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BACKGROUND: Increasing number of patients with metastatic renal cell carcinoma (mRCC) are receiving subsequent programmed cell death protein-1 (PD-1) inhibitor combination therapy following tyrosine-kinase inhibitor (TKI) resistance. To explore whether PD-1 inhibitor would further deteriorate proteinuria and renal function, we observed their proteinuria’s and renal function’s condition since the administration of PD-1 inhibitor. METHODS: To assess the change in proteinuria and renal function, the data of 141 patients with mRCC treated with TKI were collected, 66 of whom were further prescribed PD-1 inhibitor. Proteinuria and estimated glomerular filtration rate (eGFR) were measured and analyzed. Logistic regression models were established to identify the predictors of proteinuria deterioration and significant eGFR decline (≥15%). RESULTS: Of the 141 patients, 74 (52%) had an increase in proteinuria level after an average of 22.98 months of TKI treatment. In multivariate analysis, longer duration of TKI (>12 months) and administration of PD-1 inhibitor were independent predictors for proteinuria deterioration. The median eGFR decreased from 81.56 mL/min/1.73 m(2) to 66.75 mL/min/1.73 m(2) after TKI treatment. Logistic regression identified older age (>60 years old) and longer duration of TKI (>12 months) as independent predictors for significant eGFR decline. Finally, of the 66 patients who received subsequent PD-1 inhibitor, 34 had sufficient proteinuria and eGFR data at follow-up. The level of proteinuria increased further after the administration of PD-1 inhibitor, although the decrease in eGFR was not statistically significant (P=0.182). Log-rank analysis identified proteinuria deterioration and eGFR decline were both significantly associated with patent’s survival (P

Clinically, patients with urothelial carcinoma of the bladder (UCB) with tumor metastasis are incurable. To find new therapeutic strategies, the mechanisms underlying UCB invasion and metastasis should be further investigated. In this study, zinc finger and homeobox 3 (ZHX3) was first screened as a critical oncogenic factor associated with poor prognosis in a UCB dataset from The Cancer Genome Atlas (TCGA). These results were also confirmed in a large cohort of clinical UCB clinical samples. Next, we found that ZHX3 could promote the migration and invasion capacities of UCB cells both in vitro and in vivo. Mechanistically, coimmunoprecipitation (coIP) and mass spectrometry (MS) analysis indicated that ZHX3 was a target of tripartite motif 21 (TRIM21), which mediates its ubiquitination, and subsequent degradation. Notably, RNA‐seq analysis showed that ZHX3 repressed the expression of regulator of G protein signaling 2 (RGS2). Generally, our results suggest that ZHX3 plays an oncogenic role in UCB pathogenesis and might serve as a novel therapeutic target for UCB., ZHX3 promotes UCB cell invasive and metastatic capacities. ZHX3 could activate RhoA by repressing RGS2. TRIM21 promotes ZHX3 ubiquitination and degradation in UCB cells.

Multidrug resistance gene 1 (MDR1), a key factor contributing to drug insensitivity, has been associated with treatment failure and poor prognoses in various cancers, including bladder urothelial carcinoma (UC). Here we show that positive Nkx2.8 expression was associated with better prognosis of UC patients received chemotherapy. Patients with positive Nkx2.8 expression had promising prognosis from adjuvant chemotherapy. Enforced expression of Nkx2.8 promotes drug sensitivity of UC cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of MDR1 by binds directly to the MDR1 promoter and transcriptionally represses MDR1 expression. P-gp inhibitor reversed chemosensitivity inhibition by Nkx2.8 scilencing. In clinical UC specimens, expression of Nkx2.8 inversely correlated with P-gp expression, and UC patients with Nkx2.8 positivity and low P-gp expression displayed the best prognosis. Our findings uncovered a new mechanism of chemosensitivity in UC cells and proposing Nkx2.8-MDR1 axis as a novel candidate target for therapeutic intervention of UC.

