Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves ...outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.
SUMMARY
Surface waves are a particular type of seismic wave that propagate around the surface of the Earth, but which oscillate over depth ranges beneath the surface that depend on their frequency of ...oscillation. This causes them to travel with a speed that depends on their frequency, a property called dispersion. Estimating surface wave dispersion is of interest for many geophysical applications using both active and passive seismic sources, not least because the speed–frequency relationship can be used to infer the subsurface velocity structure at depth beneath the surface. We present an inversion scheme that exploits spatial and temporal relationships in the scalar Helmholtz (wave) equation to estimate dispersion relations of the elastic surface wave data in both active and passive surveys, while also reconstructing the wavefield continuously in space (i.e. between the receivers at which the wavefield was recorded). We verify the retrieved dispersive phase velocity by comparing the results to dispersion analysis in the frequency-slowness domain, and to the local calculation of dispersion using modal analysis. Synthetic elastic examples demonstrate the method under a variety of recording scenarios. The results show that despite the scalar approximation made to represent these intrinsically elastic waves, the proposed method reconstructs both the wavefield and the phase dispersion structure even in the case of strong aliasing and irregular sampling.
Both taxanes, docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to ...investigate mechanisms of taxane resistance in prostate cancer.
Two docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-docetaxel resistance and gene expression profiles were compared. (14)C-docetaxel and (14)C-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity.
Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to docetaxel and cabazitaxel.
The SLCO1B3 determines intracellular concentrations of docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.
Seismic interferometry is applied to continuous seismic recordings spanning 5 days and over 2200 stations at the Valhall Life‐of‐Field Seismic array in the Norwegian North Sea. We retrieve both ...fundamental‐mode and first‐overtone Scholte waves by cross correlation. Ambient seismic noise tomography using the vertical component of this dense array produces group velocity maps of fundamental‐mode Scholte waves with high repeatability from only 24 h of recording. This repeatability makes daily reservoir‐scale near‐surface continuous monitoring of the subsurface feasible. Such monitoring may detect production‐related changes over a long time scale (months to years) and may be useful for early detection of short time scale hazards (days to weeks) such as migrating gases and fluids. We validate our velocity maps by comparing them with maps obtained independently from controlled‐source data.
Key Points
Noise correlation retrieves fundamental and first wave modes in OBC array.
Group velocity maps show subsurface features up to 250m below the sea floor.
Daily highly repeatable group-velocity maps shows noise-monitoring feasibility.
Given the importance of soil organic carbon (SOC) as a pool in the global carbon cycle and an indicator for soil quality, there exits an urgent need to monitor this dynamic soil property. Here, we ...present a modelling approach to analyze the spatial patterns and temporal evolution of organic carbon in mineral soils under agricultural land use in Belgium. An empirical model, predicting the SOC concentration in the top 0.3 m, as a function of precipitation, land use, soil type and management has been constructed and applied within a spatial context using data from different time slices. The results show that SOC content is strongly correlated with precipitation and temperature under cropland and with texture and drainage under grassland. Total SOC stock increased with 1.3% from 6.18 ± 0.03 kg C m⁻² in 1960 to 6.26 ± 0.07 kg C m⁻² in 2006. Although this increase was not significant (P>0.05), a significant discrepancy between cropland (−8%) and grassland (+10%) was observed. Foremost, the grasslands in the hilly southern part of the country, under relatively wet climate conditions, acted as important sinks of CO₂. Under cropland, all soil types were characterized by a decrease in SOC, except for the clay soils in the north-west. Currently, croplands in the central loam region have SOC concentrations close to 10 g C kg⁻¹ indicating that these soils are at risk of a decline in aggregate stability. An overall strong SOC decline in poorly drained soils is probably caused by artificial drainage. Further research is needed to gain more insight into the processes driving the observed SOC trends. Moreover, the use of updated drainage class information and land management history would improve the empirical models.
Abstract Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and ...enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.
Knowledge on the factors that determine the composition of bacterial communities in the vicinity of roots (rhizosphere) is essential to understand plant-soil interactions. Plant species identity, ...plant growth stage and soil properties have been indicated as major determinants of rhizosphere bacterial community composition. Here we show that the presence of saprotrophic fungi can be an additional factor steering rhizosphere bacterial community composition and functioning. We studied the impact of presence of two common fungal rhizosphere inhabitants (Mucor hiemalis and Trichoderma harzianum) on the composition of cultivable bacterial communities developing in the rhizosphere of Carex arenaria (sand sedge) in sand microcosms. Identification and phenotypic characterization of bacterial isolates revealed clear shifts in the rhizosphere bacterial community composition by the presence of two fungal strains (M. hiemalis BHB1 and T. harzianum PvdG2), whereas another M. hiemalis strain did not show this effect. Presence of both M. hiemalis BHB1 and T. harzianum PvdG2 resulted in a significant increase of chitinolytic and (in vitro) antifungal bacteria. The latter was most pronounced for M. hiemalis BHB1, an isolate from Carex roots, which stimulated the development of the bacterial genera Achromobacter and Stenotrophomonas. In vitro tests showed that these genera were strongly antagonistic against M. hiemalis but also against the plant-pathogenic fungus Rhizoctonia solani. The most likely explanation for fungal-induced shifts in the composition of rhizosphere bacteria is that bacteria are being selected which are successful in competing with fungi for root exudates. Based on the results we propose that measures increasing saprotrophic fungi in agricultural soils should be explored as an alternative approach to enhance natural biocontrol against soil-borne plant-pathogenic fungi, namely by stimulating indigenous antifungal rhizosphere bacteria.
Context.
The interior of a neutron star is usually assumed to be made of cold catalyzed matter. However, the outer layers are unlikely to remain in full thermodynamic equilibrium during the formation ...of the star and its subsequent cooling, especially after crystallization occurs.
Aims.
We study the cooling and the equilibrium composition of the outer layers of a non-accreting neutron star down to crystallization. Here the impurity parameter, generally taken as a free parameter in cooling simulations, is calculated self-consistently using a microscopic nuclear model for which a unified equation of state has recently been determined.
Methods.
We follow the evolution of the nuclear distributions of the multi-component Coulomb liquid plasma fully self-consistently, adapting a general formalism originally developed for the description of supernova cores. We calculate the impurity parameter at the crystallization temperature as determined in the one-component plasma approximation.
Results.
Our analysis shows that the sharp changes in composition obtained in the one-component plasma approximation are smoothed out when a full nuclear distribution is allowed. The Coulomb coupling parameter at melting is found to be reasonably close to the canonical value of 175, except for specific values of the pressure for which supercooling occurs in the one-component plasma approximation. Our multi-component treatment leads to non-monotonic variations of the impurity parameter with pressure. Its values can change by several orders of magnitude reaching about 50, suggesting that the crust may be composed of an alternation of pure (highly conductive) and impure (highly resistive) layers. The results presented here complement the recent unified equation of state obtained within the same nuclear model.
Conclusions.
Our self-consistent approach to hot dense multi-component plasma shows that the presence of impurities in the outer crust of a neutron star is non-negligible and may have a sizeable impact on transport properties. In turn, this may have important implications not only for the cooling of neutron stars, but also for their magneto-rotational evolution.
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