Cancer-Retina Antigens in the Urine of Bladder and Prostate Cancer Patients.

It has recently been shown that combination of arrestin and recoverin can serve as an effective urinary biomarker for renal cell carcinoma with sensitivity and specificity of over 92%. In this work, we studied the possibility of detecting these antigens in the urine in other urological oncological diseases - bladder cancer (BC) and prostate cancer (PCa). Urine samples from 40 BC patients and 40 PCa patients were analyzed using an ultrasensitive microarray immunoassay with a detection limit of 0.1 pg/ml. It was shown that in BC the sensitivity of determining combination of arrestin with recoverin is 58% (AUC 0.76, 95% CI 0.66-0.86), while in PCa it is 60% (AUC 0.7, 95% CI 0.68-0.88). It has been established that in patients with bladder and prostate cancer who had a positive test, these antigens are not detected in 90% of cases after removal of the tumor. In the future, the obtained results could become the basis for developing new approaches for timely detection of relapses of such diseases and treatment control, as well as for the development of new diagnostic methods.

Preclinical comparison of superpulse thulium fiber laser and a holmium:YAG laser for lithotripsy.

PURPOSE: A superpulse (500 W peak power) thulium fiber laser operating at a 1940 nm wavelength, suitable for lithotripsy, has recently been developed. The goal of this study was to compare stone fragmentation and dusting performance of the prototype superpulse thulium fiber laser with leading commercially available, high-power holmium:YAG lithotripters (wavelength 2100 nm) in a controlled in vitro environment. METHODS: Two experimental setups were designed for investigating stone ablation rates and retropulsion effects, respectively. In addition, the ablation setup enabled water temperature measurements during stone fragmentation in the laser-stone interaction zone. Human uric acid (UA) and calcium oxalate monohydrate (COM) stones were used for ablation experiments, whereas standard BegoStone phantoms were utilized in retropulsion experiments. The laser settings were matched in terms of pulse energy, pulse repetition rate, and average power. RESULTS: At equivalent settings, thulium fiber laser ablation rates were higher than those for holmium:YAG laser in both dusting mode (threefold for COM stones and 2.5-fold for UA stones) and fragmentation mode (twofold for UA stones). For single-pulse retropulsion experiments, the threshold for onset of stone retropulsion was two to four times higher for thulium fiber laser. The holmium:YAG laser generated significantly stronger retropulsion effects at equal pulse energies. The water temperature elevation near the laser-illuminated volume did not differ between the two lasers. CONCLUSIONS: Distinctive features of the thulium fiber laser (optimal wavelength and long pulse duration) resulted in faster stone ablation and lower retropulsion in comparison to the holmium:YAG laser.

The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance.

Cysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology.

Biomarkers of Renal Tumors: the Current State and Clinical Perspectives.

Renal cell carcinoma (RCC) ranks the first death rate among the urogenital tumors, whereas its incidence follows the incidences of prostate and bladder cancer. The diagnosis of RCC at early stages allows immediately undertaking appropriate treatment, which significantly increases patients' survival rate. Early and accurate diagnosis avoids inadequate treatment, provides the disease progression forecast, and permits to apply more efficient therapy. Unfortunately, the small renal tumors are usually asymptomatic resulting in the late diagnosis and, therefore, low efficacy of treatment. Thus, sensible and preventive biomarkers are essential for early RCC detection and monitoring of its progression. So far, many attempts were performed aimed at recognizing novel informative kidney tumor biomarkers applicable for early detection of the disease and possessing prognostic and predictive capabilities. This review summarizes recent advances in renal tumor biomarkers recognition, their diagnostic and prognostic values, and clinical feasibility.

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.

In Silico, In Vitro, and Clinical Investigations of Cathepsin B and Stefin A mRNA Expression and a Correlation Analysis in Kidney Cancer.

The cysteine protease Cathepsin B (CtsB) plays a critical role in multiple signaling pathways, intracellular protein degradation, and processing. Endogenous inhibitors regulate its enzymatic activity, including stefins and other cystatins. Recent data proved that CtsB is implicated in tumor extracellular matrix remodeling, cell invasion, and metastasis: a misbalance between cathepsins and their natural inhibitors is often considered a sign of disease progression. In the present study, we investigated CtsB and stefin A (StfA) expression in renal cell carcinoma (RCC). mRNA analysis unveiled a significant CTSB and STFA increase in RCC tissues compared to adjacent non-cancerogenic tissues and a higher CtsB expression in malignant tumors than in benign renal neoplasms. Further analysis highlighted a positive correlation between CtsB and StfA expression as a function of patient sex, age, tumor size, grade, lymph node invasion, metastasis occurrence, and survival. Alternative overexpression and silencing of CtsB and StfA confirmed the correlation expression between these proteins in human RCC-derived cells through protein analysis and fluorescent microscopy. Finally, the ectopic expression of CtsB and StfA increased RCC cell proliferation. Our data strongly indicated that CtsB and StfA expression play an important role in RCC development by mutually stimulating their expression in RCC progression.

