Serum Zinc, Copper, and Other Biometals Are Associated with COVID-19 Severity Markers.

The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups of subjects with mild, moderate, and severe illness, 50 examinees each. Forty-four healthy subjects of the respective age were involved in the current study as the control group. Serum metal levels were evaluated using inductively-coupled plasma mass-spectrometry. Examination of COVID-19 patients demonstrated that heart rate, respiratory rate, body temperature, C-reactive protein levels, as well as lung damage increased significantly with COVID-19 severity, whereas SpO2 decreased gradually. Increasing COVID-19 severity was also associated with a significant gradual decrease in serum Ca, Fe, Se, Zn levels as compared to controls, whereas serum Cu and especially Cu/Zn ratio were elevated. No significant group differences in serum Mg and Mn levels were observed. Serum Ca, Fe, Se, Zn correlated positively with SpO2, being inversely associated with fever, lung damage, and C-reactive protein concentrations. Opposite correlations were observed for Cu and Cu/Zn ratio. In regression models, serum Se levels were inversely associated with lung damage independently of other markers of disease severity, anthropometric, biochemical, and hemostatic parameters. Cu/Zn ratio was also considered as a significant predictor of lower SpO2 in adjusted regression models. Taken together, these findings demonstrated that metal metabolism significantly interferes with COVID-19 pathogenesis, although the causal relations as well as precise mechanisms are yet to be characterized.

Hemiablation of Localized Prostate Cancer by High-Intensity Focused Ultrasound: A Series of 35 Cases.

Prostate cancer (PrC) is one of the most common tumors diagnosed in men. The detection rate of localized PrC has been dramatically enhanced by screening and the development of visualization methods. There are currently several techniques for focal treatment available, among which the most interesting in our opinion is high-intensity focused ultrasound (HIFU). Currently, HIFU hemiablation of PrC is not an established treatment, although evidence of its effectiveness and safety is growing. We have been performing HIFU hemiablation since 2013 and here report our results to add to the evidence on the effectiveness of the technique. Between October 2013 and December 2016, we performed HIFU hemiablation of the prostate for a total of 35 patients with confirmed PrC stage

miR-93-3p inhibition suppresses clear cell renal cell carcinoma proliferation, metastasis and invasion.

miRNA dysregulation is associated with many human diseases, including cancer. This study explored the effects of miR-93-3p on clear cell renal cell carcinoma (ccRCC). We found that miR-93-3p is upregulated an average of 38-fold in 138 ccRCC specimens compared to matched normal kidney tissues, which correlated with poor patient outcome. miR-93-3p inhibition reduced ccRCC cell growth, invasion, and migration in vitro and in a mouse xenograft model. A search of the TargetScan, miRanda, and PicTar databases revealed that miR-93-3p is predicted to regulate pigment epithelium-derived factor (PEDF). A direct PEDF-miR-93-3p interaction was confirmed via dual-luciferase reporter assays. Like miR-93-3p inhibition, PEDF overexpression induced cell apoptosis and inhibited migration and invasion. Additionally, co-transfection with PEDF siRNA reversed the effects of miR-93-3p inhibition in ccRCC cells. Thus, miR-93-3p is a likely ccRCC oncogene that acts by regulating PEDF. These results suggest that miR-93-3p may predict ccRCC patient clinical outcome and serve as a novel anti-ccRCC therapeutic target.

Identification and Functional Verification of MicroRNAs in the Obese Rat With Erectile Dysfunction.

INTRODUCTION: Obesity is a potential risk factor for erectile dysfunction (ED). MicroRNAs (miRNAs) regulate the expression of genes involved in various pathophysiologic processes. AIM: To identify the miRNA profile in the corpus cavernosum (CC) of obese rats with ED and elucidate the potential function of miRNA in the pathogenesis of ED. METHODS: Obesity was induced in rats by a high-fat diet. After the erectile function test, experimental animals were divided into two groups: obese rats with ED and obese rats with normal erectile function. The CCs from these rats were collected for miRNA microarray analysis. The results were verified by real-time polymerase chain reaction analysis. Subsequently, the targets of differentially expressed miRNAs were predicted. Bioinformatics analysis was applied to predict the functions of differentially expressed miRNAs in ED. Apomorphine-induced penile erection and intracavernous pressure measurements were used to evaluate the effects of miRNA on the erectile function of rats. MAIN OUTCOME MEASURES: MiRNA expression in the CC of obese rats with ED and those with normal erectile function was detected by miRNA microarray analysis. Candidate miRNAs were validated by real-time polymerase chain reaction. Bioinformatics analysis was used to predict the functions of miRNAs. Apomorphine-induced penile erection and intracavernous pressure measurements were used to reflect the erectile function of rats. RESULTS: Sixty-eight miRNAs were differentially expressed in the CC of obese rats with ED (≥1.5-fold change). The real-time polymerase chain reaction results were consistent with the miRNA microarray analysis results. Specifically, miR-328a was significantly upregulated in rats with ED compared with control rats and was chosen for functional evaluation in the pathogenesis of ED. Overexpression of miR-328a noticeably decreased the erectile response to apomorphine and the expression of heme oxygenase-1. CONCLUSION: MiRNAs are involved in the pathogenesis of obesity-related ED. MiR-328a might facilitate the induction of ED. Bai Y, Zhang L, Jiang Y, et al. Identification and Functional Verification of MicroRNAs in the Obese Rat With Erectile Dysfunction. Sex Med 2017;5:e261-e271.

Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma.

PURPOSE: We investigated the prognostic value of PD-1 and PD-L1 expression in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: Tissue microarrays of 423 patients treated with extirpative surgery for high grade upper tract urothelial carcinoma from the International Upper Tract Urothelial Carcinoma collaboration were stained for PD-1 and PD-L1 using antibodies, including Cell Marque™ NAT105 diluted 1:250 and prediluted E1L3N® via immunohistochemistry. A 1% or greater staining rate of tumor infiltrating lymphocytes (PD-1) and tumor cells (PD-L1) was considered positive. Univariate and multivariate analyses were performed to assess independent prognosticators of survival outcomes. RESULTS: Median patient age was 70.0 years and median followup was 37.0 months. PD-1 and PD-L1 were positive in 37.2% and 26.2% of patients, respectively. PD-1 positivity was significantly associated with adverse pathological characteristics while PD-L1 positivity was associated with favorable pT stage. On univariate analysis PD-1 expression was associated with worse recurrence-free, cancer specific and overall survival. On multivariate analysis PD-1 expression was an independent prognosticator of cancer specific survival (HR 1.7, 95% CI 1.03-2.66, p = 0.039) and overall survival (HR 1.5, 95% CI 1.05-2.24, p = 0.029) but not recurrence-free survival (HR 1.4, 95% CI 0.9-2.16, p = 0.139). On univariate analysis PD-L1 expression was not significantly associated with survival outcomes. However, on multivariate analysis in patients with organ confined disease (pT2 or less, pN0/x and cM0), PD-L1 positivity was an independent prognosticator of recurrence-free survival (HR 0.2, 95% CI 0.06-0.98, p = 0.046) and overall survival (HR 0.3, 95% CI 0.11-0.63, p = 0.003). CONCLUSIONS: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and independent prognostication of worse survival outcomes. PD-L1 positivity of tumor cells was an independent prognosticator of favorable survival outcomes in cases of organ confined disease.

The role of water-jet dissection in improving erectile function and urinary continence after nerve-sparing prostatectomy.

OBJECTIVES: The aim of this study was to assess erectile function (EF) and urinary continence (UC) recovery after nerve-sparing retropubic radical prostatectomy (NS-RRPE) and nerve-sparing laparoscopic radical prostatectomy (NS-LRPE) depending on the neurovascular bundle (NVB) dissection technique used. METHODS: Twenty-four hour pad test was used to assess the degree of postoperative UC 1, 6 and 12 months after the surgery. For the purpose of EF assessment, International Index of Erectile Function-5 (IIEF-5) questionnaire was used. In addition, EF recovery assessment included the time needed to achieve a successful sexual intercourse with or without Inhibitors Phosphodiesterase 5 (IPDE5). A successful sexual intercourse was defined as an ability to achieve a strong erection enough for penetration and maintain erection for a long time, throughout the intercourse. Assessment was performed before the surgery and 8 and 6 months after the surgery. RESULTS: In the patient group with BNS + water jet dissection (WJD), the IIEF-5 score was considerably higher 8 weeks after the surgery (by 2.8 points) (р = 0.02). In 6 months, the difference between the group become more significant and reached 3.5 points (p = 0.01). Three months after urethral catheter removal, majority (95%) of patients in the NS-RPE + WJD group had no urinary incontinence (UI). For standard NS-RPE, that figure was 87%. Mild stress UI was observed in 5% of patients after NS-RPE + WJD and in 13% of patients after NS-RPE. Six months after urethral catheter removal, no significant differences in UC assessment were observed in the two groups. CONCLUSIONS: The implementation of WJD of NVB in clinical practice has made it possible to considerably improve the quality of life for postoperative patients due to good outcomes in terms of early UC and EF recovery.

Transurethral contact ureterolithotripsy in gas (СО2) medium.

