Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as KMT2D and KDM6A but rarely in TP53, PIK3CA, and FGFR3. KMT2D mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.

The prevalence of OAB and other LUTS is high among female nurses in China, and occupational stress may be a contributing factor.

Hepatocellular carcinoma (HCC), one of the most aggressive malignancies, ranks as the fourth leading cause of cancerrelated deaths worldwide. Emerging evidence indicates that RNA N6-methyladenosine (m6A) plays a critical role in tumor progression. However, the biological function of YTHDF1 in HCC remains unclear. Here, we found that YTHDF1 expression was strikingly elevated in HCC tissues and cell lines and significantly associated with prognosis of HCC patients. Moreover, YTHDF1 expression was transcriptionally regulated by USF1 and c-MYC in HCC. Functional studies showed that YTHDF1 can promote HCC cell proliferation and metastasis both in vitro and in vivo. Multi-omics analysis revealed that YTHDF1 can accelerate the translational output of FZD5 mRNA in an m6A-dependent manner and function as an oncogene through the WNT/b-catenin pathway. Taken together, our study revealed an essential role of YTHDF1 in the progression of HCC cells, which indicated that targeting YTHDF1 may be a potential therapeutic strategy in HCC.

Background-Allograft deterioration is the major obstacle to organ transplantation as a long-term treatment of end-stage heart failure. In this study, we transduced the antioxidant gene, heme oxygenase-1 (HO-1), to heart grafts using a recombinant adeno-associated viral vector (rAAV) in a rat heart transplantation model and investigated its potentiality in prevention of chronic graft deterioration. Methods and Results-rAAV/HO-1 was administered to heart grafts through the coronary arteries during cold preservation. We investigated the expression patterns and activities of transgene, graft survival, graft histomorphology, and relevance of HO-1 expression on graft survival and chronic graft deterioration by itself. Long-term allograft survival can be achieved by rAAV/HO-1-mediated stable transgene expression. The development of graft arteriosclerosis and interstitial fibrosis was prevented in rAAV/HO-1-transduced allografts on day 100. rAAV/HO-1-mediated long-term graft protection was accompanied by remarkable downregulation of the intragraft mRNA level of macrophage migration inhibitory factor, tumor necrosis factor-␣, and transforming growth factor-␤ 1 . Blockage of HO activities by zinc protoporphyrin IX at different posttransplant phases showed that the stable expression of HO-1 is a prerequisite for both survival of grafts and prevention of graft arteriosclerosis.