A20 is an anti-inflammatory protein that is strongly linked to human disease. Here, we find that mice expressing three distinct targeted mutations of A20's zinc finger 7 (ZF7) ubiquitin-binding motif uniformly developed digit arthritis with features common to psoriatic arthritis, while mice expressing point mutations in A20's OTU or ZF4 motifs did not exhibit this phenotype. Arthritis in A20ZF7 mice required T cells and MyD88, was exquisitely sensitive to tumor necrosis factor and interleukin-17A, and persisted in germ-free conditions. A20ZF7 cells exhibited prolonged IκB kinase activity that drove exaggerated transcription of late-phase nuclear factor-κB response genes in vitro and in prediseased mouse paws in vivo. In addition, mice expressing double-mutant A20 proteins in A20's ZF4 and ZF7 motifs died perinatally with multi-organ inflammation. Therefore, A20's ZF4 and ZF7 motifs synergistically prevent inflammatory disease in a non-catalytic manner.Understanding the mechanisms that modulate helper T lymphocyte functions is crucial to decipher normal and pathogenic immune responses in humans. To identify molecular determinants influencing the pathogenicity of T cells, we separated ex vivo-isolated primary human memory T lymphocytes on the basis of their ability to produce high levels of inflammatory cytokines. We found that the inflammatory, cytokine-producing phenotype of memory T lymphocytes was defined by a specific core gene signature and was mechanistically regulated by the constitutive activation of the NF-κB pathway and by the expression of the transcriptional repressor BHLHE40. BHLHE40 attenuated the expression of anti-inflammatory factors, including miR-146a, a negative regulator of NF-κB activation and ZC3H12D, an RNase of the Regnase-1 family able to degrade inflammatory transcripts. Our data reveal a molecular network regulating the proinflammatory phenotype of human memory T lymphocytes, with the potential to contribute to disease.Globally, the life expectancy for men is 5.1 years less than for women. This gender gap in mortality is intrinsically linked to a higher proportion of premature male mortality and is a significant economic, social and healthcare issue. We explore the main causes for premature male death and also discuss the need for a dedicated men's health clinic, especially in the context of potential commercial exploitation.Men's Health is a urological subspecialty that is at the forefront of innovation, but little data exist evaluating the attitudes that andrologists have toward the current treatment modalities available for managing Men's Health conditions. A survey of 37 questions asking what providers would choose as treatment for common conditions was distributed online via Survey Monkey to members of the Sexual Medicine Society of North America and European Society for Sexual Medicine. A total of 115 respondents completed the survey after an initial screening question. For erectile dysfunction (ED), 40%, 38%, and 33% of providers indicated that they would use tadalafil daily, tadalafil on demand, or sildenafil on demand, respectively, as first-line phosphodiesterase 5 inhibitor therapy. Furthermore, a total of 74% would elect to undergo low-intensity shockwave therapy [67%], platelet rich plasma injections [15%], and stem cell injections [15%]. Sex/behavioral therapy was preferred for both premature (36%) and delayed (52%) ejaculation.  https://www.selleckchem.com/products/protosappanin-b.html  Approximately 44% of respondents indicated that they would undergo Collagenase Clostridium Histolyticum injections for Peyronie's Disease in the acute phase. In the setting of hypogonadal symptoms with borderline low total testosterone levels (300-400 ng/dL), 69% of respondents would pursue testosterone therapy. The prostatic lift procedure was the preferred procedure for men seeking symptom resolution with preservation of ejaculatory function. Many Men's Health specialists would pursue the least invasive options before considering procedural intervention for any given condition. Providers may shift their treatment preferences toward newer treatment modalities as longer term data become available.Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.Prostate cancer (PCa) innervation contributes to the progression of PCa. However, the precise impact of innervation on PCa cells is still poorly understood. By focusing on muscarinic receptors, which are activated by the nerve-derived neurotransmitter acetylcholine, we show that muscarinic receptors 1 and 3 (m1 and m3) are highly expressed in PCa clinical specimens compared with all other cancer types, and that amplification or gain of their corresponding encoding genes (CHRM1 and CHRM3, respectively) represent a worse prognostic factor for PCa progression free survival. Moreover, m1 and m3 gene gain or amplification is frequent in castration-resistant PCa (CRPC) compared with hormone-sensitive PCa (HSPC) specimens. This was reflected in HSPC-derived cells, which show aberrantly high expression of m1 and m3 under androgen deprivation mimicking castration and androgen receptor inhibition. We also show that pharmacological activation of m1 and m3 signaling is sufficient to induce the castration-resistant growth of PCa cells.