Posttranslational modification of substrates by the small ubiquitin-like modifier, SUMO, regulates diverse biological processes, including transcription, DNA repair, nucleocytoplasmic trafficking, and chromosome segregation. SUMOylation is reversible, and several mammalian homologs of the yeast SUMO-specific protease Ulp1, termed SENPs, have been identified. We demonstrate here that SENP5, a previously uncharacterized Ulp1 homolog, has SUMO C-terminal hydrolase and SUMO isopeptidase activities. In contrast to other SENPs, the C-terminal catalytic domain of SENP5 preferentially processed SUMO-3 compared to SUMO-1 precursors and preferentially removed SUMO-2 and SUMO-3 from SUMO-modified RanGAP1 in vitro. In cotransfection assays, SENP5 preferentially reduced high-molecular-weight conjugates of SUMO-2 compared to SUMO-1 in vivo. Full-length SENP5 localized to the nucleolus. Deletion of the noncatalytic N-terminal domain led to loss of nucleolar localization and increased de-SUMOylation activity in vivo. Knockdown of SENP5 by RNA interference resulted in increased levels of SUMO-1 and SUMO-2/3 conjugates, inhibition of cell proliferation, defects in nuclear morphology, and appearance of binucleate cells, revealing an essential role for SENP5 in mitosis and/or cytokinesis. These findings establish SENP5 as a SUMO-specific protease required for cell division and suggest that mechanisms involving both the catalytic and noncatalytic domains determine the distinct substrate specificities of the mammalian SUMO-specific proteases.Posttranslational modification of proteins by the small ubiquitin-like modifier SUMO is an important mechanism to regulate numerous biological processes, including nucleocytoplasmic trafficking, transcription, and DNA repair and replication, as well as mitotic and meiotic chromosome behavior (13,16,20). SUMO is covalently attached to lysine residues in substrate proteins in a process similar to ubiquitination (for review, see reference 19). SUMO conjugation requires an E1-activating enzyme (Aos1/Uba2) and an E2-conjugating enzyme (Ubc9), and SUMOylation of specific substrates may be stimulated by the action of diverse E3 ligases (8,9,34). Covalent modification of proteins by SUMO is reversible, and a number of SUMO-specific proteases have been predicted based on homology to yeast Ulp1, the first identified SUMO-specific protease (23). The SUMO-specific proteases have dual roles in the SUMOylation pathway. First, they are responsible for the initial processing of SUMO precursors to generate a C-terminal diglycine motif required for conjugation. Second, these proteases execute the deconjugation reaction that removes SUMO from high-molecular-weight SUMO conjugates. At least seven Ulp1 homologs have been identified in mammals , which share a conserved cysteine protease domain at their C termini (12,14,22,30,46). Four of these, SENP1, -2, -3, and -6, have been reported to have SUMO-specific C-terminal hydrolase and/or isopeptidase activity. In contrast, the Ulp homolog SENP8 has deconjugation activity...

Although SCA6 has, so far, not been reported in mainland Chinese, we found a geographic cluster of families with SCA6 on Taiwan. Genotyping studies suggest a founder effect in the Taiwanese patients with SCA6.

BackgroundThere has been increasing interest in en bloc resection of bladder tumour (ERBT) as an oncologically non-inferior alternative to transurethral resection of bladder tumour (TURBT) with fewer complications and better histology specimens. However, there is a lack of robust randomised controlled trial (RCT) data for making recommendations. ObjectiveWe aimed to develop a consensus statement to standardise various aspects of ERBT for clinical practice and to guide future research. Design, Setting and ParticipantsWe developed the consensus statement on ERBT using a modified Delphi method.First, two systematic reviews were performed to investigate the clinical effectiveness of ERBT versus TURBT (effectiveness review), and to identify areas of uncertainty in ERBT (uncertainties review). Next, 200 health care professionals (urologists, oncologists and pathologists) with experience in ERBT were invited to complete a two-round Delphi survey. Finally, a 16-member consensus panel meeting was held to review, discuss and re-vote on the statements as appropriate. Outcome Measurements and Statistical AnalysisMeta-analyses were performed for RCT data in the effectiveness review. Consensus statements were developed from the uncertainties review. Consensus was defined as:(1) ≥70% scoring a statement 7-9 AND ≤15% scoring the statement 1-3 (consensus agree); OR (2) ≥70% scoring a statement 1-3 AND ≤15% scoring the statement 7-9 (consensus disagree). Results and LimitationsA total of 10 RCTs were identified upon systematic review. ERBT had a shorter irrigation time (mean difference -7.24 hours, 95% CI -9.29 --5.20, I 2 =85%, p<0.001) and lower rate of bladder perforation (Risk ratio [RR] 0.30, 95% CI 0.11-0.83, I 2 =1%, p=0.02) than TURBT, both with moderate certainty of evidence. There were no significant differences in recurrences at 0-12 months, 13-24 months or 25-36 months (all very low certainty of evidence). A total of 103 statements were developed and 99

