Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in-null cell lines. EZH2 inhibition delayed tumor onset in -null cells and caused regression of-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.

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Aim:The aims of this study were to define the relationship between intravesical prostatic protrusion (IPP), prostate-specific antigen (PSA) and prostate volume (PV) and to determine which one of them is the best predictor of bladder outlet obstruction (BOO) due to benign prostatic enlargement. Methods: A prospective study of 114 male patients older than 50 years examined between November 2001 and 2002 was performed. They were evaluated with digital rectal examination, International Prostate Symptoms Score, PSA, uroflowmetry, postvoid residual urine measurement, IPP and PV using transabdominal ultrasound scan. Statistical analysis included scatter plot with Spearman's correlation coefficients and nominal logistic regression Results: Prostate volume, IPP and PSA showed parallel correlation. Although all three indices had good correlation with BOO index, IPP was the best. The Spearman rho correlation coefficients were 0.314, 0.408 and 0.507 for PV, PSA and IPP, respectively. Using receiver-operator characteristic curves, the areas under the curve for PV, PSA and IPP were 0.637, 0.703 and 0.772, respectively. The positive predictive values of PV, PSA and IPP were 65%, 68% and 72%, respectively. Using a nominal regression model, IPP remained the most significant independent index to determine BOO. Conclusions: All three non-invasive indices correlate with one another. The study showed that IPP is a better predictor for BOO than PSA or PV.

The HA2 glycopolypeptide (gp) is highly conserved in all influenza A virus strains, and it is known to play a major role in the fusion of the virus with the endosomal membrane in host cells during the course of viral infection. Vaccines and therapeutics targeting this HA2 gp could induce efficient broad-spectrum immunity against influenza A virus infections. So far, there have been no studies on the possible therapeutic effects of monoclonal antibodies (MAbs), specifically against the fusion peptide of hemagglutinin (HA), upon lethal infections with highly pathogenic avian influenza (HPAI) H5N1 virus. We have identified MAb 1C9, which binds to GLFGAIAGF, a part of the fusion peptide of the HA2 gp. We evaluated the efficacy of MAb 1C9 as a therapy for influenza A virus infections. This MAb, which inhibited cell fusion in vitro when administered passively, protected 100% of mice from challenge with five 50% mouse lethal doses of HPAI H5N1 influenza A viruses from two different clades. Furthermore, it caused earlier clearance of the virus from the lung. The influenza virus load was assessed in lung samples from mice challenged after pretreatment with MAb 1C9 (24 h prior to challenge) and from mice receiving early treatment (24 h after challenge). The study shows that MAb 1C9, which is specific to the antigenically conserved fusion peptide of HA2, can contribute to the cross-clade protection of mice infected with H5N1 virus and mediate more effective recovery from infection.