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Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.

The role of androgenic hormones in human sexuality, in the mechanism of erection and in the pathogenesis of impotence is under debate. While the use of testosterone is common in the clinical therapy of male erectile dysfunction, hypogonadism is a rare cause of impotence. We evaluated serum testosterone levels in men with erectile dysfunction resulting either from organic or non-organic causes before and after non-hormonal impotence therapy. Eighty-three consecutive cases of impotence (70% organic, 30% non-organic, vascular aetiology being the most frequent) were subjected to hormonal screening before and after various psychological, medical (prostaglandin E1, yohimbine) or mechanical therapies (vascular surgery, penile prostheses, vacuum devices). Thirty age-matched healthy men served as a control group. Compared to controls, patients with impotence resulting from both organic and non-organic causes showed reduced serum levels of both total testosterone (11.1 +/- 2.4 vs. 17.7 +/- 5.5 nmol/L) and free testosterone (56.2 +/- 22.9 vs. 79.4 +/- 27.0 pmol/L) (both p < 0.001). Irrespective of the different aetiologies and of the various impotence therapies, a dramatic increase in serum total and free testosterone levels (15.6 +/- 4.2 nmol/L and 73.8 +/- 22.5 pmol/L, respectively) was observed in patients who achieved normal sexual activity 3 months after commencing therapy (p < 0.001). On the contrary, serum testosterone levels did not change in patients in whom therapies were ineffective. Since the pre-therapy low testosterone levels were independent of the aetiology of impotence, we hypothesize that this hormonal pattern is related to the loss of sexual activity, as demonstrated by its normalization with the resumption of coital activity after different therapies. The corollary is that sexual activity may feed itself throughout the increase in testosterone levels.

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