Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer

Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Ceramide in beta cells apoptosis induced by gluco-lipotoxicity:possible role of cer flow for the biosynthesis of complex sphingolipids

CERAMIDE IN BETA CELLS APOPTOSIS INDUCED BY GLUCO-LIPOTOXICITY: POSSIBLE ROLE OF CER FLOW FOR THE BIOSYNTHESIS OF COMPLEX SPHINGOLIPIDS P. Giussani1, H. Le Stunff2, E. Gjoni1, J. Veret2, L. Riboni1, P. Viani1 1Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milano, LITA Segrate, Via Fratelli Cervi, 93, 20090 Segrate (MI) Italy 2Unit\ue9 Biologie Fonctionnelle et Adaptative - EAC CNRS 4413, Laboratoire de Biologie et Pathologie du Pancr\ue9as Endocrine, Universit\ue9 PARIS- DIDEROT (7),4, rue Marie-Andr\ue9e Lagroua Weill-Halle, 75205 PARIS Cedex 13 France Background: In type 2 diabetes the detrimental effects of chronic exposure to NEFA, in particular palmitate, on beta cell function and viability have been correlated to hyperglycaemia. De novo synthesis of ceramide (Cer) and ER stress are among the molecular pathways and regulators involved in these negative effects. In order to gain insight into the molecular mechanism(s) of gluco-lipotoxicity we studied the effect of palmitate and high glucose concentrations on ceramide metabolism in INS-1 cells. Results: The results obtained demonstrated that in INS-1 cells palmitate and glucose taken separately did not induce cell death, whereas the combined treatment with both nutrients resulted in an extensive cell apoptosis and this was associated to a significant increase of Cer levels. The presence of fumonisin-B1 partially reversed the apoptosis induced by the combined treatment with palmitate and glucose thus suggesting a role for ER-associated Cer in gluco-lipotoxicity in INS-1 cells. Metabolic studies show that treatment with palmitate results in the inhibition of Cer utilization for SM biosynthesis. Fluorescence microscopy studies suggest a reduced ER to Golgi flow of Cer. To evaluate if Cer accumulation could be due to a defect in the vesicular and/or CERT-mediated transport of Cer, we studied Cer metabolism in INS-1 cells silenced for CERT incubated with glucose in the presence or not of palmitate. In downregulated cells palmitate inhibited Cer utilization for SM biosynthesis; these results indicated that the vesicle-mediated transport is involved in the reduced ER to Golgi flow of Cer. Conclusions: Altogether these data suggest that the accumulation of Cer can be due to a decrease in utilization of newly synthesized Cer for SM biosynthesis thus supporting a role of ER-associated Cer in the regulation of beta cell death induced by gluco-lipotoxicity

A process based model of cohesive sediment resuspension under bioturbators’ influence

Macrozoobenthos may affect sediment stability and erodibility via their bioturbating activities, thereby impacting both the short- and long-term development of coastal morphology. Process-based models accounting for the effect of bioturbation are needed for the modelling of erosion dynamics. With this work, we explore whether the fundamental allometric principles of metabolic activity scaling with individual and population size may provide a framework to derive general patterns of bioturbation effect on cohesive sediment resuspension. Experimental flumes were used to test this scaling approach across different species of marine, soft-sediment bioturbators. The collected dataset encompasses a range of bioturbator functional diversity, individual densities, body sizes and overall population metabolic rates. Measurements were collected across a range of hydrodynamic stress from 0.02 to 0.25 Pa. Overall, we observed that bioturbators are able to slightly reduce the sediment resuspension at low hydrodynamic stress, whereas they noticeably enhance it at higher levels of stress. Along the whole hydrodynamic stress gradient, the quantitative effect of bioturbators on sediment resuspension can be efficiently described by the overall metabolic rate of the bioturbating benthic communities, with significant variations across the bioturbators’ taxonomic and functional diversity. One of the tested species (the gallery-builder Polychaeta Hediste diversicolor) had an effect that was partially deviating from the general trend, being able to markedly reduce sediment resuspension at low hydrodynamic stress compared to other species. By combining bioturbators’ influence with hydrodynamic force, we were able to produce a process-based model of biota-mediated sediment resuspension

Synthesis of nanoscopic optical fibers using lipid membranes as templates

High-aspect-ratio, monocryst. Cd chloride nanowires doped with fluorescent CdS nanoparticles were synthesized using planar lipid membranes as templates. Cd2+ ions bound to the lipid bilayers (a) are released at low pH to the nanometer-sized, interlamellar H2O films (b) where the sudden increase in concn. gives nanowires (c) that show excellent light-waveguiding properties. [on SciFinder (R)

Gluco-lipotoxicity inhibits ceramide transport between endoplasmic reticulum and Golgi apparatus in pancreatic beta cells

