CLIC3 interacts with NAT10 to inhibit N4-acetylcytidine modification of p21 mRNA and promote bladder cancer progression.

Chromatin accessibility plays important roles in revealing the regulatory networks of gene expression, while its application in bladder cancer is yet to be fully elucidated. Chloride intracellular channel 3 (CLIC3) protein has been reported to be associated with the progression of some tumors, whereas the specific mechanism of CLIC3 in tumor remains unclear. Here, we screened for key genes in bladder cancer through the identification of transcription factor binding site clustered region (TFCR) on the basis of chromatin accessibility and TF motif. CLIC3 was identified by joint profiling of chromatin accessibility data with TCGA database. Clinically, CLIC3 expression was significantly elevated in bladder cancer and was negatively correlated with patient survival. CLIC3 promoted the proliferation of bladder cancer cells by reducing p21 expression in vitro and in vivo. Mechanistically, CLIC3 interacted with NAT10 and inhibited the function of NAT10, resulting in the downregulation of ac4C modification and stability of p21 mRNA. Overall, these findings uncover an novel mechanism of mRNA ac4C modification and CLIC3 may act as a potential therapeutic target for bladder cancer.

The Whitaker test: a predictive tool for evaluating the surgical efficacy of upper urinary tract reconstruction in patients carrying a nephrostomy tube after surgery.

PURPOSE: To explore the role of the Whitaker test in evaluating the postoperative outcome of upper urinary tract reconstruction surgery in patients carrying a nephrostomy tube after surgery. PATIENTS AND METHODS: This was a prospective observational study performed in 42 patients with nephrostomy tube undergoing the Whitaker test after upper urinary tract reconstruction surgery between January 2020 and December 2021. Data on clinical information, the Whitaker test and surgical procedure were collected prospectively, and the long-term follow-up results were analysed retrospectively. RESULTS: The 46 ureters of 42 patients (right 16, left 22, bilateral 4) underwent six common upper urinary tract surgical reconstruction procedures and one combined procedure, including pyeloplasty, ureteroureterostomy, lingual mucosal onlay graft, appendiceal onlay flap, ureteral reimplantation, Boari flap, and ipsilateral lingual mucosal onlay graft combined ureteral reimplantation. All patients underwent the Whitaker test successfully without any discomfort after examination. The postoperative Whitaker test showed 43 kidneys without obstruction and 3 kidneys with obstruction. At a median follow-up of 18 months (range 13-31), the follow-up results showed that the overall success rate of the surgery was 100% (46/46). Concerning the concordance Whitaker test and follow-up results, the observed proportion of agreement was 93.5% (43/46). CONCLUSION: The Whitaker test can achieve similar consistency with the long-term follow-up results after upper urinary tract reconstruction surgery and can be used as a tool to evaluate the surgical efficacy of upper urinary tract reconstruction surgery, which can provide a prognostic efficacy evaluation for patients carrying a nephrostomy tube after surgery.

Treating Multifocal Ureteral Strictures with Combined Techniques: 14 Cases of Initial Experience.

Purpose: To evaluate the safety and feasibility of lingual mucosal graft ureteroplasty (LMGU) combined with ureteral reimplantation (UR) for repairing managing multifocal ureteral strictures (MUS). Methods: Between December 2020 and December 2022, 14 patients underwent LMGU combined with UR. Their perioperative data were collected retrospectively and analyzed. For the proximal diseased ureter, the narrow segment was incised longitudinally to open the ventral wall of ureter, and a lingual mucosal graft was placed as an onlay graft. Meanwhile, UR was applied to treat distal ureteral strictures. Results: Of 14 patients, three (21.4%) had previously undergone a failed ureteral reconstruction. The mean (standard deviation [SD]) proximal stricture length was 4.0 cm (1.56), and distal ureteral stricture length was 4.3 cm (0.94). The mean (SD) operative time was 236 minutes (57), the estimated blood loss was 78 mL (41.5), and the length of postoperative stay was 6 days. One (7%) patient underwent double LMGU to treat proximal 2 segments of ureteral stricture. No open conversions and intraoperative complications occurred. With a mean follow-up of 15 months (range 6-29), the recurrence-free rate was 14/14 (100%). Conclusions: LMGU combined with UR is a feasible and effective technique for managing MUS and can be an alternative to ileal ureteral replacement or renal autotransplantation in some selected patients with MUS.

Correction: Metformin inhibits the proliferation of benign prostatic epithelial cells.

[This corrects the article DOI: 10.1371/journal.pone.0173335.].

Robotic-assisted appendiceal onlay flap ureteroplasty combined with ureteral reimplantation for multifocal ureteral strictures: Case report and technical description.

