Regulation der Genexpression von MYCN in humanen Neuoblastomzellen durch Transkriptionsfaktoren der E2F-Familie

Seit fast 30 Jahren ist bekannt, dass die Amplifikation und Expression des Onkogens MYCN in Neuroblastomen mit einer sehr ungünstigen Prognose für die Patienten einhergeht. Dennoch liegen die Mechanismen der Genregulation von MYCN weiterhin größtenteils im Dunkeln. Die Präsenz potentieller Bindungsstellen für E2F-Proteine im Promotor des MYCN-Gens sowie Zellkulturexperimente lieferten Hinweise auf eine Rolle der Transkriptionsfaktoren der E2F-Familie in der Regulation der N-myc-Expression. Ziel dieser Arbeit war die Beantwortung der Frage, ob E2F-Proteine notwendig sind, um eine primär hohe Expression von N-myc in Neuroblastomzellen mit Amplifikation des Onkogens aufrechtzuerhalten, und ob sie hinreichend sind, um die Transkription von MYCN in Zellen ohne endogene Expression von N-myc einzuleiten. Durch Überexpression des Tumorsuppressorproteins p16, welches zu einer Inaktivierung endogener E2F-Proteine führt, konnte die MYCN-mRNA-Menge in Neuroblastomzellen deutlich gesenkt werden. Vergleichbare Resultate wurden durch Expression von dominant negativem E2F-1 erzielt. Da in einigen Studien gezeigt werden konnte, dass Myc-Proteine ihrerseits E2F-Gene aktivieren können, nehmen wir an, in aggressiven Neuroblastomen könnte eine positive Rückkopplungsschleife zwischen E2F-Transkriptionsfaktoren auf der einen und N-myc auf der anderen Seite existieren, die die gesteigerte Aktivität des MYCN-Onkogens aufrechterhält. Stabil transfizierte E2F-ER-Fusionsproteine waren jedoch nicht in der Lage, das endogene MYCN-Gen in Neuroblastomzellen ohne Expression von N-myc anzuschalten. E2F-Proteine werden folglich für das volle Ausmaß der starken Expression von N-myc in Neuroblastomen benötigt, sind aber nicht ausreichend, um das Onkogen MYCN in Zellen ohne endogenes N-myc zu aktivieren. In der Zukunft könnte durch Verhinderung der Bindung von E2F-Proteinen an den MYCN-Promotor oder durch gentherapeutische Ansätze, die z.B. mittels viraler Infektion den Signalweg zwischen p16 und E2F rekonstruieren, die Expression von N-myc in Neuroblastomen gesenkt werden, so dass die Aggressivität der Tumore reduziert und die individuelle Prognose der Patienten verbessert werden könnte

The HIPASS Catalogue - II. Completeness, Reliability, and Parameter Accuracy

The HI Parkes All Sky Survey (HIPASS) is a blind extragalactic HI 21-cm emission line survey covering the whole southern sky from declination -90 to +25. The HIPASS catalogue (HICAT), containing 4315 HI-selected galaxies from the region south of declination +2, is presented in Meyer et al. (2004a, Paper I). This paper describes in detail the completeness and reliability of HICAT, which are calculated from the recovery rate of synthetic sources and follow-up observations, respectively. HICAT is found to be 99 per cent complete at a peak flux of 84 mJy and an integrated flux of 9.4 Jy km/s. The overall reliability is 95 per cent, but rises to 99 per cent for sources with peak fluxes >58 mJy or integrated flux > 8.2 Jy km/s. Expressions are derived for the uncertainties on the most important HICAT parameters: peak flux, integrated flux, velocity width, and recessional velocity. The errors on HICAT parameters are dominated by the noise in the HIPASS data, rather than by the parametrization procedure.Comment: Accepted for publication in MNRAS. 12 pages, 11 figures. Paper with higher resolution figures can be downloaded from http://hipass.aus-vo.or

The Northern HIPASS catalogue - Data presentation, completeness and reliability measures

The Northern HIPASS catalogue (NHICAT) is the northern extension of the HIPASS catalogue, HICAT (Meyer et al. 2004). This extension adds the sky area between the declination range of +2 deg < dec. < +25.5 deg to HICAT's declination range of -90 deg < dec. < +2 deg. HIPASS is a blind HI survey using the Parkes Radio Telescope covering 71% of the sky (including this northern extension) and a heliocentric velocity range of -1,280 km/s to 12,700 km/s . The entire Virgo Cluster region has been observed in the Northern HIPASS. The galaxy catalogue, NHICAT, contains 1002 sources with v_hel > 300 km/s . Sources with -300 km/s < v_hel < 300 km/s were excluded to avoid contamination by Galactic emission. In total, the entire HIPASS survey has found 5317 galaxies identified purely by their HI content. The full galaxy catalogue is publicly-available at .Comment: 12 pages, accepted for publication by MNRA

