Rectifying disorder of extracellular matrix to suppress urethral stricture by protein nanofilm-controlled drug delivery from urinary catheter.

Urethral stricture secondary to urethral injury, afflicting both patients and urologists, is initiated by excessive deposition of extracellular matrix in the submucosal and periurethral tissues. Although various anti-fibrotic drugs have been applied to urethral stricture by irrigation or submucosal injection, their clinical feasibility and effectiveness are limited. Here, to target the pathological state of the extracellular matrix, we design a protein-based nanofilm-controlled drug delivery system and assemble it on the catheter. This approach, which integrates excellent anti-biofilm properties with stable and controlled drug delivery for tens of days in one step, ensures optimal efficacy and negligible side effects while preventing biofilm-related infections. In a rabbit model of urethral injury, the anti-fibrotic catheter maintains extracellular matrix homeostasis by reducing fibroblast-derived collagen production and enhancing metalloproteinase 1-induced collagen degradation, resulting in a greater improvement in lumen stenosis than other topical therapies for urethral stricture prevention. Such facilely fabricated biocompatible coating with antibacterial contamination and sustained-drug-release functionality could not only benefit populations at high risk of urethral stricture but also serve as an advanced paradigm for a range of biomedical applications.

Perioperative Circulating Tumor Cells (CTCs), MCTCs, and CTC-White Blood Cells Detected by a Size-Based Platform Predict Prognosis in Renal Cell Carcinoma.

To explore the clinical significance of the perioperative counts of circulating tumor cells (CTCs), mesenchymal CTCs (MCTCs), and CTC- white blood cells (WBCs) in renal cell carcinoma patients. A total of 131 patients with renal cancer who underwent operation excision from our hospital were enrolled. In addition, 20 patients with benign renal diseases were recruited as a control. Blood samples were collected from the 131 patients, before operation and 3 months after surgery. Samples were also obtained simultaneously from the control group. CanPatrol CTC detection technique was used to enrich and identify CTCs, MCTCs, and CTC-WBCs. All enrolled patients were T1-3N0M0. From these, 52 patients with renal cancer underwent radical resection, while other 79 patients underwent nephron-sparing surgery. The positive rate of CTC, MCTC, and CTC-WBC before surgery were 95.4% (125/131), 61.1% (80/131), and 11.5% (15/131), respectively. Preoperative total CTCs, MCTCs, or CTC-WBCs were poorly correlated with patients' parameters. Preoperative CTC, MCTC, or CTC-WBC showed no association with progression-free survival (PFS). In contrast, postoperative total CTCs (≥6), positive MCTCs, and positive CTC-WBCs significantly correlated with recurrence and metastasis. These results remained independent indicators for worse PFS. In addition, the increased CTC and MCTC count after surgery also correlated with unfavorable PFS. The detection of six or more total CTCs, MCTC, or CTC-WBCs in peripheral blood after surgery might help to identify a subset of patients that have higher recurrent risk than the overall population of patients with at different stages of renal cancer.

Clinical application of drug sensitive gene detection in postoperative instillation for non-muscle invasive bladder cancer.

BACKGROUND: Bladder cancer is the most common malignant tumor of the urinary system. One of the biological characteristics of NMIBC is the high recurrence rate after surgery. The implementation of this project aimed to investigate the role of pharmacogenomic testing-guided intravesical perfusion of chemotherapeutic agents in the postoperative perfusion therapy for non-muscle invasive bladder cancer. METHOD: From January 2015 to December 2016, 298 patients with non-muscle-invasive bladder cancer were enrolled in this prospective study. These patients received chemotherapy drugs after electrotherapy. According to the presence or absence of tumor susceptibility gene detection after surgery, they were divided into two groups, including the drug sensitive group(N = 44) and the control group(N = 254). The drug sensitive group received bladder infusion therapy with sensitive chemotherapy drugs based on drug sensitivity gene detection results. The control group received intravesical instillation of pirarubicin. The preoperative general data and tumor grade of patients were recorded. Cystoscopy was performed before and every 3 months after surgery. The chest CT, upper abdomen CT, renal function, and urinary routine tests were performed. Tumor recurrence, metastasis and tumor-related death were recorded and evaluated during follow-up. RESULTS: The drug sensitive group, which selected high-sensitivity drugs for intravesical instillation therapy based on gene expression, has a significantly lower relapse rate (11.36% vs 37.40%, P < 0.05) and a significantly longer time to relapse (17.80 ± 7.20 month vs11.20 ± 6.10 month, P < 0.05) compared with the control group. There were no significant differences in the time of mortality and death time between two groups. CONCLUSION: The pharmacogenomic testing-directed bladder instillation of chemotherapeutic drugs may be more effective than empiric drug administration in reducing the recurrence rate of non-muscle-invasive bladder cancer.