BACKGROUND: To describe the surgical technique of robotic-assisted appendiceal onlay flap ureteroplasty combined with ureteral reimplantation to repair unilateral multifocal ureteral strictures in one stage and report 9-month follow-up outcomes. METHOD: A longitudinal ventral incision of proximal ureter strictures No. 1 and 2 was performed, and the appendix was detubularised along its antimesenteric border. Then, the appendiceal onlay flap was anastomosed with the spatulated ureter in an onlay fashion. To manage the distal ureteral stricture No. 3, ureteral reimplantation was performed in a tension-free manner. RESULTS: Voiding cystourethrography and antegrade urography showed urine regurgitation into the ureter without dilation and no obstruction of the reconstructed ureteral segment 7 weeks after surgery. No postoperative complications occurred during the 9-month follow-up. CONCLUSIONS: Robotic-assisted appendiceal onlay flap ureteroplasty combined with ureteral reimplantation appears to be a safe and effective surgical method for repairing the unilateral multifocal ureteral strictures.

Robotic-assisted double lingual mucosal graft ureteroplasty for multifocal ureteral strictures: Case report and technical description.

BACKGROUND: Ureteroplasty with a single onlay graft for proximal ureter stricture has been widely used in the clinic. However, robotic ureteroplasty with a double lingual mucosal graft (RU-DLMG) has not been reported. METHODS: The intraoperative measured ureteral stricture lengths of patient 1 were 1.8, 2.5, and 4.6 cm, and those of patient 2 were 2.5 and 3.5 cm. We performed a RU-DLMG in which the diseased ureter was incised longitudinally from the ventral side and repaired with a double lingual mucosal graft to widen the ureteral lumen. Because of the presence of a distal ureter stricture, RU-DLMG combined with ureteral reimplantation was performed in patient 1. RESULTS: Antegrade urography showed no obstruction of the reconstructed ureteral segment after removing the ureteral stent. The patients had no complaints about the donor site and flank pain during the 12-month follow-up. CONCLUSIONS: RU-DLMG appears to be a suitable option for multifocal ureteral strictures.

ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer.

OBJECTIVE: Cisplatin (CDDP)-based chemotherapy is a first-line, drug regimen for muscle-invasive bladder cancer (BC) and metastatic bladder cancer. Clinically, resistance to CDDP restricts the clinical benefit of some bladder cancer patients. AT-rich interaction domain 1A (ARID1A) gene mutation occurs frequently in bladder cancer; however, the role of CDDP sensitivity in BC has not been studied. METHODS: We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology. IC50 determination, flow cytometry analysis of apoptosis, and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A. qRT-PCR, Western blotting, RNA interference, bioinformatic analysis, and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC. RESULTS: It was found that ARID1A inactivation was associated with CDDP resistance in BC cells. Mechanically, loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3 (EIF4A3) through epigenetic regulation. Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399 (circ0008399), a novel circular RNA (circRNA) identified in our previous study, which, to some extent, showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells. Importantly, EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP. CONCLUSION: Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.

Regulation of CD8+ T cells infiltration and immunotherapy by circMGA/HNRNPL complex in bladder cancer.

The limited success of immunotherapies targeting immune checkpoint inhibitors is largely ascribed to the lack of infiltrating CD8+ T lymphocytes. Circular RNAs (circRNAs) are a novel type of prevalent noncoding RNA that have been implicated in tumorigenesis and progression, while their roles in modulating CD8+ T cells infiltration and immunotherapy in bladder cancer have not yet been investigated. Herein, we uncover circMGA as a tumor-suppressing circRNA triggering CD8+ T cells chemoattraction and boosting the immunotherapy efficacy. Mechanistically, circMGA functions to stabilize CCL5 mRNA by interacting with HNRNPL. In turn, HNRNPL increases the stability of circMGA, forming a feedback loop that enhances the function of circMGA/HNRNPL complex. Intriguingly, therapeutic synergy between circMGA and anti-PD-1 could significantly suppress xenograft bladder cancer growth. Taken together, the results demonstrate that circMGA/HNRNPL complex may be targetable for cancer immunotherapy and the study advances our understanding of the physiological roles of circRNAs in antitumor immunity.

Oral mucosal graft ureteroplasty versus ileal ureteric replacement: a meta-analysis.

