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

Exogenous SPARC Suppresses Proliferation and Migration of Prostate Cancer by Interacting With Integrin β1

BACKGROUND The matricellular protein secreted protein acidic and rich in cysteine (SPARC) plays an important role on tumor metastasis and progression in several cancers. However, the roles of SPARC in prostate cancer (PCa) remain unclear. METHODS To identify SPARC protein in prostate tissue, immunohistochemical analysis of SPARC was conducted using human prostate tissue microarray. To detect SPARC expression in prostate cancer (LNCaP, DU145, and PC‐3) and stromal cells, RT‐PCR, western blot analysis, and ELISA was conducted. To reveal the function of exogenous SPARC in PCa cells, AKT phosphorylation was confirmed by western blot analysis after coculture with stromal cells. Proliferation and migration of PCa cells were examined by addition of SPARC. The interaction between SPARC and integrin β1 was confirmed by western blot analysis after immunoprecipitation. RESULTS SPARC protein was expressed well in normal tissue compared with PCa tissue. ELISA showed high secreted SPARC protein in normal prostate‐derived stromal cell (PrSC) compared with PCa‐derived stromal cell (PCaSC) and PCa. PCa cells cocultured with PrSC showed reduced AKT phosphorylation more than with PCaSC. PCa cells cocultured with PrSC whose SPARC was knocked‐down restored AKT phosphorylation. Moreover, PCa cells treated with SPARC led to reduced AKT phosphorylation. Immunoprecipitation with SPARC revealed interaction of SPARC and integrin β1 in PCa cells. Inhibited proliferation and migration of PCa cells by SPARC was restored by integrin β1 neutralizing antibody. CONCLUSIONS Reduced SPARC secretion from stromal cells might affect PCa progression mediating through limiting AKT phosphorylation after interaction with integrin β1. Prostate 73: 1159–1170, 2013. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98803/1/pros22664.pd

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

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

Adaptation et diversité génétique des sapins méditerranéens : bilan des tests de provenance de sapins de Céphalonie dans le sud de la France et perpectives en matière d'hybridation

Le sapin de Céphalonie est installé en plantations comparatives en France par l'INRA depuis les années 1970. Les résultats acquis ont montré l'intérêt des provenances du Mainalon et du Parnon. Des expérimentations plus modestes sur sapin de Turquie, indiquent que le sapin de Bornmuller présente lui aussi des potentialités intéressantes. Parallèlement, des essais de comparaisons d'hybrides interspécifiques démontrent l'existence d'un effet d'hétérosis durable

Lutter contre l'illettrisme et le décrochage. L'engagement du ministère de la défense

Pommery François-Xavier de. Lutter contre l'illettrisme et le décrochage. L'engagement du ministère de la défense. In: Diplômées, n°248, 2014. L'illetrisme aujourd hui. pp. 17-19