Background Radical/cytoreductive nephrectomy or nephron-sparing surgery may be thought to be not safe or unfeasible in some renal cell carcinoma (RCC) patients in which tumor is locally advanced or highly complicated. Neoadjuvant therapy may reduce the volume of the tumor, thus facilitates surgery. The aim the study is to evaluate the efficacy and safety of neoadjuvant combination of pazopanib or axitinib and PD-1-activated dendritic cell-cytokine-induced killer (PD-1/DC-CIK) cell immunotherapy in those patients. Methods Data from 16 RCC patients who received neoadjuvant pazopanib (Group P, n=9) or axitinib (Group A, n=7) plus PD-1/DC-CIK cells immunotherapy were reviewed retrospectively. A total of 9 participants that were potential candidates for radical/cytoreductive nephrectomy (RN/CN) had locally advanced tumor and 5 participants with partial nephrectomy (PN) absolute indications had highly complicated tumors. The efficacy outcomes were based on volume changes of the primary tumor, lymph nodes, and tumor thrombus in 13 participants with complete computed tomography (CT) imaging. The treatment-related toxicities and surgical complications were also reported. Results With a median of 2.1 months treatment, the overall volume of the tumors decreased by a median of 42.30% [interquartile range (IQR): 19.37-66.78%]. Specifically, the median reduction of tumor volume was 88.77 and 15.50 cm3 in group P and group A, respectively (P=0.014). However, participants in Group P were more likely to experience grade 3 or 4 treatment-related adverse events (AEs) than those in Group A (44.4% vs. 0). Finally, all participants were candidates for appropriate surgery after neoadjuvant therapy (as assessed by the surgeon), and 10 participants accepted surgery, including 5 PN, 4 RN/CN, and 1 lymph node dissection. A solitary participant had Clavien grade IV acute renal failure required dialysis and another had grade II lymphatic leakage. Conclusions Neoadjuvant combination of pazopanib or axitinib and PD-1/DC-CIK cells immunotherapy was well-tolerated and could effectively reduce the volume of tumors in locally advanced or highly complicated RCC patients.

Background The ileal conduit and ileal orthotopic neobladder were the most popular methods for urinary diversion following radical cystectomy. Stenting the anastomosis of ileo-ureter or ureter-neobladder was a common practice. However, it is still controversial if ureteral stents could prevent complications such as ureteroileal anastomosis stricture (UIAS) and ureteroileal anastomosis leakage (UIAL) after ureteral anastomosis. Objectives This study aims to investigate the role of the ureteral stent in preventing UIAS and UIAL. Data sources We systematically searched the related studies in PubMed, Embase, and Cochrane Library up to June 2020. Study eligibility criteria Cohort studies that identified the use of stent and the incidence of UIAS or UIAL were recorded. Data synthesis Comparative meta-analysis was conducted on four cohort studies for comparison of UIAS and UIAL between the stented and nonstented groups. Besides, eleven studies which reported the events of UIAS and UIAL were used for meta-analysis of single proportion. Results A total of 11 studies were qualified for analysis. Comparative meta-analysis identified that the incidence of UIAS was higher in the stented group than that in the nonstented group, but this did not reach a significant difference (odds ratio [OR]: 1.64; 95% confidence interval [CI]: 0.88–3.05; P = 0.12). Besides, there was no difference in the incidences of UIAL between the stented and the nonstented groups. On meta-analysis of single proportion, the incidence of UIAS was 7% (95% CI: 3%–10%) in the stented group and 3% (95% CI: 1%–6%) in the nonstented group. The UIAL rate was 1% (95% CI, 0%–4%) in stented patients and 2% (95% CI, 1%–4%) in nonstented patients. Conclusion Stenting the ureteroileal anastomosis resulted in a higher incidence of UIAS. There is no evidence to support ureteral stents could prevent the occurrence of UIAL after urinary diversion.

This article presents theoretical studies for parametrically excited vibrations of marine riser of the floating production, drilling, storage, and offloading system under random wave forces and earthquake excitation. The equation of motion of the riser is obtained by a mathematical method utilizing Euler beam theory and Galerkin method. The trigonometric series method is used to formulate random wave force and earthquake excitation in time domain. The dynamic analysis, spectral response analysis, and key parameters’ sensitivity analysis are conducted for the riser system. Parameter studies are conducted for the effects of wave and earthquake parameters and structural parameters on dynamics response of the riser system. The results from this study can provide valuable recommendations for the design and construction of the parametrically excited marine riser system under random wave forces and earthquake excitation and can promote widely practical application of the deep water riser in complicated environmental conditions.

This paper presents parametric studies of nonlinear wave forces on large-scale submerged tunnel element. A transportation project of submerged tunnel element under irregular wave conditions is taken as the research background. Three-dimensional diffraction potential and radiation potential associating with the motion of the floating body are utilized, and an efficient three dimensional Green function is implemented to solve the radiation-diffraction problem. A computational method for calculating the nonlinear wave forces of the submerged tunnel element is developed. The present method is validated by the existed methods and experimental data, and good agreements are observed for all test models. The effects of wave parameters and structural parameters on the second-order nonlinear wave forces are studied. Results from the present study can provide valuable recommendations for the weather window and downtime frequencies, the configuration of tugboats, the arrangement of sea-route, and the size and type of the design and construction of the submerged tunnel element.