Chromatic periodic activity down to 120 MHz in a Fast Radio Burst

Fast radio bursts (FRBs) are extragalactic astrophysical transients whose brightness requires emitters that are highly energetic, yet compact enough to produce the short, millisecond-duration bursts. FRBs have thus far been detected between 300 MHz and 8 GHz, but lower-frequency emission has remained elusive. A subset of FRBs is known to repeat, and one of those sources, FRB 20180916B, does so with a 16.3 day activity period. Using simultaneous Apertif and LOFAR data, we show that FRB 20180916B emits down to 120 MHz, and that its activity window is both narrower and earlier at higher frequencies. Binary wind interaction models predict a narrower periodic activity window at lower frequencies, which is the opposite of our observations. Our detections establish that low-frequency FRB emission can escape the local medium. For bursts of the same fluence, FRB 20180916B is more active below 200 MHz than at 1.4 GHz. Combining our results with previous upper-limits on the all-sky FRB rate at 150 MHz, we find that there are 3-450 FRBs/sky/day above 50 Jy ms at 90% confidence. We are able to rule out the scenario in which companion winds cause FRB periodicity. We also demonstrate that some FRBs live in clean environments that do not absorb or scatter low-frequency radiation.Comment: 50 pages, 14 figures, 3 tables, submitte

Sexuality and Body Image After Uterine Artery Embolization and Hysterectomy in the Treatment of Uterine Fibroids: A Randomized Comparison

In this paper the effect of uterine artery embolization (UAE) on sexual functioning and body image is investigated in a randomized comparison to hysterectomy for symptomatic uterine fibroids. The EMbolization versus hysterectoMY (EMMY) trial is a randomized controlled study, conducted at 28 Dutch hospitals. Patients were allocated hysterectomy (n = 89) or UAE (n = 88). Two validated questionnaires (the Sexual Activity Questionnaire [SAQ] and the Body Image Scale [BIS]) were completed by all patients at baseline, 6 weeks, and 6, 12, 18, and 24 months after treatment. Repeated measurements on SAQ scores revealed no differences between the groups. There was a trend toward improved sexual function in both groups at 2 years, although this failed to reach statistical significance except for the dimensions discomfort and habit in the UAE arm. Overall quality of sexual life deteriorated in a minority of cases at all time points, with no significant differences between the groups (at 24 months: UAE, 29.3%, versus hysterectomy, 23.5%; p = 0.32). At 24 months the BIS score had improved in both groups compared to baseline, but the change was only significant in the UAE group (p = 0.009). In conclusion, at 24 months no differences in sexuality and body image were observed between the UAE and the hysterectomy group. On average, both after UAE and hysterectomy sexual functioning and body image scores improved, but significantly so only after UAE

Clinical-decision taking in primary pelvic organ prolapse; the effects of diagnostic tests on treatment selection in comparison with a consensus meeting

INTRODUCTION AND HYPOTHESIS: The objective of the study was to establish the effects of additional diagnostic tests compared to a consensus outcome on treatment selection in primary pelvic organ prolapse. METHODS: Three expert gynecologists individually defined a management plan in 53 patients after magnetic resonance imaging, defecography, urodynamic, and anorectal function test information was provided. These management plans were compared with basic treatment advices in the absence of any test and with consensus advices (opinion-based references). The experts assigned a subjective score (assigned diagnostic value [ADV], 0-100%) to rate the test's relative importance. RESULTS: On average, additional diagnostic testing resulted in a revised initial management plan in 38% of the cases; 24% of the individual management plans did not meet the consensus reference. Overall defecography was regarded most valuable (ADV range 19-65%) vs. magnetic resonance imaging rated least (ADV range 0-37%). CONCLUSIONS: Although additional diagnostic tests frequently led to adaptations of basic treatment proposals, consensus was not reached in a fourth of the case

Comprehensive Geriatric Assessment and Transitional Care in Acutely Hospitalized Patients The Transitional Care Bridge Randomized Clinical Trial