Frontiers in urethra regeneration: current state and future perspective.

Despite the positive achievements attained, the treatment of male urethral strictures and hypospadiases still remains a challenge, particularly in cases of severe urethral defects. Complications and the need for additional interventions in such cases are common. Also, shortage of autologous tissue for graft harvesting and significant morbidity in the location of harvesting present problems and often lead to staged treatment. Tissue engineering provides a promising alternative to the current sources of grafts for urethroplasty. Since the first experiments in urethral substitution with tissue engineered grafts, this topic in regenerative medicine has grown remarkably, as many different types of tissue-engineered grafts and approaches in graft design have been suggested and testedin vivo. However, there have been only a few clinical trials of tissue-engineered grafts in urethral substitution, involving hardly more than a hundred patients overall. This indicates that the topic is still in its inception, and the search for the best graft design is continuing. The current review focuses on the state of the art in urethral regeneration with tissue engineering technology. It gives a comprehensive overview of the components of the tissue-engineered graft and an overview of the steps in graft development. Different cell sources, types of scaffolds, assembling approaches, options for vascularization enhancement and preclinical models are considered.

Long Non-Coding PROX1-AS1 Expression Correlates with Renal Cell Carcinoma Metastasis and Aggressiveness.

Long non-coding RNAs (lncRNAs) can be specifically expressed in different tissues and cancers. By controlling the gene expression at the transcriptional and translational levels, lncRNAs have been reported to be involved in tumor growth and metastasis. Recent data demonstrated that multiple lncRNAs have a crucial role in renal cell carcinoma (RCC) progression-the most common malignant urogenital tumor. In the present study, we found a trend towards increased PROX1 antisense RNA 1 (PROX1-AS1) expression in RCC specimens compared to non-tumoral margins. Next, we found a positive correlation between PROX1-AS1 expression and the occurrence of distant and lymph node metastasis, higher tumor stage (pT1 vs. pT2 vs. pT3-T4) and high-grade (G1/G2 vs. G3/G4) clear RCC. Furthermore, global demethylation in RCC-derived cell lines (769-P and A498) and human embryonic kidney 293 (HEK293) cells induced a significant increase of PROX1-AS1 expression level, with the most remarkable change in HEK293 cells. In line with this evidence, bisulfite sequencing analysis confirmed the specific demethylation of bioinformatically selected CpG islands on the PROX1-AS1 promoter sequence in the HEK293 cell line but not in the tumor cells. Additionally, the human specimen analysis showed the hemimethylated state of CG dinucleotides in non-tumor kidney tissues, whereas the tumor samples presented the complete, partial, or no demethylation of CpG-islands. In conclusion, our study indicated that PROX1-AS1 could be associated with RCC progression, and further investigations may define its role as a new diagnostic marker and therapeutic target.

Proteolyzed Variant of IgG with Free C-Terminal Lysine as a Biomarker of Prostate Cancer.

The differential diagnosis of prostate cancer is problematic due to the lack of markers with high diagnostic accuracy. We previously demonstrated the increased binding of IgG to human plasminogen (PLG) in plasma of patients with prostate cancer (PC) compared to healthy controls. Heavy and light chains of PLG (PLG-H and PLG-L) were immobilized on 96-well plates and the binding of IgG to PLG-H and PLG-L was analyzed in serum from 30 prostate cancer (PC) patients, 30 patients with benign prostatic hyperplasia (BPH) and 30 healthy controls using enzyme-linked immunosorbent assay (ELISA). Our results demonstrate that IgG from PC sera bind to PLG-H but not to PLG-L. This interaction occurred through the free IgG C-terminal lysine (Lys) that becomes exposed as a result of IgG conformational changes associated with proteolysis. Circulating levels of modified IgG with exposed C-terminal Lys (IgG-Lys) were significantly higher in PC patients than in healthy controls and in BPH. We used Receiver Operating Characteristic (ROC) analysis to calculate the sensitivity (SN) and specificity (SP) of circulating IgG-Lys for differentiating PC from BPH as 77% and 90%, respectively. The area under the curve (AUC) was 0.87. We demonstrated that the diagnostic accuracy of circulating levels of IgG-Lys is much higher than diagnostic accuracy of total PSA (tPSA).

Can new immunoassay techniques improve bladder cancer diagnostics With protein biomarkers?