BACKGROUND: Transurethral intracorporeal lithotripsy is the modality of choice for the endoscopic disintegration of large, long-standing, radiolucent or high-density stones. Despite several advantages and proven benefits of contact ureterolithotripsy/ureterolithoextraction (CULT), the application of irrigation carries significant risks of untoward perioperative events including retrograde stone migration and postoperative pyelonephritis. METHODS: We describe a new technique - endoscopic intracorporeal lithotripsy in the gas (СО2) medium. It is a prospective randomized, single blinded pilot study that included total of (n = 60) patients with urolithiasis who were allocated to either experimental or control group. Out of the total pool of patients, 30 underwent treatment with the new approach (experimental group) and other 30 (control group) had contact ureterolithotripsy in a standard of care 0.9% NaCL medium. We included patients >18 years old, with known symptomatic renal calculi disease who were eligible and scheduled for CULT and free from significant coexisting pathologies of urinary tract. RESULTS: No retrograde migration of the stone fragments into the kidney was reported in the experimental group [complications rate 0%, confidence interval (CI): 0-11.6%]. In the control group, complications were observed in eight cases (complications rate 26.7%, CI: 14.7-42.3%); retrograde migration was in five patients (16.6%), and acute pyelonephritis/exacerbation of chronic pyelonephritis was seen in three (10%) patients. There was not any acute pyelonephritis in the experimental group. Reliability of frequency differences - p = 0.0023 (χ2). CONCLUSIONS: The novel method of contact ureterolithotripsy is a safe and promising alternative to the conventional contact ureterolithotripsy in a fluid medium in a carefully selected patient population.

Postoperative Nomogram for Relapse-Free Survival in Patients with High Grade Upper Tract Urothelial Carcinoma.

PURPOSE: We developed a prognostic nomogram for patients with high grade urothelial carcinoma of the upper urinary tract after extirpative surgery. MATERIALS AND METHODS: Clinical data were available for 2,926 patients diagnosed with high grade urothelial carcinoma of the upper urinary tract who underwent extirpative surgery. Cox proportional hazard regression models identified independent prognosticators of relapse in the development cohort (838). A backward step-down selection process was applied to achieve the most informative nomogram with the least number of variables. The L2-regularized logistic regression was applied to generate the novel nomogram. Harrell's concordance indices were calculated to estimate the discriminative accuracy of the model. Internal validation processes were performed using bootstrapping, random sampling, tenfold cross-validation, LOOCV, Brier score, information score and F1 score. External validation was performed on an external cohort (2,088). Decision tree analysis was used to develop a risk classification model. Kaplan-Meier curves were applied to estimate the relapse rate for each category. RESULTS: Overall 35.3% and 30.7% of patients experienced relapse in the development and external validation cohort. The final nomogram included age, pT stage, pN stage and architecture. It achieved a discriminative accuracy of 0.71 and 0.76, and the AUC was 0.78 and 0.77 in the development and external validation cohort, respectively. Rigorous testing showed constant results. The 5-year relapse-free survival rates were 88.6%, 68.1%, 40.2% and 12.5% for the patients with low risk, intermediate risk, high risk and very high risk disease, respectively. CONCLUSIONS: The current nomogram, consisting of only 4 variables, shows high prognostic accuracy and risk stratification for patients with high grade urothelial carcinoma of the upper urinary tract following extirpative surgery, thereby adding meaningful information for clinical decision making.

Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis.

Emerging evidence has suggested the critical role of endothelial to mesenchymal transition (EndMT) in fibrotic diseases. The present study was designed to examine whether EndMT is involved in arsenic trioxide (As2O3)-induced cardiac fibrosis and to explore the underlying mechanisms. Cardiac dysfunction was observed in rats after exposure to As2O3 for 15 days using echocardiography, and the deposition of collagen was detected by Masson's trichrome staining and electron microscope. EndMT was indicated by the loss of endothelial cell markers (VE-cadherin and CD31) and the acquisition of mesenchymal cell markers (α-SMA and FSP1) determined by RT-PCR at the mRNA level and Western blot and immunofluorescence analysis at the protein level. In the in-vitro experiments, endothelial cells acquired a spindle-shaped morphology accompanying downregulation of the endothelial cell markers and upregulation of the mesenchymal cell markers when exposed to As2O3. As2O3 activated the AKT/GSK-3ß/Snail signaling pathway, and blocking this pathway with PI3K inhibitor (LY294002) abolished EndMT in As2O3-treated endothelial cells. Our results highlight that As2O3 is an EndMT-promoting factor during cardiac fibrosis, suggesting that targeting EndMT is beneficial for preventing As2O3-induced cardiac toxicity.

The cancer-retina antigen recoverin as a potential biomarker for renal tumors.

The renal cell carcinoma is the ninth most common cancer with an increasing occurrence and mortality. Recoverin is the first retina-specific photoreceptor protein that was shown to undergo aberrant expression, due to its promoter demethylation, as a cancer-retina antigen in a number of malignant tumors. In this work, we demonstrated that recoverin is indeed expressed in 68.4 % of patients with different subtypes of renal cell carcinoma, and this expression has tendency to correlate with tumor size. Interestingly, 91.7 % of patients with the benign renal tumor, oncocytoma, express recoverin as well in their tumor. Epigenetic analysis of the recoverin gene promoter revealed a stable mosaic methylation pattern with the predominance of the methylated state, with the exception of -80 and 56 CpG dinucleotides (CpGs). While the recoverin expression does not correlate withoverall survival of the tumor patients, the methylation of the recoverin gene promoter at -80 position is associated with better overall survival of the patients. This work is the first report pointing towards the association of overall survival of renal cell carcinoma (RCC) patients with promoter methylation of a cancer-retina antigen. Taken together, these data allow to consider recoverin as a potential therapeutic target and/or marker for renal tumors.