OBJECTIVES: To describe outcomes of oral mucosal graft ureteroplasty (OMGU) and ileal ureter replacement (IUR) and determine the relative merits of both procedures. METHODS: Databases (including PubMed, Embase and Cochrane) were interrogated for eligible trials that assessed outcomes of OMGU or IUR from 2000 to 30 July 2022. The variables analysed were reconstruction success rates, stricture length, hospital stays, perioperative complications and long-term complications. RESULTS: A total of 23 single-arm studies were included. The pooled reconstruction success rates for OMGU and IUR were 94.9% (95% confidence interval [CI] 91.0%-97.7%) and 85.8% (95% CI 81.0%-90.0%), respectively. Stricture length of patients in the OMGU and IUR groups were 3.73 (95% CI 3.17-4.28) and 11.55 (95% CI 9.82-13.29) cm, respectively. The maximal stricture length repaired by OMGU was 8 cm. The hospital stays were 5.85 (95% CI 3.88-7.82) and 11.55 (95% CI 6.93-16.17) days in the OMGU and IUR groups, respectively. The incidences of low-grade postoperative complications were 13.6% (95% CI 6.9%-20.3%) and 27.3% (95% CI 19.5%-35.1%), high-grade postoperative complications were 4.6% (95% CI 1.8I-8.5%) and 13.0% (95% CI 9.4%-17.1%), and long-term complications (occurred at > 3months) were 9.0% (95% CI 1.7%-20.0%) and 35.4% (95% CI 25.8%-45.6%) in the OMGU and IUR groups, respectively. CONCLUSION: An OMGU is an effective, minimally invasive, and safe alternative to IUR for the management of long ureteric strictures. OMGU was the preferred treatment for long ureteric strictures, especially obstructed ureter segments of ≤8 cm.

Changes in the Water-Energy Coupling Relationship in Grain Production: A Case Study of the North China Plain.

Water consumption and energy consumption are inevitable in grain production, but few studies have focused on the integrated assessment of these two indicators and their relationships. To address the research deficiency, taking the North China Plain (NCP) as a case study, this paper quantifies the changes in grain crop planting structure and the accompanying changes in irrigation water consumption (IWC) and energy consumption (EC) in the NCP. On this basis, the water-energy coupling index (CI) is constructed to analyze the water-energy coupling relationship in the context of grain crop planting structure change. The results revealed that the sown area of three of the four main grain crops in the NCP, namely winter wheat, summer maize, and rice, roughly increased in the south and decreased in the north, while the sown area of spring maize increased in most counties where it was planted in the NCP from 2000 to 2015. With the change of grain crop planting structure, IWC and EC of winter wheat in the NCP decreased by 19.87 × 106 m3 and 16.78 × 108 MJ, respectively, mainly distributed in the Beijing-Tianjin-Hebei region, while IWC and EC of other crops all increased. In terms of CI values, although that of spring maize increased, those of winter wheat, summer maize, and rice all decreased, and the overall CI values of grain production in the NCP decreased from 0.442 in 2000 to 0.438 in 2015, indicating that grain crop distribution has been optimized toward a less water- and energy-intensive and more sustainable layout in the NCP. This paper can add case and methodological support to the food-water-energy (FEW) nexus research and can also provide policy suggestions for regional crop optimization layout and conservation of both water and energy resources.

Lingual Mucosal Graft Ureteroplasty for Long Proximal Ureteral Stricture: 6 Years of Experience with 41 Cases.

BACKGROUND: Management of a long proximal ureteral stricture is challenging. Lingual mucosal graft ureteroplasty (LMGU) is a novel minimally invasive technique for ureteral reconstruction that avoids the morbidity of bowel interposition or autotransplantation. OBJECTIVE: To evaluate the long-term effectiveness of LMGU for managing long, complex proximal ureteral strictures in a multi-institutional cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study involved data for 41 patients treated with LMGU at three centers between June 2015 and January 2021. SURGICAL PROCEDURE: LMGU was performed using either an onlay ureteroplasty in which the diseased ureter was incised ventrally and repaired with a lingual mucosal graft (LMG) to widen the ureteral lumen, or an augmented anastomotic technique in which the obliterated segment of the ureter was excised and reanastomosed primarily on dorsal side, and an LMG was placed on the ventral side. MEASUREMENTS: Pre-, intra-, and postoperative variables and outcomes were assessed. A descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: Of 41patients, 40 were operated with laparoscopic procedures and one with a robot. Twenty-four (59%) patients underwent an onlay ureteroplasty, and 17 (41%) underwent an augmented anastomotic ureteroplasty. The reconstructed ureter was wrapped with omentum in 90% of cases. The median (range) stricture length was 4.8 cm (2.0-8.0), operative time was 166 min (98-306), and estimated blood loss was 65 ml (15-220). No open conversions and intraoperative complications occurred. At a median follow-up of 35 mo (range 13-80), the overall success rate was 97.6% (40/41). CONCLUSIONS: LMGU is a safe, feasible, and effective long-term technique for managing long, complex proximal ureteral strictures. PATIENT SUMMARY: We reported a novel technique for long proximal complex ureteral strictures using an onlay lingual mucosal graft (LMG). Our 6-yr outcomes demonstrate that onlay LMG ureteroplasty is a safe, feasible, and effective long-term procedure for ureteral reconstruction.

