. The mean duration of postoperative hospitalization was 5.5 ± 7.2 days. Conclusions Prophylactic defect closure using OTSCs may be effective in reducing severe adverse events after duodenal ESD.

Endoscopic submucosal dissection (ESD) is known as a curative treatment for colorectal superficial neoplasms. There is however a need for more long-term clinical data to establish the full advantages of colorectal ESD regarding very low recurrence rates. The aim of this retrospective study was to determine long-term clinical outcomes of colorectal ESD. A total of 423 lesions treated by ESD for colorectal adenoma/dysplasia or adenocarcinoma between 1998 and 2008 at a single high volume referral center were included. We conducted a retrospective survey on patients with follow-up and obtained complete 1-, 3-, and 5-year outcome data for 358 (85 %), 292 (69 %), and 209 (49 %) lesions, respectively. Curative resection was defined when the pathological specimen had carcinoma-free resection margins, irrespective of piecemeal or en bloc resection, without submucosal deep invasion (≥ 1000 µm), lymphovascular involvement, or a poorly differentiated adenocarcinoma component.After a median 4.9 years of follow-up, the 3-year overall cumulative endoscopic recurrence rate and cancerous recurrence rate were 2.9 % (95 % confidence interval [95 %CI] 1.2 - 4.7) and 1.1 % (0 - 2.1), respectively. The 5-year overall cumulative endoscopic recurrence and cancerous recurrence rates were 3.8 % (1.7 - 5.9) and 1.6 % (0.1 - 3.0), respectively. In 361 lesions eligible for endoscopic follow-up, the 3-year endoscopic recurrence and cancerous recurrence rates were 2.4 % (0.8 - 4.1) and 0.4 % (0 - 1.4), respectively. Multivariate analysis revealed that piecemeal resection and submucosal deep tumor invasion were associated with recurrence. The current study demonstrated favorable long-term clinical outcomes of colorectal ESD when en bloc curative resection is achieved.

Small-cell lung cancer (SCLC) is a highly aggressive disease that exhibits rapid growth and genetic instability. We found earlier frequent overexpression of the miR-17-92 microRNA cluster, and showed that SCLC cells were addicted to continued expressions of miR-17-5p and miR-20a, major components of this microRNA cluster. In this study, we identified the frequent presence of constitutively phosphorylated H2AX (c-H2AX), which reflects continuing DNA damage, preferentially in SCLC. Knockdown of RB induced c-H2AX foci formation in non-small cell lung cancer (NSCLC) cells with wild-type RB, in association with growth inhibition and reactive oxygen species (ROS) generation, which was canceled by overexpression of miR-17-92. Conversely, induction of c-H2AX was observed in a miR-17-92-overexpressing SCLC cell line with miR-20a antisense oligonucleotides. These findings suggest that miR-17-92 overexpression may serve as a fine-tuning influence to counterbalance the generation of DNA damage in RB-inactivated SCLC cells, thus reducing excessive DNA damage to a tolerable level and consequently leading to genetic instability. Therefore, miR-17-92 may be an excellent therapeutic target candidate to elicit excessive DNA damage in combination with DNA-damaging chemotherapeutics.