Association of ATG7 Polymorphisms and Clear Cell Renal Cell Carcinoma Risk.

BACKGROUND: Kidney cancer is one of the most common cancers worldwide. Recent studies have suggested that single nucleotide polymorphisms (SNPs) in autophagy-related gene are associated with the risk of kidney cancer. OBJECTIVE: This study was undertaken to investigate the association of autophagyrelated gene 7 (ATG7) polymorphisms with the risk of clear cell renal cell carcinoma (ccRCC) in the Chinese Han population. METHODS: Blood samples were collected from 293 ccRCC patients and 297 healthy controls. Three ATG7 polymorphisms (rs1375206, rs2606736 and rs6442260) were genotyped by Agena MassARRAY. The association was estimated by genetic models and stratification analyses. RESULTS: A significant association was observed between allele A of rs6442260 and ccRCC risk (OR = 0.76, 95% CI: 0.58-0.99, p = 0.039). Genetic model analysis revealed that rs2606736 (OR = 0.57, 95% CI: 0.34-0.95, p = 0.031) and rs6442260 (OR = 0.44, 95% CI: 0.22-0.90, p = 0.021) were associated with decreased risk of ccRCC under recessive model. Age stratification analysis showed that rs2606736 (OR = 0.67, 95% CI: 0.46-0.98, p = 0.036) and rs6442260 (OR = 0.26, 95% CI: 0.07-0.89, p = 0.014) were significantly decreased risk of ccRCC under the log-additive model in age > 55 years old and ≤ 55 years old, respectively. CONCLUSIONS: This study indicated that ATG7 polymorphisms (rs2606736 and rs6442260) have a protective role for ccRCC risk. Further large sample size and functional assays are needed to confirm our findings and reveal the role of ATG7 polymorphisms in ccRCC carcinogenesis.

Dynamic changes of different phenotypic and genetic circulating tumor cells as a biomarker for evaluating the prognosis of RCC.

BACKGROUND: Circulating tumor cells (CTCs) and relevant autophagy Beclin-1 genes expression are critical biomarkers for tumorigenesis and tumor progress. Here we investigated the relationship of dynamic changes of CTCs and Beclin-1 expression of CTCs with renal cell carcinoma (RCC) prognosis. MATERIALS AND METHODS: A total of 69 patients with RCC were enrolled and divided into two groups based on the postoperative status of distant metastasis, including metastasis-free group (n = 58) and metastatic group (n = 11). Demographic characteristics of each patient were recorded in detail. All 69 enrolled patients had received multiple CTC tests and peripheral blood samples were obtained at three different time points (1 day before operation, 6 months and 12 months after operation). Peripheral blood samples were drawn before each time point and CTCs were separated by using Can Patrol CTC enrichment technique. CTCs were divided into epithelial, mesenchymal and mixed phenotype based on different surface biomarkers. RNA in situ hybridization assay was used to detect the expression of Beclin1 gene. RESULTS: The percentages of epithelial, mesenchymal and mixed CTCs were 11.64%, 28.04% and 60.32%, respectively. There were no significant differences of initial CTCs counts between metastasis-free group (8.43 ± 5.15) and metastatic group (7.71 ± 3.82) (P > 0.05). As for metastatic group, the number of mixed CTCs at 12 months postoperatively was significantly higher than that of mixed CTCs preoperatively and 6 months postoperatively (P < 0.05). In the metastatic group, the number of Beclin1 positive CTCs was significantly higher than that of Beclin1 negative CTCs preoperatively (P < 0.05), moreover, there were several significantly changes of Beclin1 positive CTCs with different types and at different time points. CONCLUSION: The recurrence or metastasis of RCC was uncorrelated with initial CTCs counts, but probably related with the variation trend of CTCs, especially mesenchymal CTCs and Beclin1 positive CTCs.

Low-energy shock wave preconditioning reduces renal ischemic reperfusion injury caused by renal artery occlusion.

