Disruption of prostate cancer cell—macrophage—osteoclast crosstalk by a novel TRAF6 inhibitor

Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key regulator of the pro-inflammatory NFkB pathway and plays a key role in immunity and osteoclast formation through the regulation of RANK/CD40-mediated NFkB signalling. TRAF/NFkB signalling is implicated in cancer, but its role in the prostate cancer\u2014immune cell crosstalk remains unknown. Here, we report that TRAF6 is highly expressed in a panel of androgen-independent, bone-seeking cell lines including C42B4, PC3 and DU145 cells compared to the androgensensitive LNCaP. Stable knockdown and the pharmacological inhibition of TRAF6 using the verified TRAF6 inhibitor 6877002 and its novel and more potent congener FSAS3 reduced PC3 cell viability (50% reduction, p.05), migration (23% reduction, p.05) and invasion (35% reduction, p.05). Conditioned medium from M2 macrophage\u2014but not M0 and M1 phenotype\u2014enhanced human PC3 proliferation, migration and invasion and these effects were significantly inhibited by treatment with FSAS3 (0.3-1lL\u2014proliferation, 22% reduction; migration, 35% reduction; invasion, 79% reduction) (p.005). 6877002 and FSAS3 reduced the ability of M0 macrophage to form osteoclasts in the presence of RANKL and PC3 cells and/or their derived factors. Interestingly, FSAS has no effect on the ability of M1 macrophage to inhibit the proliferation of PC3 cells. Mechanistically, FSAS3 (1lL) reduced IjB phosphorylation induced by RANKL and macrophage-derived factors in PC3 cells, indicative of NFjB inhibition. We conclude that inhibition of TRAF6 in prostate cancer cells reduces their ability to influence the differentiation of bone marrow macrophage into osteoclast and tumour associated macrophage in vitro. In vivo studies to test the effects of FSAS, alone and in combination with chemotherapeutic agents, on mouse models of prostate cancer metastasis are ongoing.

Laguna di Venezia, bocca di porto di Malamocco: attività di protezione dei relitti “del Molo Sud” e “Faro Rocchetta 1”

Contributo dedicato alla metodologia di spostamento e protezione dei due relitti ottocenteschi denominati "del Molo Sud" e "del Faro Rocchetta 1", rinvenuti nella bocca di porto di Malamocco, laguna di Venezia. I lavori di spostamento, prima della protezione definitiva, si sono resi necessari nell'ambito dell'avanzamento delle opere pubbliche alle bocche di porto.Article dedicated to the methodology and underwater works of displacement and protection of the two nineteenth-century wrecks called "del Molo Sud" and "del Faro Rocchetta 1", found in the Malamocco inlet, Venice lagoon. The displacement works, before the final protection of both wrecks, were necessary within the progress of public works at the inlets

Legal and ethical issues related to multifetal pregnancy reduction (MPR) in spontaneously conceived twin pregnancies: an interdisciplinary analysis based on a case study

Following the uncertainty expressed by a group of healthcare professionals working in the gynaecology and obstetrics department of an Italian public hospital on how to proceed in the case of patients asking for a multifetal preg- nancy reduction (MPR), the need to further investigate the topic led to the constitution of a working group devoted to discussing the topic through an interdisciplinary approach. The purpose of this work is therefore to present the legal and ethical issues ad- dressed through the analysis of: 1) the literature on the subject; 2) legislation, doctrine and case-law related to the foetal reduction procedure; 3) the ethical issues raised by the request and implementation of that procedure. Although, under certain conditions, the legal and ethical legitimacy of this procedure can be sustained, we argue that there is a need for clarification with regard to the definition of the term and its links to existing legislation, as well as for the development of guidelines to assist health professional