Oncogenic Roles of Polycomb Repressive Complex 2 in Bladder Cancer and Upper Tract Urothelial Carcinoma.

Cancers of the urinary tract are one of the most common malignancies worldwide, causing high morbidity and mortality, and representing a social burden. Upper tract urothelial carcinoma (UTUC) accounts for 5−10% of urinary tract cancers, and its oncogenic mechanisms remain elusive. We postulated that cancers of the lower and the upper urinary tract may share some important oncogenic mechanisms. Therefore, the oncogenic mechanisms discovered in the lower urinary tract may guide the investigation of molecular mechanisms in the upper urinary tract. Based on this strategy, we revisited a high-quality transcriptome dataset of 510 patients with non-muscle invasive bladder cancer (NMIBC), and performed an innovative gene set enrichment analysis of the transcriptome. We discovered that the epigenetic regulation of polycomb repressive complex 2 (PRC2) is responsible for the recurrence and progression of lower-track urinary cancers. Additionally, a PRC2-related gene signature model was discovered to be effective in classifying bladder cancer patients with distinct susceptibility of subsequent recurrence and progression (log-rank p < 0.001 and = 0.001, respectively). We continued to discover that the same model can differentiate stage T3 UTUC patients from stage Ta/T1 patients (p = 0.026). Immunohistochemical staining revealed the presence of PRC2 components (EZH2, EED, and SUZ12) and methylated PRC2 substrates (H3K27me3) in the archived UTUC tissues. The H3K27me3 exhibited higher intensity and area intensity product in stage T3 UTUC tissues than in stage Ta/T1 tissues (p = 0.006 and 0.015, respectively), implicating stronger PRC2 activity in advanced UTUC. The relationship between H3K27 methylation and gene expression is examined using correlations. The H3K27me3 abundance is positively correlated with the expression levels of CDC26, RP11-2B6, MAPK1IP1L, SFR1, RP11-196B3, CDK5RAP2, ANXA5, STX11, PSMD5, and FGFRL1. It is also negatively correlated with CNPY2, KB-1208A12, RP11-175B9, ZNF692, RANP8, RP11-245C17, TMEM266, FBXW9, SUGT1P2, and PRH1. In conclusion, PRC2 and its epigenetic effects are major oncogenic mechanisms underlying both bladder cancer and UTUC. The epigenetically regulated genes of PRC2 in urothelial carcinoma were also elucidated using correlation statistics.

The comparison of different BCG strains in the intravesical treatment of non-muscle invasive urothelial carcinoma of urinary bladder-A real-world practice.

BACKGROUND: Bacillus Calmette-Guérin (BCG) has been well recognized as the first-line intravesical therapy for high-risk non-muscle-invasive bladder cancer (NMIBC). Oncotice, the Tice strain of BCG, serves as a viable alternative to the Connaught strain owing to the worldwide shortage of the latter. We retrospectively compared these two strains in terms of efficacy and adverse effects (AE) in patients who underwent at least one maintenance course after induction. METHODS: In this single-institution, retrospective study, patients diagnosed with NMIBC who were administered either Connaught or Tice intravesical therapy were enrolled. Recurrence was defined as the reappearance of urothelial carcinoma. Progression was defined as stage/grade advance, metastasis, or cancer-related death. The primary outcomes were recurrence-free survival (RFS) and progression-free survival (PFS), and the secondary outcome was AE. RESULTS: A total of 76 and 84 patients receiving Tice and Connaught, respectively were enrolled. The median follow-up periods for the Tice and Connaught groups were 32.0 months (range, 7-69 months) and 81.5 months (range, 9-154 months), respectively. Kaplan-Meier method showed no intergroup difference with regard to 3-year RFS and PFS. On Cox multivariate regression analysis, Tice was a significant predictor for inferior PFS (HR = 5.30; 95% CI, 1.11-25.29; p = 0.036). The AE incidence was 38.3% in the Connaught group and 25.0% in the Tice group (p = 0.079). CONCLUSION: Tice and Connaught were comparable in terms of RFS, PFS, and AE for patients with NMIBC accepting BCG induction and at least one maintenance course in our real-world practice. However, Tice was a predictor of inferior PFS on multivariate analysis.

Fortified S-Allyl L-Cysteine: Animal Safety, Effect on Retinal Ischemia, and Role of Wnt in the Underlying Therapeutic Mechanism.

PURPOSE: Retinal ischemia is a medical condition associated with numerous retinal vascular disorders, such as age-related macular degeneration, glaucoma, and diabetic retinopathy. This in vitro cell and in vivo animal study investigated not only the protective effect of S-allyl L-cysteine (SAC, an active component of garlic) against retinal ischemia but also its associated protective mechanisms. METHODS: Retinal ischemia was mimicked by raising the intraocular pressure to 120 mmHg for 1 hour in one eye. The effects of pre-/postischemic administration of vehicle vs. SAC 0.18 mg vs. SAC 0.018 mg vs. SAC 0.0018 mg treatments on retina cells were evaluated through cellular viability (MTT assay), flash electroretinograms (ERGs), and fluorogold retrograde labelling (retinal ganglion cell (RGC) counting). Also, protein immunoblot was utilized to assess the role of Wnt, hypoxia inducible factor (HIF)-1α, and vascular endothelium factor (VEGF) in the proposed anti-ischemic mechanism. Lastly, the safety of drug consumption was investigated for changes in the animal's body weight, ERG waves, and blood biochemical parameters (e.g., glucose levels). RESULTS: The characteristic ischemic changes including significant reduction in ERG b-wave ratio and RGC number were significantly counteracted by pre- and postischemic low dose of SAC. Additionally, ischemia-induced overexpression of Wnt/HIF-1α/VEGF protein was ameliorated significantly by preischemic low dose of SAC. In terms of the animal safety, no significant body weight and electrophysiological differences were observed among defined different concentrations of SAC without following ischemia. In low SAC dosage and vehicle groups, various blood biochemical parameters were normal; however, high and medium concentrations of SAC significantly lowered the levels of uric acid, Hb, and MCHC. CONCLUSION: This study shows that preischemic administration of low SAC dosage has been proved to be safe and most effective against rat retinal ischemia electrophysiologically and/or histopathologically. Moreover, counteracting the ischemia-induced overexpression of Wnt/HIF-1α/VEGF might presently explain SAC's anti-ischemic mechanism.