Laparoscopic onlay lingual mucosal graft ureteroplasty combined with ureterovesical reimplantation for one-stage reconstruction of complex ureteral strictures: a case report.

The treatment of ureteral stricture is a challenging task, especially when multiple strictures are present. Here, we report on a 63-year-old male patient diagnosed with hydronephrosis with left ureteral strictures who was admitted to our hospital. During treatment, a left percutaneous nephrostomy tube was inserted for hydronephrosis. Antegrade and retrograde pyelography were performed simultaneously. The results suggested there were 3 segment ureteral strictures in the left ureter: 2 located in the distal ureter and 1 in the proximal ureter. The treatment choices for multiple ureteral strictures are kidney autotransplantation or an ileal ureteral replacement (IUR), which are both morbid procedures and are technically challenging. With the excellent results of lingual mucosal graft (LMG) in ureteroplasty, this patient underwent a one-stage left ureter reconstruction with combined laparoscopic LMG ureteroplasty and ureterovesical reimplantation. However, disease of the oral mucosa and a reduced bladder volume caused by radio cystitis or chemical cystitis, may limit the use of this technique. Regular postoperative antegrade pyelography and the Whitaker test showed the unimpeded drainage of the left ureter. Based on the satisfactory outcome of this patient, combined laparoscopic LMG ureteroplasty and ureterovesical reimplantation for unilateral multiple ureteral strictures is a viable option that has fewer complications.

Circ0008399 Interaction with WTAP Promotes Assembly and Activity of the m6A Methyltransferase Complex and Promotes Cisplatin Resistance in Bladder Cancer.

Cisplatin (CDDP)-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer, yet most patients rapidly develop resistance. N6-methyladenosine (m6A) methylation is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of CDDP chemosensitivity in bladder cancer remain unclear. Furthermore, studies have not yet fully elucidated whether circular RNA (circRNA) can directly regulate m6A modification of mRNA. Here we report upregulation of a novel circRNA, hsa_circ_0008399 (circ0008399), by eukaryotic translation initiation factor 4A3 (EIF4A3) in bladder cancer tissues and cell lines. Functionally, circ0008399 inhibited apoptosis of bladder cancer cells. Mechanistically, circ0008399 bound Wilms' tumor 1-associating protein (WTAP) to promote formation of the WTAP/METTL3/METTL14 m6A methyltransferase complex. Circ0008399 increased expression of TNF alpha-induced protein 3 (TNFAIP3) by increasing its mRNA stability in an m6A-dependent manner. In patients with bladder cancer, high expression of circ0008399 and WTAP was associated with poor outcomes. Importantly, activation of the circ0008399/WTAP/TNFAIP3 pathway decreased bladder cancer chemosensitivity to CDDP, and targeting the circ0008399/WTAP/TNFAIP3 axis enhanced the CDDP efficacy. Collectively, these findings give novel insights into circRNA-mediated regulation of m6A modifications and provide potential therapeutic targets for bladder cancer. SIGNIFICANCE: A newly characterized circRNA circ0008399 binds WTAP to modulate expression of target RNA through m6A modification and reduce cisplatin sensitivity in bladder cancer, implicating the potential therapeutic value of targeting this axis.

Should surgical drainage after lateral transperitoneal laparoscopic adrenalectomy be routine?-A retrospective comparative study.

BACKGROUND: Whether to use surgical drains after abdominal surgery or not has received much attention since a hundred years ago. Nowadays, lateral transperitoneal laparoscopic adrenalectomy (LTLA) is a widely used technique to treat adrenal tumors worldwide. However, the placement of drains after LTLA remains controversial. METHODS: Data of 150 patients, who underwent LTLA between October 2014 and September 2020 by the same lead surgeon, were collected, including demographic, pathology, preoperative, operative variables and postoperative complications. The patients were divided into two groups, with and without drainage. The postoperative recovery of the two groups was compared. RESULTS: Among 150 patients (65 men and 85 women, median age 48 years, median BMI 23.53), 89 patients had no drainage and 61 patients had drainage after surgery. Variables of the two groups were analyzed. Placement of drains correlated with long operative time (P<0.01). Patients with drain had longer hospital stays (P<0.001) and a higher incidence of postoperative complications (P=0.022). Other factors, including tumor size (P=0.61), tumor location (P=0.387), ASA score (P=0.687), pathology (P=0.55), VAS pain score (P=0.41), intraoperative blood loss (P=0.11), were not found to be significantly associated with drain placement. There was no conversion to open surgery in both groups. Moreover, no mortality was observed in either group. CONCLUSIONS: This study revealed that it is feasible and safe not to leave a drain in selective and uncomplicated patients and that surgical drainage should not be routine after LTLA.