PURPOSE:: To evaluate whether low energy shock wave preconditioning could reduce renal ischemic reperfusion injury caused by renal artery occlusion. METHODS:: The right kidneys of 64 male Sprague Dawley rats were removed to establish an isolated kidney model. The rats were then divided into four treatment groups: Group 1 was the sham treatment group; Group 2, received only low-energy (12 kv, 1 Hz, 200 times) shock wave preconditioning; Group 3 received the same low-energy shock wave preconditioning as Group 2, and then the left renal artery was occluded for 45 minutes; and Group 4 had the left renal artery occluded for 45 minutes. At 24 hours and one-week time points after reperfusion, serum inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), creatinine (Cr), and cystatin C (Cys C) levels were measured, malondialdehyde (MDA) in kidney tissue was detected, and changes in nephric morphology were evaluated by light and electron microscopy. RESULTS:: Twenty-four hours after reperfusion, serum iNOS, NGAL, Cr, Cys C, and MDA levels in Group 3 were significantly lower than those in Group 4; light and electron microscopy showed that the renal tissue injury in Group 3 was significantly lighter than that in Group 4. One week after reperfusion, serum NGAL, KIM-1, and Cys C levels in Group 3 were significantly lower than those in Group 4. CONCLUSION:: Low-energy shock wave preconditioning can reduce renal ischemic reperfusion injury caused by renal artery occlusion in an isolated kidney rat model.

Low-energy shock wave preconditioning reduces renal ischemic reperfusion injury caused by renal artery occlusion

Abstract Purpose: To evaluate whether low energy shock wave preconditioning could reduce renal ischemic reperfusion injury caused by renal artery occlusion. Methods: The right kidneys of 64 male Sprague Dawley rats were removed to establish an isolated kidney model. The rats were then divided into four treatment groups: Group 1 was the sham treatment group; Group 2, received only low-energy (12 kv, 1 Hz, 200 times) shock wave preconditioning; Group 3 received the same low-energy shock wave preconditioning as Group 2, and then the left renal artery was occluded for 45 minutes; and Group 4 had the left renal artery occluded for 45 minutes. At 24 hours and one-week time points after reperfusion, serum inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), creatinine (Cr), and cystatin C (Cys C) levels were measured, malondialdehyde (MDA) in kidney tissue was detected, and changes in nephric morphology were evaluated by light and electron microscopy. Results: Twenty-four hours after reperfusion, serum iNOS, NGAL, Cr, Cys C, and MDA levels in Group 3 were significantly lower than those in Group 4; light and electron microscopy showed that the renal tissue injury in Group 3 was significantly lighter than that in Group 4. One week after reperfusion, serum NGAL, KIM-1, and Cys C levels in Group 3 were significantly lower than those in Group 4. Conclusion: Low-energy shock wave preconditioning can reduce renal ischemic reperfusion injury caused by renal artery occlusion in an isolated kidney rat model.

The Effect of Stone Composition on the Efficacy of Retrograde Intrarenal Surgery: Kidney Stones 1 - 3 cm in Diameter.

PURPOSE: The goal of this study was to analyze the effect of stone composition on the efficacy of retrograde intrarenal surgery (RIRS) with kidney stones of 1-3 cm, 1-2 cm, and 2-3 cm in diameter. METHODS: We undertook a retrospective analysis of 74 patients with kidney stones who underwent RIRS. The patients were divided into two groups based on stone composition: Group I (n=47) (calcium oxalate monohydrate and calcium phosphate) was the hard to fragment stone group and group II (n=27) (calcium oxalate dihydrate, magnesium ammonium phosphate, and uric acid) was the easy to fragment stone group. Forty-six patients with kidney stones 1 to 2 cm in diameter were divided into group A (n=30) (smaller than 20 mm, hard to fragment stones) and group B (n=16) (smaller than 20 mm, easy to fragment stones). Twenty-eight patients with stones 2 to 3 cm in diameter were divided into group C (n=17) (larger than 20 mm, hard to fragment stones) and group D (n=11) (larger than 20 mm, easy-to-crush stones). RESULTS: The stone clearance rates of group I and group II were 66.0% and 88.9%, respectively (P<0.05). The stone clearance rates of group A and group B were 73.3% and 100% (P<0.05). The stone clearance rates of group C and group D were 52.9% and 72.7%, respectively. CONCLUSION: Stone composition has a significant impact on the efficacy of RIRS in the management of 1 to 3 cm kidney stones. For 2-3 cm calcium oxalate dihydrate stones, uric acid stones, and magnesium ammonium phosphate stones, the outcome of RIRS treatment was relatively good, and RIRS is recommended.

Shock wave induces chronic renal lesion through activation of the nuclear factor kappa B signaling pathway.