Urothelial carcinoma (UC), arising from the urothelium of the urinary tract, can occur in the upper (UTUC) and the urinary bladder (UBUC). A representative molecular aberration for UC characteristics and prognosis remains unclear. Data mining of Gene Expression Omnibus focusing on UBUC, we identified sulfatase-1 (SULF1) upregulation is associated with UC progression. SULF1 controls the sulfation status of heparan sulfate proteoglycans and plays a role in tumor growth and metastasis, while its role is unexplored in UC. To first elucidate the clinical significance of SULF1 transcript expression, real-time quantitative RT-PCR was performed in a pilot study of 24 UTUC and 24 UBUC fresh samples. We identified that increased SULF1 transcript abundance was associated with higher primary tumor (pT) status. By testing SULF1 immunoexpression in independent UTUC and UBUC cohorts consisted of 340 and 295 cases, respectively, high SULF1 expression was significantly associated with advanced pT and nodal status, higher histological grade and presence of vascular invasion in both UTUC and UBUC. In multivariate survival analyses, high SULF1 expression was independently associated with worse DSS (UTUC hazard ratio [HR] = 3.574, P < 0.001; UBUC HR = 2.523, P = 0.011) and MeFS (UTUC HR = 3.233, P < 0.001; UBUC HR = 1.851, P = 0.021). Furthermore, depletion of SULF1 expression by using RNA interference leaded to impaired cell proliferative, migratory, and invasive abilities

We sought to examine the effect of tumor location on the prognosis of patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). This retrospective study came from the Taiwan UTUC Collaboration Group, which consisted of 2658 patients at 15 institutions in Taiwan from 1988 to 2019. Patients with kidney-sparing management, both renal pelvic and ureteral tumors, as well as patients lacking complete data were excluded; the remaining 1436 patients were divided into two groups: renal pelvic tumor (RPT) and ureteral tumor (UT), with 842 and 594 patients, respectively. RPT was associated with more aggressive pathological features, including higher pathological T stage (p < 0.001) and the presence of lymphovascular invasion (p = 0.002), whereas patients with UT often had synchronous bladder tumor (p < 0.001), and were more likely to bear multiple lesions (p = 0.001). Our multivariate analysis revealed that UT was a worse prognostic factor compared with RPT (overall survival: HR 1.408, 95% CI 1.121–1.767, p = 0.003; cancer-specific survival: HR 1.562, 95% CI 1.169–2.085, p = 0.003; disease-free survival: HR 1.363, 95% CI 1.095–1.697, p = 0.006; bladder-recurrence-free survival: HR 1.411, 95% CI 1.141–1.747, p = 0.002, respectively). Based on our findings, UT appeared to be more malignant and had a worse prognosis than RPT.

Background 5α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5α-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, using the Taiwan National Health Insurance database. Methods The data of this retrospective cohort study were sourced from the Longitudinal Health Insurance Database of Taiwan, compiled by the Taiwan National Health Insurance database from 1996 to 2010. It consists of 18,530 men with bladder cancer, of whom 474 were 5-ARIs recipients and 4384 men with upper tract urothelial carcinoma, of whom 109 were 5-ARIs recipients. Propensity Score Matching on the age and geographic data was done at the ratio of 1:10. We analyzed the odds ratios (OR) and 95% confidence interval (CI) of the risk of bladder cancer death, bladder cancer recurrence rate and upper tract urothelial carcinoma related death by the 5-ARIs administration. Results Those who received 5-ARIs showed a lower risk of bladder cancer related death compared to nonusers in multivariable adjusted analysis (OR 0.835, 95% CI 0.71–0.98). However, there was no significant difference in the bladder cancer recurrence rate (OR 0.956, 95% CI 0.82–1.11) and upper tract urothelial carcinoma related mortality in multivariable adjusted analysis (OR 0.814, 95% CI 0.6–1.1). Conclusions Patients who receive 5-ARIs have lower bladder cancer related mortality compared to those who don’t. 5-ARIs may prove to be a viable strategy to improve bladder cancer outcomes.

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Background The pandemic of COVID-19 has disrupted the clinical pathway for patients with suspected upper tract urothelial carcinoma (UTUC). This aims to investigate the optimal management of UTUC during the pandemic by determining 1) Whether a three-month delay of RNU leads to worsened overall survival, 2) Whether radical nephroureterectomy (RNU) can be performed without prior diagnostic ureteroscopy (URS). Methods Consecutive patients with RNU performed for suspected UTUC in four hospitals in Hong Kong and Taiwan were included. Patients with histologically proven UTUC and with RNU performed within one year were dichotomized into early (≤3 months) and delayed (>3 months) RNU groups. Diagnostic performances of predictive models based on pre-URS factors (gross haematuria, suspicious or malignant urine cytology, and filling defect or contrast-enhancing mass on computed tomography), with or without URS, were analysed using receiver operating characteristics and area under curve (AUC). Overall survival was analysed using Kaplan-Meier method and multivariate Cox regression analysis. Results Between 2000 and 2019, 665 patients underwent RNU, and 491 of them had prior diagnostic URS. The early RNU group had a better overall survival ( P = 0.015). Early RNU was associated with a better overall survival upon multivariate analysis (HR 1.55, 95% CI 1.03–2.33, P = 0.035). Large tumour size, multi-focal tumour, T2 or above disease, and positive nodal status were associated with a poorer overall survival. A combination of any 2 out of the 3 pre-URS factors achieved a positive predictive value of 99.5 to 100%. Presence of all 3 pre-URS factors achieved an AUC of 0.851 with URS, and AUC of 0.809 without URS. Conclusions A delay of RNU for over 3 months was associated with poorer overall survival and has to be avoided despite the current COVID-19. We can also consider direct RNU based on clinical factors alone. This also avoids URS hospitalization and expedites the clinical pathway of UTUC.