Nomograms for Predicting the Risk of SIRS and Urosepsis after Uroscopic Minimally Invasive Lithotripsy.

Objective: To analyze the potential risk factors that affect the development of urosepsis following uroscopic minimally invasive lithotripsy and to develop a nomogram that predicts the probability of postoperative urosepsis. Methods: We retrospectively analyzed the clinical data from patients that underwent percutaneous nephrolithotripsy (PCNL) or ureteroscopic lithotripsy (URL) between January 2018 and December 2019. The enrolled patients were grouped twice according to systemic inflammatory response syndrome (SIRS) and quick sequential organ failure assessment (qSOFA). After univariate and multivariate logistic regression analyses, we identified the independent predictive factors affecting the development of postoperative SIRS and urosepsis, and built the nomograms. Results: From January 2018 to December 2019, 1959 patients underwent PCNL or URL, of whom 236 patients were accorded with the inclusion criteria. Of all 236 patients, 64 (27.12%) patients developed postoperative SIRS, and 17 (7.20%) patients developed postoperative urosepsis. Multivariate logistic regression analysis showed that positive preoperative urine culture (PUC+) (OR = 2.331, P = 0.044), procalcitonin (PCT) (OR = 1.093, P = 0.037), C-reactive protein (CRP) (OR = 1.017, P < 0.001), and neutrophil ratio (NEUT%) (OR = 1.091, P = 0.004) of postoperative were independent predictors of SIRS, and PCT (OR = 1.017, P = 0.003) and CRP (OR = 1.080, P < 0.001) were independent predictors of urosepsis. Additionally, the nomograms demonstrated good accuracy in predicting SIRS and urosepsis with a C-index of 0.884 (95% CI: 0.835-0.934) and 0.941 (95% CI: 0.885-0.996), respectively. Conclusions: The nomograms achieved the prediction of SIRS and urosepsis after uroscopic minimally invasive lithotripsy. Using this model, the risk of SIRS or urosepsis for an individual patient can be determined, which facilitates early diagnosis and rational treatment.

MicroRNA-34a Attenuates Paclitaxel Resistance in Prostate Cancer Cells via Direct Suppression of JAG1/Notch1 Axis.

BACKGROUND/AIMS: Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically centered on paclitaxel-based chemotherapy. In this study, we aimed to evaluate whether miR-34a attenuates chemoresistance to paclitaxel by regulating target genes associated with drug resistance. METHODS: We used data from The Cancer Genome Atlas to compare miR-34a expression levels in prostate cancer (PC) tissues with normal prostate tissues. The effects of miR-34a inhibition and overexpression on PC proliferation were evaluated in vitro via Cell Counting Kit-8 (CCK-8) proliferation, colony formation, apoptosis, and cell-cycle assays. A luciferase reporter assay was employed to identify the interactions between miR-34a and specific target genes. To determine the effects of up-regulation of miR-34a on tumor growth and chemo-resistance in vivo, we injected PC cells overexpressing miR-34a into nude mice subcutaneously and evaluated the rate of tumor growth during paclitaxel treatment. We examined changes in the expression levels of miR-34a target genes JAG1 and Notch1 and their downstream genes via miR-34a transfection by quantitative reverse transcription PCR (qRT-PCR) and western blot assay. RESULTS: miR-34a served as an independent predictor of reduced patient survival. MiR-34a was down-regulated in PC-3PR cells compared with PC-3 cells. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to paclitaxel while miR-34a down-regulation resulted in chemoresistance to paclitaxel in vitro. A study of gain and loss in a series of functional assays revealed that PC cells expressing miR-34a were chemosensitive. Furthermore, the overexpression of miR-34a increased the sensitivity of PC-3PR cells to chemotherapy in vivo. The luciferase reporter assay confirmed that JAG1 and Notch1 were directly targeted by miR-34a. Interestingly, western blot analysis and qRT-PCR confirmed that miR-34a inhibited the Notch1 signaling pathway. We found that miR-34a increased the chemosensitivity of PC-3PR cells by directly repressing the TCF1/ LEF1 axis. CONCLUSION: Our results showed that miR-34a is involved in the development of chemosensitivity to paclitaxel. By regulating the JAG1/Notch1 axis, miR-34a or its target genes JAG1 or Notch1 might serve as potential predictive biomarkers of response to paclitaxel-based chemotherapy and/or therapeutic targets that will help to overcome chemoresistance at the mCRPC stage.

Expression and function of muscarinic subtype receptors in bladder interstitial cells of cajal in rats.

PURPOSE: To locate the muscarinic (M) M2 and M3 receptors in bladder interstitial cells of Cajal (ICCs) and to determine the effects of M2 and M3 agonists on bladder ICCs. MATERIALS AND METHODS: A total of 30 adult male Sprague-Dawley rats weighing 225-250 g were used in this study. Double-labeled fluorescence of muscarinic receptors and c-kit was performed for co-localization. To evaluate the effect of muscarinic agents on the excitation of bladder ICCs, we analyzed the inward current of bladder ICCs using the whole-cell patch clamp. The effect of muscarinic agents on the carbachol-induced inward currents was evaluated with the whole-cell patch clamp. RESULTS: M2 and M3 receptors were confirmed in the stroma ICCs in rats' bladders with double-labeled immunofluorescence. Spontaneous action potential was observed in freshly isolated bladder ICCs. The carbachol-induced inward Ca2+ current in ICCs can be blocked by atropine. The M2 receptor antagonist methoctramine (1 µM) showed a weak inhibitory capability on the inward Ca2+ current [from 74.8 ± 9.6 to 63.3 ± 13.8 Pascal (pA), n = 12, P = .03]. While the M3 receptor antagonist 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (4-DAMP) (1 µM) significantly inhibited the inward Ca2+ current (from 78.4 ± 11.2 to 17.3 ± 7.9 pA, n = 12, P < .001). CONCLUSION: Bladder ICCs express M2 and M3 cholinergic receptors. Most muscarinic cholinergic receptor antagonists, especially the M3 antagonists, can effectively inhibit the carbamylcholine- induced inward current of bladder ICCs.