The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1 pulmonary circulation

Pulmonary arterial hypertension (PAH) is a devastating vasculopathy that predominates in women and has been associated with dysregulated estrogen and serotonin signaling. Overexpression of the serotonin transporter (SERT+) in mice results in an estrogen-dependent development of pulmonary hypertension (PH). Estrogen metabolism by cytochrome P450 1B1 (CYP1B1) contributes to the pathogenesis of PAH, and serotonin can increase CYP1B1 expression in human pulmonary arterial smooth muscle cells (hPASMCs). We hypothesized that an increase in intracellular serotonin via increased SERT expression may dysregulate estrogen metabolism via CYP1B1 to facilitate PAH. Consistent with this hypothesis, we found elevated lung CYP1B1 protein expression in female SERT+ mice accompanied by PH, which was attenuated by the CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS). Lungs from female SERT+ mice demonstrated an increase in oxidative stress that was marked by the expression of 8-hydroxyguanosine; however, this was unaffected by CYP1B1 inhibition. SERT expression was increased in monocrotaline-induced PH in female rats; however, TMS did not reverse PH in monocrotaline-treated rats but prolonged survival. Stimulation of hPASMCs with the CYP1B1 metabolite 16α-hydroxyestrone increased cellular proliferation, which was attenuated by an inhibitor (MPP) of estrogen receptor alpha (ERα) and a specific ERα antibody. Thus, increased intracellular serotonin caused by increased SERT expression may contribute to PAH pathobiology by dysregulation of estrogen metabolic pathways via increased CYP1B1 activity. This promotes PASMC proliferation by the formation of pathogenic metabolites of estrogen that mediate their effects via ERα. Our studies indicate that targeting this pathway in PAH may provide a promising antiproliferative therapeutic strategy

Medida da concentração plasmática do fator de crescimento do endotélio vascular em pacientes com câncer prostático: relação com estado clinico, gleason score, volume prostático e PSA sérico

OBJETIVO: Analisar os níveis circulantes do fator de crescimento do endotélio vascular em pacientes com câncer prostático comparados com uma população de indivíduos eutróficos. MÉTODOS: Vinte e seis indivíduos eutróficos e oitenta pacientes com câncer de próstata foram analisados nesse estudo. A coleta sangüínea foi realizada da mesma maneira em todos os pacientes e o plasma foi extraído para a determinação dos níveis do fator de crescimento do endotélio vascular, utilizando-se o método quantitativo ELISA (enzyme-linked immunosorbent assay). RESULTADOS: Os níveis de fator de crescimento do endotélio vascular plasmático encontraram-se significativamente elevados nos pacientes com doença metastática quando comparados com pacientes com doença localizada e com indivíduos sadios. Pacientes com PSA sérico maior que 20 ng/ml apresentaram níveis maiores de fator de crescimento do endotélio vascular plasmático quando comparados com pacientes com PSA menor que 20 ng/ml. Houve uma tendência dos pacientes com escore de Gleason de 8 a 10 apresentarem níveis maiores do fator de crescimento do endotélio vascular plasmático em relação a pacientes com escores de Gleason menores que 8. Não houve relação entre fator de crescimento do endotélio vascular plasmático e estado clínico, ou entre fator de crescimento do endotélio vascular e volume prostático em pacientes com câncer de próstata localizado. CONCLUSÃO: Os dados indicam que pacientes com câncer de próstata metastático apresentam níveis significativamente mais elevados de fator de crescimento do endotélio vascular plasmático quando comparados com pacientes com câncer localizado e com indivíduos normais.PURPOSE: This study focused on circulating levels of vascular endothelial growth factor in patients with prostate cancer compared to a normal population. METHODS: We analyzed 26 normal individuals and 80 patients with prostate cancer. Blood was drawn from all subjects, and plasma was extracted to determine the concentration of vascular endothelial growth factor using a quantitative immunoassay technique (ELISA-enzyme-linked immunosorbent assay). RESULTS: The median plasma level of vascular endothelial growth factor was significantly elevated in patients with metastatic disease compared to patients with localized disease and with healthy controls. Patients with serum prostate-specific antigen >; 20 ng/mL had significantly higher levels of plasma vascular endothelial growth factor than patients with serum prostate-specific antigen < 20 ng/mL. There was a trend for patients with a Gleason score of 8 to 10 to have higher levels of plasma vascular endothelial growth factor when compared to patients with lower Gleason scores. No relationship was found between plasma vascular endothelial growth factor and clinical staging, or between plasma vascular endothelial growth factor and prostate volume, in patients with localized prostate cancer. CONCLUSION: This study indicates that patients with metastatic prostate cancer have higher plasma vascular endothelial growth factor levels than patients with localized disease or in healthy controls

Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension

&lt;p&gt;Aims: Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH.&lt;/p&gt; &lt;p&gt;Methods and results: Dfen (5 mg kg−1 day−1 PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1−/− mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17β-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17β-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice.&lt;/p&gt; &lt;p&gt;Conclusion: CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.&lt;/p&gt

Mapping Hazard Zones, Rapid Warning Communication and Understanding Communities: Primary Ways to Mitigate Pyroclastic Flow Hazard

Co-auteur étrangerInternational audienc

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

What determines cell size?

AbstractFirst paragraph (this article has no abstract) For well over 100 years, cell biologists have been wondering what determines the size of cells. In modern times, we know all of the molecules that control the cell cycle and cell division, but we still do not understand how cell size is determined. To check whether modern cell biology has made any inroads on this age-old question, BMC Biology asked several heavyweights in the field to tell us how they think cell size is controlled, drawing on a range of different cell types. The essays in this collection address two related questions - why does cell size matter, and how do cells control it

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level