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.

A retrospective study of 36 patients with xanthogranulomatous pyelonephritis who underwent nephrectomy at our hospital was performed. The disease occurred most frequently in middle-aged women with a history of recurrent urinary tract disorder. There were 2 cases of focal xanthogranulomatous pyelonephritis, 2 associated with emphysematous pyelonephritis, 2 that manifested as fistula formation between the colon or skin, and 1 with deep sinus formation into the hip joint that presented as septic arthritis. Flank pain and fever were the most frequent complaints. Escherichia coli (67%) and Proteus mirabilis (26%) were the most common organisms isolated from the voided urine, kidney and blood stream. Cephalothin plus gentamicin or tobramycin were the drugs of choice before surgical intervention.

The clinical manifestations and histopathological features of sorafenib-induced skin reactions are unique. The most relevant histopathological findings of hand-foot skin reaction include keratinocyte vacuolar degeneration, the presence of intracytoplasmic eosinophilic bodies, and intraepidermal blisters in the stratum malpighii. Further studies are warranted to elucidate the mechanisms of this novel multitargeted kinase inhibitor-associated skin reaction.