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Research on recruitment variability has gained momentum in the last years, undoubtedly due to the many unknowns related to climate change impacts. Knowledge about recruitment—the process of small, young fish transitioning to an older, larger life stage—timing and success is especially important for commercial fish species, as it allows predicting the availability of fish and adapting fishing practices for its sustainable exploitation. Predicting tools for determining the combined effect of temperature rise and food quality and quantity reduction (two expected outcomes of climate change) on early-life history traits of fish larvae are valuable for anticipating and adjusting fishing pressure and policy. Here we use a previously published and validated dynamic energy budget (DEB) model for the common sole (Solea solea) and adapt and use the same DEB model for the Senegalese sole (S. senegalensis) to predict the effects of temperature and food availability on Solea spp. early life-history traits. We create seven simulation scenarios, recreating RCP 4.5 and 8.5 Intergovernmental Panel on Climate Change (IPCC) scenarios and including a reduction in food availability. Our results show that temperature and food availability both affect the age at metamorphosis, which is advanced in all scenarios that include a temperature rise and delayed when food is limited. Age at puberty was also affected by the temperature increase but portrayed a more complex response that is dependent on the spawning (batch) period. We discuss the implications of our results in a climate change context.

[Abstract] Background: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. Methods: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. Results: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. Conclusions: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

Formalin fixation and paraffin-embedding (FFPE) is the most common method to preserve human tissue for clinical diagnosis and FFPE archives represent an invaluable resource for biomedical research. Proteins in FFPE material are stable over decades but their efficient extraction and streamlined analysis by mass spectrometry (MS)-based proteomics has so far proven challenging. Here, we describe an MS-based proteomic workflow for quantitative profiling of large FFPE tissue cohorts directly from histopathology glass slides. We demonstrate broad applicability of the workflow to clinical pathology specimens and variable sample amounts, including low-input cancer tissue isolated by laser microdissection. Using state-of-the-art data dependent acquisition (DDA) and data independent (DIA) MS workflows, we consistently quantify a large part of the proteome in 100 min single-run analyses. In an adenoma cohort comprising more than 100 samples, total work up took less than a day. We observed a moderate trend towards lower protein identifications in long-term stored samples (>15 years) but clustering into distinct proteomic subtypes was independent of archival time. Our results underline the great promise of FFPE tissues for patient phenotyping using unbiased proteomics and prove the feasibility of analyzing large tissue cohorts in a robust, timely and streamlined manner. This article is protected by copyright. All rights reserved.

PURPOSE: Increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis and its development is poorly understood.EXPERIMENTAL DESIGN: We applied mass spectrometry-based proteomics to a unique set of 17 prostate cancer patient-derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST occupied regions in prostate cancer cells were correlated to the expression changes in vivoto investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation.RESULTS: An average of 4881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell cycle regulation and DNA repair were found upregulated elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST regulated gene Secretagogin (SCGN), correlated with in increased risk of suffering disease relapse after radical prostatectomy.CONCLUSIONS: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

Bladder cancer associated protein (Blcap) expression is commonly down-regulated in invasive bladder cancer, and may have prognostic value given that its expression is negatively correlated with patient survival. We have previously investigated the expression patterns and cellular localization of Blcap in bladder cancer, where we found that about 20% of the lesions examined displayed strong nuclear expression of Blcap, and that this phenotype was associated with overall poor disease outcome. Here we report on the analysis of possible functional associations between nuclear expression of Blcap and canonical signaling pathways. We performed serial immunohistochemistry (IHC) analysis of bladder tissue samples, with serial sections stained with phospho-specific antibodies recognizing key signaling intermediates, such as P-Stat3, P-Akt, and P-Erk1/2, among others, in an immunophenotyping approach we have established and reported previously. Using this approach, we found that nuclear localization of Blcap was associated with expression of P-Stat3. A parallel analysis, cytokine profiling of bladder tumor interstitial fluids of samples expressing (or not) Blcap, showed interleukin (IL)-6, IL-8, and monocyte chemotactic protein 1 (MCP-1) to be correlated with nuclear expression of Blcap, independently supporting a role for Stat3 signaling in localization of Blcap. Multiple indirect immunofluorescence analysis of tissue biopsies confirmed that Blcap co-localized with Stat3. Furthermore, we could also demonstrate, using an in situ proximity ligation assay that Blcap and Stat3 are in close physical proximity of each other in bladder tissue, and that Blcap physically interacts with Stat3 as determined by co-immunoprecipitation of these proteins. Our data indicates that Blcap is a novel Stat3 interaction partner and suggests a role for Blcap in the Stat3-mediated progression of precancerous lesions to invasive tumors of the bladder.