IMPORTANCE Older adults acutely hospitalized are at risk of disability. Trials on comprehensive geriatric assessment (CGA) and transitional care present inconsistent results.OBJECTIVE To test whether an intervention of systematic CGA, followed by the transitional care bridge program, improved activities of daily living (ADLs) compared with systematic CGA alone.DESIGN, SETTING, AND PARTICIPANTS This study was a double-blind, multicenter, randomized clinical trial conducted at 3 hospitals with affiliated home care organizations in the Netherlands between September 1, 2010, and March 1, 2014. In total, 1070 consecutive patients were eligible, 674 (63.0%) of whom enrolled. They were 65 years or older, acutely hospitalized to a medical ward for at least 48 hours with an Identification of Seniors at Risk-Hospitalized Patients score of 2 or higher, and randomized using permuted blocks stratified by study site and Mini-Mental State Examination score (= 24). The dates of the analysis were June 1, 2014, to November 15, 2014.INTERVENTIONS The transitional care bridge program intervention was started during hospitalization by a visit from a community care registered nurse (CCRN) and continued after discharge with home visits at 2 days and at 2, 6, 12, and 24 weeks. The CCRNs applied the CGA care and treatment plan.MAIN OUTCOMES AND MEASURES The main outcome was the Katz Index of ADL at 6 months compared with 2 weeks before admission. Secondary outcomes were mortality, cognitive functioning, time to hospital readmission, and the time to discharge from a nursing home.RESULTS The study cohort comprised 674 participants. Their mean age was 80 years, 42.1% (n = 284) were male, and 39.2%(n = 264) were cognitively impaired at admission. Intent-to-treat analysis found no differences in the mean Katz Index of ADL at 6 months between the intervention arm (mean, 2.0; 95% CI, 1.8-2.2) and the CGA-only arm (mean, 1.9; 95% CI, 1.7-2.2). For secondary outcomes, there were 85 deaths (25.2%) in the intervention arm and 104 deaths (30.9%) in the CGA-only arm, resulting in a lower risk on the time to death within 6 months after hospital admission (hazard ratio, 0.75; 95% CI, 0.56-0.99; P =.045; number needed to treat to prevent 1 death, 16). No other secondary outcome was significant.CONCLUSIONS AND RELEVANCE A systematic CGA, followed by the transitional care bridge program, showed no effect on ADL functioning in acutely hospitalized older patients.</p

A multibeam HI survey of the Virgo cluster - two isolated HI clouds?

International audienceWe have carried out a fully sampled large area (4°× 8°) 21-cm HI line survey of part of the Virgo cluster using the Jodrell Bank multibeam instrument. The survey has a sensitivity some three times better than the standard HIJASS (HI Jodrell All Sky Survey) and HIPASS (HI Parkes All Sky Survey) surveys. We detect 31 galaxies, 27 of which are well-known cluster members. The four new detections have been confirmed in the HIPASS data and by follow-up Jodrell Bank pointed observations. One object lies behind M86, but the other three have no obvious optical counterparts upon inspection of the digital sky survey fields. These three objects were mapped at Arecibo with a smaller 3.6-arcmin half power beam width (HPBW) and a four times better sensitivity than the Jodrell Bank data, which allow an improved determination of the dimensions and location of two of the objects, but surprisingly failed to detect the third. The two objects are resolved by the Arecibo beam, giving them a size far larger than any optical images in the nearby field. To our mass limit of 5 × 107(Deltav/50 km s-1) Msolar and column density limit of 3 × 1018(Deltav/50 km s-1) atom cm-2, these new detections represent only about 2 per cent of the cluster atomic hydrogen mass. Our observations indicate that the HI mass function of the cluster turns down at the low-mass end, making it very different to the field galaxy HI mass function. This is quite different to the Virgo cluster optical luminosity function, which is much steeper than that in the general field. Many of the sample galaxies are relatively gas-poor compared with HI selected samples of field galaxies, confirming the `anaemic spirals' view of Virgo cluster late-type galaxies. The velocity distribution of the HI detected galaxies is also very different to that of the cluster as a whole. There are relatively more high-velocity galaxies in the HI sample, suggesting that they form part of a currently infalling population. The HI sample with optical identifications has a minimum HI column density cut-off more than an order of magnitude above that expected from the sensitivity of the survey. This observed column density is above the normally expected level for star formation to occur. The two detections with no optical counterparts have very much lower column densities than that of the rest of the sample, below the star formation threshold