The search for new diagnostic tests for cancer or ways to improve existing tests is primarily driven by the desire to identify the disease as early as possible. In this report, we summarize the current knowledge of the most promising diagnostic protein bladder cancer (BC) markers reported over the last decade. Unfortunately, analysis of published data suggests that a reliable, highly sensitive biomarker test-system based on ELISA for detecting BC has not yet been developed. The use of more sensitive assays to detect ultra-low concentrations of biomarkers not available for ELISA, could be very beneficial. Based on the literature and pilot experimental data, we conclude that a highly sensitive immunoassay using microarrays and magnetic labels, could be an effective and cheap technique suitable for the detection of diagnostically relevant BC biomarkers.

15 years' survey of safety and efficacy of Serenoa repens extract in benign prostatic hyperplasia patients with risk of progression.

AIM:: The aim of this study is to investigate the efficacy and safety of long-term therapy with Serenoa repens extract with regard to halting benign prostatic hyperplasia progression. MATERIAL AND METHODS:: An open non-comparative observational study of the continuous use of S. repens plant extract at a dosage of 320 mg once a day for 15 years was performed in 30 patients at risk for benign prostatic hyperplasia progression. Changes in IPSS (International Prostatic Symptoms Scale) and QoL (Quality of life) scores and changes in Qmax, voided volume, residual urine volume, and prostate volume were evaluated during the study. RESULTS:: The study showed an absence of progression based on both subjective (the sum of scores on the IPSS and QoL scales) and objective (prostate volume, urination rate, residual urine volume) criteria. Furthermore, the patients had no adverse events related to the study drug, including prostate cancer. CONCLUSIONS:: The 15 years' study results suggest that taking S. repens plant extract continuously at a daily dose of 320 mg is an effective and safe way to prevent the progression of benign prostatic hyperplasia.

Holter Monitoring (24-Hour ECG) Parameter Dynamics in Patients with Ischemic Heart Disease and Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia.

INTRODUCTION: This study examined the dynamics of 24-h electrocardiogram (ECG) monitoring parameters (Holter monitoring) in patients with ischemic heart disease (IHD) before and after conservative or surgical treatment of patients with voiding and storage lower urinary tract symptoms (LTS) due to benign prostatic hyperplasia (BPH). METHODS: A total of eighty-three 57 to 81-year-old (mean age 70.4 ± 5.75 years) patients with LUTS/BPH and accompanying IHD were examined and treated at the Institute of Urology and Human Reproductive Health and Clinic of Cardiology of Sechenov University. All patients received recommended cardiac therapy at least 6 months before inclusion in the study. RESULTS: Our study demonstrated that there is correlation between voiding and storage LUTS/BPH and Holter-detected cardiac impairments in patients with IHD/BPH. These data make it possible to consider LUTS/BPH (voiding and storage) as a factor in the additional functional and psychological load on the activity of patients with ischemic heart disease. Improvement of voiding and storage LUTS due to BPH and objective parameters of urination (Qmax) in patients treated with alpha-1 adrenoceptor blocker tamsulosin correlated with improvement of 24-h ECG monitoring parameters (Holter monitoring) in 72% of patients. Improvement of 24-h ECG monitoring parameters (Holter monitoring) 1 month after transurethral resection of the prostate (TURP) in IHD/BPH patients and indications for surgical treatment was observed in 65.7%. Negative dynamics of the Holter-based ECG was not registered in patients who were operated on. CONCLUSION: Holter monitoring helps to identify groups of patients in whom urinary impairments caused by prostatic hyperplasia negatively affect the course of IHD. Restored urination (either conservatively or operatively) in patients with BPH in 72% of cases decreased the number of fits of angina, thus influencing favourably the course of IHD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03856242.

Autoantibody against arrestin-1 as a potential biomarker of renal cell carcinoma.

Renal cell carcinoma (RCC) is the second-most common uronephrological cancer. In the absence of specific symptoms, early diagnosis of RCC is challenging. Monitoring of the aberrant expression of tumour-associated antigens (TAAs) and related autoantibody response is considered as a novel approach of RCC diagnostics. The aim of this study was to examine the aberrant expression of arrestin-1 in renal tumours, to investigate the possible epigenetic mechanism underlying arrestin-1 expression, and to assess the frequency of anti-arrestin-1 autoantibody response. Immunohistochemistry was used to assess the presence of arrestin-1 in primary tumours and metastases of 39 patients with RCC and renal oncocytoma. Bisulfite sequencing was employed to analyse the methylation status of the promoter of the SAG gene encoding arrestin-1. Western blot analysis was performed to detect autoantibodies against arrestin-1 in serum samples of 36 RCC and oncocytoma patients. Arrestin-1 was found to be expressed in RCC (58.7% of cases) and renal oncocytoma (90% of cases) cells, while being absent in healthy kidney. The expression of arrestin-1 in RCC metastases was more prominent than in primary tumours. Hypomethylation of the SAG gene promoter is unlikely to be the mechanism for the aberrant expression of arrestin-1. Autoantibodies against arrestin-1 were detected in sera of 75% of RCC patients. Taken together, our findings suggest employment of autoantibody against arrestin-1 as biomarker of RCC.

Cell therapy for stress urinary incontinence: Present-day frontiers.

Stress urinary incontinence (SUI) significantly diminishes the quality of patients' lives. Currently available surgical and nonsurgical therapies remain far from ideal. At present, advances in cellular technologies have stirred growing interest in the use of autologous cell treatments aimed to regain urinary control. The objective was to conduct a review of the literature and analyse preclinical and clinical studies dedicated to various cell therapies for SUI, assessing their effectiveness, safety, and future prospects. A systematic literature search in PubMed was conducted using the following key terms: "stem," "cell," "stress," "urinary," and "incontinence." A total of 32 preclinical studies and 15 clinical studies published between 1946 and December 2014 were included in the review. Most preclinical trials have used muscle-derived stem cells and adipose-derived stem cells. However, at present, the application of other types of cells, such as human amniotic fluid stem muscle-derived progenitor cells and bone marrow mesenchymal stromal cells, is becoming more extensive. While the evidence shows that these therapies are effective and safe, further work is required to standardize surgical techniques, as well as to identify indications for their use, doses and number of doses. Future research will have to focus on clinical applications of cell therapies; namely, it will have to determine indications for their use, doses of cells, optimal surgical techniques and methods, attractive cell sources, as well as to develop clinically relevant animal models and make inroads into understanding the mechanisms of SUI improvement by cell therapies.

Efficacy and safety of Afalaza in men with symptomatic benign prostatic hyperplasia at risk of progression: a multicenter, double-blind, placebo-controlled, randomized clinical trial.

INTRODUCTION: In order to investigate the efficacy and safety of Afalaza in men with benign prostatic hyperplasia (BPH) at risk of progression, this multicenter, double-blind, placebo-controlled, randomized clinical trial was performed. Derived by technological treatment of antibodies to prostate-specific antigen (PSA) and endothelial nitric oxide synthase (eNOs), Afalaza was previously proved to modulate its molecular targets. The mechanism of action of the drug is associated with the modulating effect of the antibiodies (RA-Abs) on the molecular targets (PSA and eNOS) by way of conformational changes. MATERIAL AND METHODS: A total of 49 patients aged 45-60 years with BPH and moderate lower urinary tract symptoms (LUTS), total prostate volume (TPV) ≥30 cm3, Qmax 10-15 ml/s, and serum PSA<4 ng/ml were randomly assigned to receive either Afalaza (n = 125) or placebo (n = 124) for 12 months. Changes in BPH/LUTS symptoms (according to the International Prostate Symptom Score), Qmax, TPV, PSA, BPH clinical progression, occurrence of acure urinary retention (AUR) events or BPH-related surgery were estimated as the study endpoints. RESULTS: IPSS mean change was -3.7 ±3.0 (95% CI -4.3 to -3.2) after 12 months of Afalaza (vs. -2.9 ±2.4; 95% CI -3.3 to -2.4 in placebo; р = 0.02). Qmax growth was 2.5 ±4.3 ml/s (vs. 1.4 ±3.3 in placebo; p = 0.049), TPV reduced by 11.8 ±16.0% (vs. 6.5 ±14.7%; p = 0.01, and PSA remained unchanged. Afalaza therapy resulted in a significant decrease in the total sum of BPH progression symptoms (p = 0.01). The maximum effect of Afalaza was registered after 12 months without a tendency to form a 'plateau'. During the study, no patients experienced AUR or BPH-related surgery. CONCLUSIONS: A 12-month course of Afalaza therapy is effective and safe for patients with BPH. The results of end points measurements revealed asignificant advantage of Afalaza compared to placebo in the overall symptoms benefit and a decline in the risk of BPH progression.ClinicalTrials.gov: NCT01716104.

The potential role of tissue-engineered urethral substitution: clinical and preclinical studies.

Urethral strictures and anomalies remain among the difficult problems in urology, with urethroplasty procedures being the most effective treatment options. The two major types of urethroplasty are anastomotic urethroplasty and widening the urethral lumen using flaps or grafts (i.e. substitution urethroplasty). However, no ideal material for the latter has been found so far. Designing and selecting such a material is a necessary and challenging endeavour, driving the need for further bioengineered urethral tissue research. This article reviews currently available studies on the potentialities of tissue engineering in urethral reconstruction, in particular those describing the use of both acellular and recellularized tissue-engineered constructs in animal and human models. Possible future developments in this field are also discussed. Copyright © 2015 John Wiley & Sons, Ltd.