Background and aims: In type 2 diabetes (TD2) the chronic adverse effects of fatty acids (FA) on beta cell function and viability have been correlated to hyperglycaemia. Gluco-lipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival. Gluco-lipotoxicity caused beta-cell apoptosis and may thus contribute to progressive beta-cell loss in TD2. The molecular pathways and regulators involved in the detrimental effects of chronic exposure to FA, in particular palmitate, include the de novo synthesis of ceramide (Cer) in the endoplasmic reticulum (ER). However, increasing Cer levels in ER can also be due to a reduction of Cer utilization for complex sphingolipids synthesis. Therefore, we studied the effect of gluco-lipotoxicity on Cer metabolism in beta cells and its impact on beta-cell apoptosis. Materials and methods: INS-1 cells were cultured with 0.4 mM palmitate and 5 or 30 mM of glucose. INS-1 cell apoptosis was determined by caspase 3/7 activity assay. Sphingolipid metabolites were analyzed by liquid chromatography mass spectrometry. Metabolism of Cer was measured in INS-1 beta cells with [3H]sphingosine, a precursor of sphingolipid biosynthesis. Transport of C5-Bodipy-ceramides between ER and Golgi apparatus was analysed by fluorescence confocal microscopy. Down-regulation of Cer transporter CERT was made by specific siRNA. Results: Both nutrients taken separately did not induce INS-1 cell death, whereas the combined treatment with palmitate and glucose resulted in an extensive beta cell apoptosis and this was associated to a significant increase of Cer levels. The presence of fumonisin-B1, an inhibitor of Cer biosynthesis, partially reversed the apoptosis induced by the combined treatment with palmitate and glucose. Metabolic studies using [3H]sphingosine as precursor of sphingolipid biosynthesis show that treatment with palmitate results in a small but significant increase of [3H]Cer associated to a decrease of [3H] sphingomyelin (SM) at 5 mM glucose. Inhibition of Cer utilization for SM biosynthesis was significantly potentiated by the presence of 30 mM glucose. Lipidomic analysis showed that gluco-lipotoxicity inhibited biosynthesis of complex sphingolipids. Fluorescence microscopy studies using C5-Bodipy- Cer show that at high gluco-lipotoxicity reduces the fluorescence accumulation in the perinuclear region representative of the Golgi apparatus. Interestingly, this was associated with an inhibition of the Cer transporter CERT function. Inhibition of CERT was mediated by a decrease of its expression and an increase of its phosphorylation status. Finally, selective silencing of CERT expression increased INS-1 cell apoptosis induced by palmitate. Conclusion: Altogether these data suggest that gluco-lipotoxicity increased Cer accumulation in the ER through also through a decreased utilization of newly synthesized Cer for SM biosynthesis. Moreover, these results support a role of Cer transport between ER and Golgi apparatus in the regulation of beta cell death induced by gluco-lipotoxicity

A process based model of cohesive sediment resuspension under bioturbators’ influence

Macrozoobenthos may affect sediment stability and erodibility via their bioturbating activities, thereby impacting both the short- and long-term development of coastal morphology. Process-based models accounting for the effect of bioturbation are needed for the modelling of erosion dynamics. With this work, we explore whether the fundamental allometric principles of metabolic activity scaling with individual and population size may provide a framework to derive general patterns of bioturbation effect on cohesive sediment resuspension. Experimental flumes were used to test this scaling approach across different species of marine, soft-sediment bioturbators. The collected dataset encompasses a range of bioturbator functional diversity, individual densities, body sizes and overall population metabolic rates. Measurements were collected across a range of hydrodynamic stress from 0.02 to 0.25 Pa. Overall, we observed that bioturbators are able to slightly reduce the sediment resuspension at low hydrodynamic stress, whereas they noticeably enhance it at higher levels of stress. Along the whole hydrodynamic stress gradient, the quantitative effect of bioturbators on sediment resuspension can be efficiently described by the overall metabolic rate of the bioturbating benthic communities, with significant variations across the bioturbators’ taxonomic and functional diversity. One of the tested species (the gallery-builder Polychaeta Hediste diversicolor) had an effect that was partially deviating from the general trend, being able to markedly reduce sediment resuspension at low hydrodynamic stress compared to other species. By combining bioturbators’ influence with hydrodynamic force, we were able to produce a process-based model of biota-mediated sediment resuspension.Accepted Author ManuscriptEnvironmental Fluid MechanicsOLD Urban Composition

Biological and physical drivers of bio-mediated sediment resuspension: a flume study on Cerastoderma edule

Predictive models accounting for the effect of bioturbation on sediment resuspension must be based on ecological theory as well as on empirical parametrizations. The scaling trend of individual metabolic and activity rates with body mass may be a key to the mechanistic understanding of the observed patterns. With this study we tested if general size scaling rules in bio-mediated sediment resuspension may apply to a broad range of physical contexts. To this end, we performed factorial flume experiments by using Cerastoderma edule as model organisms. The effect on sediment resuspension of populations of C. edule differing by individual size was measured across physical gradients of current velocity and sediment composition in terms of fraction of fine particles. C. edule were able to enhance the resuspension of sediment containing silt, while they had scarce effect on the resuspension of coarse sediment. The effect of bioturbation was maximal at intermediate current velocity, when the hydrodynamic forcing is not strong enough to overcome the abiotic sediment resistance but it is able to suspend the bioturbated sediment. Although differences in sediment silt content and intensities of hydrodynamic stress have a relevant influence in determining the bioturbators individual contribution to sediment resuspension, the observed mass scaling trend is consistent across all treatments and close to theoretical expectation for size scaling of individual metabolic rates. This observation supports the hypothesis that the contribution of individual bioturbators to sediment resuspension is directly related to their energy requirements. Therefore, the proposed approach allows the formulation of expectations of biotic contribution to sediment resuspension based on the general size scaling laws of individual energy use