PURPOSE: The mechanisms responsible for the pathogenesis of long-term renal damage induced by extracorporeal shock wave lithotripsy (ESWL) are not clear. The present study was designed to investigate the role of nuclear factor κB (NFκB) signal pathway in the pathogenesis of chronic shock wave-induced renal damage in rat model. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were exposed to ESWL under the guidance of X-rays. On days 1, 3, 7, 35, and 105 postexposures to shock wave, the animals were killed to examine the changes in renal histology and functions, and NFκB activity. The expression of NFκB-dependent fibrogenic genes was also analyzed. Pyrrolidine dithiocarbamate (PDTC), a specific NFκB inhibitor, was used to further investigate the involvement of NFκB. RESULTS: The applied shock wave caused a transient decline in renal function and induced chronic morphological changes such as tubular injury and interstitial fibrosis. NFκB was significantly activated in renal cortex. PDTC had little or no effects on the shock-wave-induced transient renal damage, but attenuated the long-term renal lesions associated with NFκB activation. In addition, the shock wave exposure also up-regulated the expression of transforming growth factor-ß1 (TGF-ß1), which was also blocked by PDTC. CONCLUSION: NFκB plays an important role in the progression of shock-wave- induced long-term renal damage in rat model.

Shock wave induced kidney injury promotes calcium oxalate deposition.

PURPOSE: Extracorporeal shock wave lithotripsy is the preferred treatment for upper urinary tract renal calculi. However, this treatment is associated with a high rate of recurrent renal calculi. Shock wave therapy can result in renal epithelial cell injury, which in turn is a most important factor in calculus formation. We investigated the influence of kidney damage secondary to shock waves on Ca oxalate crystal retention in the kidney. MATERIALS AND METHODS: A total of 32 rats were randomly divided into 4 groups, including group 1--controls, group 2--sham treated rats given 25 ml 0.75% ethylene glycol per day for 14 days, group 3--rats given 15 kV 1 Hz shock waves 500 times to the left kidney, followed by 25 ml 0.75% ethylene glycol daily for 14 days, and group 4--rats with the same treatment as group 3 except the number of impacts was increased to 1,000. The 2 kidneys were removed at the end of the experiment. Ca oxalate crystals were observed by surgical microscopy in kidney sections stained with hematoxylin and eosin. Crystal morphology was determined using polarizing microscopy. Acidified kidney tissue homogenate was examined for Ca and oxalate content by colorimetry (Sigma). RESULTS: Kidney sections showed that kidneys that did not receive shock waves had fewer crystals than kidneys with shock waves, which had crystals in major areas. In the left kidney in groups 2 to 4 the mean +/- SD quantity of Ca was 16.88 +/- 6.41, 28.58 +/- 7.54 and 40.81 +/- 15.29 micromol/gm wet kidney and the mean quantity of oxalate was 8.44 +/- 6.80, 20.52 +/- 7.70, 31.76 +/- 14.14 micromol/gm wet kidney, respectively. Ca oxalate density increased with the number of shock wave impacts. CONCLUSIONS: Kidney damage caused by shock wave treatment can increase Ca oxalate crystal retention in the kidneys of rats in this stone model.

Pyrrolidine dithiocarbamate attenuate shock wave induced MDCK cells injury via inhibiting nuclear factor-kappa B activation.

Shock wave lithotripsy (SWL)-induced renal damage appears to be multifactorial. Recent data indicated that the mechanism of renal tissue damage secondary to SWL is similar to that of ischemia reperfusion injury. Nuclear factor-kappa B (NFkappaB) and its target genes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), have been demonstrated to play a very important role in a variety of cells or tissues ischemia reperfusion injuries. Thus in the present study, using an in vitro model MDCK cells, we investigated the role of NFkappaB and its target cytotoxic enzyme in shock wave-induced renal cellular damage. We also examined whether inhibition this pathway by pyrrolidine dithiocarbamate (PDTC) is contributed to alleviate SWL-caused cell damage. Suspensions of MDCK cells were placed in containers for shock wave exposure. Three groups of six containers each were examined: control group, no shock wave treatment and SWL group, which received 100 shocks at 18 kV; 3 SWL + PDTC group. PDTC were added to the suspensions before shock wave exposure. After shock wave 0, 2, 4, 6 and 8 h, respectively, the cell supernatants were detected for the level of MDA and release of LDH. At post-shock wave 8 h, cells were harvested to detect the nuclear translocation of NFkappaBp65 by immunofluorescence staining. Degradation of IkappaB-a (an inhibitor protein of NFkappaB) and expression of iNOS and COX-2 were also examined by western blotting. Our results indicated that shock wave initiated the apparent activation of NFkappaB, which in turn induced high expression of iNOS and COX-2. Blocking degradation of IkappaB-a by PDTC was contributed to decrease the expression of iNOS. And the level of MDA and the release of LDH were also significantly reduced by using PDTC. However, the degree of COX-2 expression does not differ significantly between SWL and SWL + PDTC groups. Activation of NFkappaB and subsequent expression of its target cytotoxic enzyme have been demonstrated to be a potential and crucial mechanism in SWL-induced renal cell damage. Blocking this pathway by PDTC is contributed to protect against cellular damage from shock wave.