In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.

respondents selected a link to an informed consent page, followed by the survey. Participants were asked to rate how often they experienced individual LUTS during the previous 4 weeks, on a five-point Likert scale, and, if experienced, how much the symptom bothered them. Descriptive statistics were used to summarize and present the data. RESULTSResponses rates for the USA, the UK and Sweden were 59.6%, 60.6% and 52.3%, respectively, with a final sample of 30 000 (USA 20 000; UK 7500; Sweden 2500). The mean age (range) of the participants was 56.6 (40-99) years; the mean percentages for race were 82.9% white, 6.7% black, 6.0% Hispanic and 4.4% Asian/other. The prevalence of LUTS was defined by two symptom frequency thresholds, i.e. at least 'sometimes' and at least 'often' for all LUTS except incontinence, where frequency thresholds were at least 'a few times per month' and at least 'a few times per week' .The prevalence of at least one LUTS at least 'sometimes' was 72.3% for men and 76.3% for women, and 47.9% and 52.5% for at least 'often' for men and women, respectively. For most LUTS, at least half of the participants were bothered 'somewhat' or more using a frequency threshold of at least 'sometimes' . For a threshold of at least 'often', 'somewhat' or more bother was reported by ≥ 70% of participants except for terminal dribble in men and split stream in women. CONCLUSIONIn this large population study of three countries, LUTS are highly prevalent among men and women aged > 40 years. In general, LUTS experienced 'often' or more are bothersome to most people.

The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.

perception of bladder problems, anxiety and depression. RESULTSThe overall survey response rate was 59.2%; 30 000 subjects (14 139 men and 15 861 women) participated. Men and women with LUTS in the all LUTS subgroup (storage, voiding and postmicturition) reported the lowest levels of HRQL and highest levels of anxiety and depression, with 35.9% of men and 53.3% of women meeting self-reported screening criteria for clinical anxiety (Hospital Anxiety and Depression Scale, HADS, Anxiety ≥ 8), and 29.8% of men and 37.6% of women meeting self-reported criteria for clinical depression (HADS Depression ≥ 8). In both men and women, storage symptoms were significantly associated with greater perceived bladder impact, whereas voiding symptoms were not. Significant predictors of anxiety included nocturia, urgency, stress urinary incontinence, leaking during sexual activity, weak stream and split stream in women; and nocturia, urgency, incomplete emptying and bladder pain in men. For depression, weak stream, urgency and stress urinary incontinence were significant for women, and perceived frequency and incomplete emptying were significant for men. CONCLUSIONThe negative effect of LUTS is apparent across several domains of HRQL and on overall perception of bladder problems, general health status and mental health. The high level of psychiatric morbidity in patients with multiple LUTS has important implications for treatment and highlights the need for further research to pinpoint specific mechanisms underlying this association. KEYWORDSLUTS, depression, anxiety, health-related quality of life, OAB, BPH, burden OBJECTIVETo evaluate the impact of lower urinary tract symptoms (LUTS) on urinary-specific healthrelated quality of life (HRQL), generic health indices, depression and anxiety in a population-representative sample of men and women, as research has linked LUTS with reduced HRQL and depression, but little is known about the effects of individual LUTS on HRQL, depression and anxiety.

The OAB-q SF captures the full spectrum of OAB Symptom Bother and HRQL impact with good reliability, validity, and responsiveness, while being less time-consuming for patients to complete.