Phosphorylation of the androgen receptor is associated with reduced survival in hormonerefractory prostate cancer patients

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (<i>P</i>=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (<i>P</i>=0.014), and an increase in expression of pAkt<sup>473</sup> and pAR<sup>210</sup> were associated with decreased disease-specific survival (<i>P</i>=0.0019 and 0.0015, respectively). Protein expression of pAkt<sup>473</sup> and pAR<sup>210</sup> also strongly correlated (<i>P</i><0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target

Performance of a full scale prototype detector at the BR2 reactor for the SoLid experiment

The SoLid collaboration has developed a new detector technology to detect electron anti-neutrinos at close proximity to the Belgian BR2 reactor at surface level. A 288 kg prototype detector was deployed in 2015 and collected data during the operational period of the reactor and during reactor shut-down. Dedicated calibration campaigns were also performed with gamma and neutron sources. This paper describes the construction of the prototype detector with a high control on its proton content and the stability of its operation over a period of several months after deployment at the BR2 reactor site. All detector cells provide sufficient light yields to achieve a target energy resolution of better than 20%/√E(MeV). The capability of the detector to track muons is exploited to equalize the light response of a large number of channels to a precision of 3% and to demonstrate the stability of the energy scale over time. Particle identification based on pulse-shape discrimination is demonstrated with calibration sources. Despite a lower neutron detection efficiency due to triggering constraints, the main backgrounds at the reactor site were determined and taken into account in the shielding strategy for the main experiment. The results obtained with this prototype proved essential in the design optimization of the final detector

Convergent synthesis of new N -substituted 2-{[5-(1H -indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides as suitable therapeutic agents

abstract A series of N-substituted 2-{[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides (8a-w) was synthesized in three steps. The first step involved the sequential conversion of 2-(1H-indol-3-yl)acetic acid (1) to ester (2) followed by hydrazide (3) formation and finally cyclization in the presence of CS2 and alcoholic KOH yielded 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). In the second step, aryl/aralkyl amines (5a-w) were reacted with 2-bromoacetyl bromide (6) in basic medium to yield 2-bromo-N-substituted acetamides (7a-w). In the third step, these electrophiles (7a-w) were reacted with 4 to afford the target compounds (8a-w). Structural elucidation of all the synthesized derivatives was done by 1H-NMR, IR and EI-MS spectral techniques. Moreover, they were screened for antibacterial and hemolytic activity. Enzyme inhibition activity was well supported by molecular docking results, for example, compound 8q exhibited better inhibitory potential against α-glucosidase, while 8g and 8b exhibited comparatively better inhibition against butyrylcholinesterase and lipoxygenase, respectively. Similarly, compounds 8b and 8c showed very good antibacterial activity against Salmonella typhi, which was very close to that of ciprofloxacin, a standard antibiotic used in this study. 8c and 8l also showed very good antibacterial activity against Staphylococcus aureus as well. Almost all compounds showed very slight hemolytic activity, where 8p exhibited the least. Therefore, the molecules synthesized may have utility as suitable therapeutic agents

Suivi de la qualité des eaux d'alimentation en cours de traitement : intérêt des tests biologiques de toxicité

Le contrôle de la qualité des eaux d'alimentation se limitait, jusqu'à ces dernières années, au seul aspect analytique. Actuellement, face au nombre sans cesse croissant de composés chimiques susceptibles de contaminer les eaux, l'analyse n'est plus toujours suffisante. De plus, elle ne permet pas d'apprécier les effets synergiques ou antagonistes qui peuvent résulter de la présence simultanée de plusieurs polluants, ni de prévoir leur devenir au cours des traitements. Dans bien des cas, il est difficile d'évaluer le risque toxique potentiel pour le consommateur. Les essais biologiques de toxicité, déjà développés dans le cadre des eaux rési-duaires, permettent une approche plus globale des effets toxiques. Leur application à l'étude de la qualité des eaux d'alimentation est plus délicate en raison de leur faible charge polluante. Néanmoins, quelques uns d'entre eux, particulièrement sensibles, sont utilisables sans concentration préalable. A titre comparatif, plusieurs tests de toxicité à court et à moyen terme ont été pratiqués sur les eaux d'une station de potabilisation d'eau de surface aux différents stades de traitement. Parmi les bio essais expérimentés, le test de cytotoxicité basé sur la mesure de la vitesse de synthèse d'ARN s'est avéré le mieux adapté à ce type d'étude

Cytotoxicite des polluants atmospheriques gazeux pour les macrophages alveolaires en survie en phase gazeuse

Comite: Milieux physiques: AirSIGLEAvailable from Centre de Documentation Scientifique et Technique, CNRS, 26 rue Boyer, 75971 Paris Cedex 20 (France) / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Novel N-(4-Piperidinyl)benzamide Antimalarials with Mammalian Protein Farnesyltransferase Inhibitory Activity

International audienceProtein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations