Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

Isometric tension measurement using a selective Rho-kinase inhibitor ( þ )-(R)-trans4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y-27632) and a selective myosin light chain kinase (MLCK) inhibitor 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML7) were used in rabbit clitoral cavernosum smooth muscle (CSM). N G -nitro-L-arginine methyl ester (L-NAME) was used to evaluate the relationship between NO release and Rho-kinase. Y-27632 significantly attenuated contractions induced by ANG II, dose-dependently. However, ML7 did not affect the contractile response to ANG II except in the high concentrations of ML7. Y-27632 inhibited contraction with phenylephrine (PhE), but ML7 did not inhibit contraction with PhE. Nitric oxide synthase inhibitor (NAME) did not affect the Y-27632-induced relaxation in the pre-contracted strip with PhE. The present study demonstrates that G-protein-coupled increase in myofilament Ca 2þ sensitivity mediated through the RhoA=Rho-kinase signal pathway is involved in the control by ANG II of the clitoral CSM tone. RhoA=Rho-kinase pathway acts in the ANG IIinduced contraction independently of the NO pathway.

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There are limited data on the clinical significance of positive central venous catheter (CVC) tip cultures associated with concomitant negative blood cultures performed at the time of CVC removal. A retrospective cohort study of all patients who yielded isolated positive CVC tip cultures was conducted in a tertiary-care hospital with 2200 beds during a 10-year period. All patients with isolated positive CVC tip cultures were observed for the development of subsequent bacteraemia or fungaemia between 2 and 28 days after CVC removal. An isolated positive CVC tip culture was defined as a case in which (i) a CVC tip culture yielded > or = 15 colonies using a semiquantitative culture method and (ii) at least two sets of blood samples revealed no organism at, or close to, the time of CVC removal (48 h before to 48 h after CVC removal). During the study period, 312 patients with isolated positive CVC cultures were enrolled. Eight (2.6%; 95% CI 1.2-5.1) of the 312 patients yielding isolated bacterial or fungal CVC tip cultures developed subsequent bloodstream infection (BSI) caused by the same species as that isolated from the tip culture (Staphylococcus aureus, 1: Enterococcus spp.; 2: Pseudomonas aeruginosa; and 3: Candida spp.). Among 125 patients from whose CVC tips the above four organisms were grown, seven (12.3%) of 57 patients who did not receive appropriate antibiotic therapy within 48 h after CVC removal subsequently developed BSI, but only one (1.5%) of 68 patients who did receive appropriate therapy developed BSI (OR 0.11, p 0.02).