BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications

Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma

Small non-coding RNAs, in particular microRNAs(miRNAs), regulate fine-tuning of gene expression and can act as oncogenes or tumor suppressor genes. Differential miRNA expression has been reported to be of functional relevance for tumor biology. Using next-generation sequencing, the unbiased and absolute quantification of the small RNA transcriptome is now feasible. Neuroblastoma(NB) is an embryonal tumor with highly variable clinical course. We analyzed the small RNA transcriptomes of five favorable and five unfavorable NBs using SOLiD next-generation sequencing, generating a total of >188 000 000 reads. MiRNA expression profiles obtained by deep sequencing correlated well with real-time PCR data. Cluster analysis differentiated between favorable and unfavorable NBs, and the miRNA transcriptomes of these two groups were significantly different. Oncogenic miRNAs of the miR17-92 cluster and the miR-181 family were overexpressed in unfavorable NBs. In contrast, the putative tumor suppressive microRNAs, miR-542-5p and miR-628, were expressed in favorable NBs and virtually absent in unfavorable NBs. In-depth sequence analysis revealed extensive post-transcriptional miRNA editing. Of 13 identified novel miRNAs, three were further analyzed, and expression could be confirmed in a cohort of 70 NBs

From gradual spreading to catastrophic collapse - Reconstruction of the 1888 Ritter Island volcanic sector collapse from high-resolution 3D seismic data

Volcanic island flank collapses have the potential to trigger devastating tsunamis threatening coastal communities and infrastructure. The 1888 sector collapse of Ritter Island, Papua New Guinea (in the following called Ritter) is the most voluminous volcanic island flank collapse in historic times. The associated tsunami had run-up heights of more than 20 m on the neighboring islands and reached settlements 600 km away from its source. This event provides an opportunity to advance our understanding of volcanic landslide-tsunami hazards. Here, we present a detailed reconstruction of the 1888 Ritter sector collapse based on high-resolution 2D and 3D seismic and bathymetric data covering the failed volcanic edifice and the associated mass-movement deposits. The 3D seismic data reveal that the catastrophic collapse of Ritter occurred in two phases: (1) Ritter was first affected by deep-seated, gradual spreading over a long time period, which is manifest in pronounced compressional deformation within the volcanic edifice and the adjacent seafloor sediments. A scoria cone at the foot of Ritter acted as a buttress, influencing the displacement and deformation of the western flank of the volcano and causing shearing within the volcanic edifice. (2) During the final, catastrophic phase of the collapse, about 2.4 km³ of Ritter disintegrated almost entirely and travelled as a highly energetic mass flow, which incised the underlying sediment. The irregular topography west of Ritter is a product of both compressional deformation and erosion. A crater-like depression underlying the recent volcanic cone and eyewitness accounts suggest that an explosion may have accompanied the catastrophic collapse. Our findings demonstrate that volcanic sector collapses may transform from slow gravitational deformation to catastrophic collapse. Understanding the processes involved in such a transformation is crucial for assessing the hazard potential of other volcanoes with slowly deforming flanks such as Mt. Etna or Kilauea

RV SONNE 252 Cruise Report / Fahrtbericht, Yokohama : 05.11.2016 - Nouméa : 18.12.2016. SO252 : RITTER ISLAND Tsunami potential of volcanic flank collapses

Large volcanic debris flows associated with volcanic island flank collapses may cause devastating tsunamis as they enter the ocean. Computer simulations show that the largest of these volcanic debris flows on oceanic islands such as Hawaii or the Canaries can cause ocean-wide tsunamis (Løvholt et al., 2008; Waythomas et al., 2009). However, the magnitude of these tsunamis is subject to on-going debate as it depends particularly on landslide transport and emplacement processes (Harbitz et al. 2013). A robust understanding of these factors is thus essential in order to assess the hazard of volcanic flank collapses. Recent studies have shown that emplacement processes are far more complex than assumed previously. With a collapsed volume of about 5 km3 the 1888 Ritter Island flank collapse is the largest in historic times and represents an ideal natural laboratory for several reasons: (I) The collapse is comparatively young and the marine deposits are clearly visible, (II) the pre-collapse shape of the island is historically documented and (III) eyewitness reports documenting tsunami arrival times, run-up heights and inundation levels on neighboring islands are available. We propose to collect bathymetric, high resolution 2D and 3D seismic data as well as seafloor samples from the submarine deposits off Ritter Island to learn about the mobility and emplacement dynamics of the 1888 flank collapse landslide. A comparison to similar studies from other volcanic islands will provide an improved understanding of emplacement processes of volcanic island landslides and their overall tsunamigenic potential. In addition, a detailed knowledge of the 1888 landslide processes in combination with tsunami constraints from eyewitness reports provides a unique possibility to determine the landslide velocity, which can then be used in subsequent hazard analyses for ocean islands.peer-reviewe

Associations between depressive symptoms and disease progression in older patients with chronic kidney disease: results of the EQUAL study

Background Depressive symptoms are associated with adverse clinical outcomes in patients with end-stage kidney disease; however, few small studies have examined this association in patients with earlier phases of chronic kidney disease (CKD). We studied associations between baseline depressive symptoms and clinical outcomes in older patients with advanced CKD and examined whether these associations differed depending on sex. Methods CKD patients (>= 65 years; estimated glomerular filtration rate <= 20 mL/min/1.73 m(2)) were included from a European multicentre prospective cohort between 2012 and 2019. Depressive symptoms were measured by the five-item Mental Health Inventory (cut-off <= 70; 0-100 scale). Cox proportional hazard analysis was used to study associations between depressive symptoms and time to dialysis initiation, all-cause mortality and these outcomes combined. A joint model was used to study the association between depressive symptoms and kidney function over time. Analyses were adjusted for potential baseline confounders. Results Overall kidney function decline in 1326 patients was -0.12 mL/min/1.73 m(2)/month. A total of 515 patients showed depressive symptoms. No significant association was found between depressive symptoms and kidney function over time (P = 0.08). Unlike women, men with depressive symptoms had an increased mortality rate compared with those without symptoms [adjusted hazard ratio 1.41 (95% confidence interval 1.03-1.93)]. Depressive symptoms were not significantly associated with a higher hazard of dialysis initiation, or with the combined outcome (i.e. dialysis initiation and all-cause mortality). Conclusions There was no significant association between depressive symptoms at baseline and decline in kidney function over time in older patients with advanced CKD. Depressive symptoms at baseline were associated with a higher mortality rate in men

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements