Hypermethylation of CpG islands and shores around specific microRNAs and mirtrons is associated with the phenotype and presence of bladder cancer

PURPOSE To analyze the role and translational potential for hypermethylation of CpG islands and shores in the regulation of small RNAs within urothelial cell carcinoma (UCC). To examine microRNAs (miR) and mirtrons, a new class of RNA located within gene introns and processed in a Drosha-independent manner. EXPERIMENTAL DESIGN The methylation status of 865 small RNAs was evaluated in normal and malignant cell lines by using 5-azacytidine and microarrays. Bisulfite sequencing was used for CpG regions around selected RNAs. Prognostic and diagnostic associations for epigenetically regulated RNAs were examined by using material from 359 patients, including 216 tumors and 121 urinary samples (68 cases and 53 controls). Functional analyses examined the effect of silencing susceptible RNAs in normal urothelial cells. RESULTS Exonic/UTR-located miRs and mirtons are most susceptible to epigenetic regulation. We identified 4 mirtrons and 16 miRs with CpG hypermethylation across 35 regions in normal and malignant urothelium. For several miRs, hypermethylation was more frequent and dense in CpG shores than islands (e.g., miRs-9/149/210/212/328/503/1224/1227/1229), and was associated with tumor grade, stage, and prognosis (e.g., miR-1224 multivariate analysis OR = 2.5; 95% CI, 1.3-5.0; P = 0.006). The urinary expression of epigenetically silenced RNAs (miRs-152/328/1224) was associated with the presence of UCC (concordance index, 0.86; 95% CI, 0.80-0.93; ANOVA P < 0.016). CONCLUSIONS Hypermethylation of mirtrons and miRs is common in UCC. Mirtrons appear particularly susceptible to epigenetic regulation. Aberrant hypermethylation of small RNAs is associated with the presence and behavior of UCC, suggesting potential roles as diagnostic and prognostic biomarkers

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JUDY COCHRAN: Editorial MICHAEL TANGEMAN: Haikus 2-5 ELISE ALBRECHT, CURTIS PLOWGIAN: French Calligrams 6 JASON VARDEN: Waiting 7 ALEXANDER GREEN: Photo 8 EDUARDO JARAMILLO: Formas violentas 9-11 GABRIELE DILLMANN: Photo 12 MICHAEL GOLDSBERG: Funf fur Ashley 13 MEGAN CARLSON: Fur Jared (German) 14 MAGGIE GLOVER: For Jared 14-15 CHRIS FAUR: Painting 16 LINDSEY ESHELMAN: Stuhl (The Chair) 17 HALLE THOMPSON, GWENN DOBOS: Les Bouches 18 JILL BOO: Lacheln (A Smile) 19 ALEXANDER GREEN: Photo 20 JULIA GRAWEMEYER: Villanelle 21, Expressions francaises (French Figures) 22-23, Pour me rappeler (So that I\u27d remember) 24 MICHEL CLIQUET: Photo 25 CHARLES O\u27KEEFE: Photos 26-28 LINE LERYCKE: Photos 29-32 MICHEL CLIQUET: Pierre docile (Docile Stone) 29-32 LOGAN FAVIA: Ataraxia 33 AVRITA SINGH: Absence 34 RACHEL GROTHEER: Compassion 35, Ligne (Line) 36, Nuit, douce nuit (Night, gentle night) 37, Rouge (Red) 38, Bonjour Bleu (Hello Blue) 39, Ligne courbe (Curved Line) 40 AMELIA DUNLAP: Compassion 41-42 KYLE SIMPSON: Separation 43 ALEXANDER GREEN: Photo 44 GWENN DOBOS: Ataraxia 45 SARAH SLOTKIN: Separation 46 CURTIS PLOWGIAN: Absence 47 ELISA VER MERRIS: Photo 48, Attachement (Attachment) 49 JENNIFER JOHNSON: Attachement (Attachment)50 ANNA KELLY: Compassion 51 RICHARD BANAHAN: Photo 52, Mon grand-pere et moit (My grandfather and me) 53 MEREDITH KATZ: Separation 54 BRENDA HEATER: Compassion 55 ZACHARY WALSH: Ataraxia 56 MICHEL CLIQUET: Photos 57-5

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

First low-frequency Einstein@Home all-sky search for continuous gravitational waves in Advanced LIGO data

We report results of a deep all-sky search for periodic gravitational waves from isolated neutron stars in data from the first Advanced LIGO observing run. This search investigates the low frequency range of Advanced LIGO data, between 20 and 100 Hz, much of which was not explored in initial LIGO. The search was made possible by the computing power provided by the volunteers of the Einstein@Home project. We find no significant signal candidate and set the most stringent upper limits to date on the amplitude of gravitational wave signals from the target population, corresponding to a sensitivity depth of 48.7 [1/root Hz]. At the frequency of best strain sensitivity, near 100 Hz, we set 90% confidence upper limits of 1.8 x 10(-25). At the low end of our frequency range, 20 Hz, we achieve upper limits of 3.9 x 10(-24). At 55 Hz we can exclude sources with ellipticities greater than 10(-5) within 100 pc of Earth with fiducial value of the principal moment of inertia of 10(38) kg m(2)