Corrigendum to "Recognition motifs for importin 4 [(L)PPRS(G/P)P] and importin 5 [KP(K/Y)LV] binding, identified by bio-informatic simulation and experimental in vitro validation" [Comput Struct Biotechnol J 20 (2022) 5952-5961]

Nuclear translocation of large proteins is mediated through karyopherins, carrier proteins recognizing specific motifs of cargo proteins, known as nuclear localization signals (NLS). However, only few NLS signals have been reported until now. In the present work, NLS signals for Importins 4 and 5 were identified through an unsupervised in silico approach, followed by experimental in vitro validation. The sequences LPPRS(G/P)P and KP(K/Y)LV were identified and are proposed as recognition motifs for Importins 4 and 5 binding, respectively. They are involved in the trafficking of important proteins into the nucleus. These sequences were validated in the breast cancer cell line T47D, which expresses both Importins 4 and 5. Elucidating the complex relationships of the nuclear transporters and their cargo proteins is very important in better understanding the mechanism of nuclear transport of proteins and laying the foundation for the development of novel therapeutics, targeting specific importins

Management of urinary stones: state of the art and future perspectives by experts in stone disease

Aim: To present state of the art on the management of urinary stones from a panel of globally recognized urolithiasis experts who met during the Experts in Stone Disease Congress in Valencia in January 2024. Options of treatment: The surgical treatment modalities of renal and ureteral stones are well defined by the guidelines of international societies, although for some index cases more alternative options are possible. For 1.5 cm renal stones, both m-PCNL and RIRS have proven to be valid treatment alternatives with comparable stone-free rates. The m-PCNL has proven to be more cost effective and requires a shorter operative time, while the RIRS has demonstrated lower morbidity in terms of blood loss and shorter recovery times. SWL has proven to be less effective at least for lower calyceal stones but has the highest safety profile. For a 6mm obstructing stone of the pelviureteric junction (PUJ) stone, SWL should be the first choice for a stone less than 1 cm, due to less invasiveness and lower risk of complications although it has a lower stone free-rate. RIRS has advantages in certain conditions such as anticoagulant treatment, obesity, or body deformity. Technical issues of the surgical procedures for stone removal: In patients receiving antithrombotic therapy, SWL, PCN and open surgery are at elevated risk of hemorrhage or perinephric hematoma. URS, is associated with less morbidity in these cases. An individualized combined evaluation of risks of bleeding and thromboembolism should determine the perioperative thromboprophylactic strategy. Pre-interventional urine culture and antibiotic therapy are mandatory although UTI treatment is becoming more challenging due to increasing resistance to routinely applied antibiotics. The use of an intrarenal urine culture and stone culture is recommended to adapt antibiotic therapy in case of postoperative infectious complications. Measurements of temperature and pressure during RIRS are vital for ensuring patient safety and optimizing surgical outcomes although techniques of measurements and methods for data analysis are still to be refined. Ureteral stents were improved by the development of new biomaterials, new coatings, and new stent designs. Topics of current research are the development of drug eluting and bioresorbable stents. Complications of endoscopic treatment: PCNL is considered the most invasive surgical option. Fever and sepsis were observed in 11 and 0.5% and need for transfusion and embolization for bleeding in 7 and 0.4%. Major complications, as colonic, splenic, liver, gall bladder and bowel injuries are quite rare but are associated with significant morbidity. Ureteroscopy causes less complications, although some of them can be severe. They depend on high pressure in the urinary tract (sepsis or renal bleeding) or application of excessive force to the urinary tract (ureteral avulsion or stricture). Diagnostic work up:  Genetic testing consents the diagnosis of monogenetic conditions causing stones. It should be carried out in children and in selected adults. In adults, monogenetic diseases can be diagnosed by systematic genetic testing in no more than 4%, when cystinuria, APRT deficiency, and xanthinuria are excluded. A reliable stone analysis by infrared spectroscopy or X-ray diffraction is mandatory and should be associated to examination of the stone under a stereomicroscope. The analysis of digital images of stones by deep convolutional neural networks in dry laboratory or during endoscopic examination could allow the classification of stones based on their color and texture. Scanning electron microscopy (SEM) in association with energy dispersive spectrometry (EDS) is another fundamental research tool for the study of kidney stones. The combination of metagenomic analysis using Next Generation Sequencing (NGS) techniques and the enhanced quantitative urine culture (EQUC) protocol can be used to evaluate the urobiome of renal stone formers. Twenty-four hour urine analysis has a place during patient evaluation together with repeated measurements of urinary pH with a digital pH meter. Urinary supersaturation is the most comprehensive physicochemical risk factor employed in urolithiasis research. Urinary macromolecules can act as both promoters or inhibitors of stone formation depending on the chemical composition of urine in which they are operating. At the moment, there are no clinical applications of macromolecules in stone management or prophylaxis. Patients should be evaluated for the association with systemic pathologies. Prophylaxis: Personalized medicine and public health interventions are complementary to prevent stone recurrence. Personalized medicine addresses a small part of stone patients with a high risk of recurrence and systemic complications requiring specific dietary and pharmacological treatment to prevent stone recurrence and complications of associated systemic diseases. The more numerous subjects who form one or a few stones during their entire lifespan should be treated by modifications of diet and lifestyle. Primary prevention by public health interventions is advisable to reduce prevalence of stones in the general population. Renal stone formers at "high-risk" for recurrence need early diagnosis to start specific treatment. Stone analysis allows the identification of most “high-risk” patients forming non-calcium stones: infection stones (struvite), uric acid and urates, cystine and other rare stones (dihydroxyadenine, xanthine). Patients at “high-risk” forming calcium stones require a more difficult diagnosis by clinical and laboratory evaluation. Particularly, patients with cystinuria and primary hyperoxaluria should be actively searched. Future research: Application of Artificial Intelligence are promising for automated identification of ureteral stones on CT imaging, prediction of stone composition and 24-hour urinary risk factors by demographics and clinical parameters, assessment of stone composition by evaluation of endoscopic images and prediction of outcomes of stone treatments. The synergy between urologists, nephrologists, and scientists in basic kidney stone research will enhance the depth and breadth of investigations, leading to a more comprehensive understanding of kidney stone formation

Ileal neobladder mucosa modifications after radical cystectomy

Motive to perform this study was to assess the long term histological, apoptotic and proliferating alterations of the mucosa of ileal orthotopic neobladder and conduit. Fifty patients (46 males, 4 females), aged 52-78 years old that underwent urinary diversion with either ileal orthotopic neobladder (group A: 20 patients) or ileal conduit (group B: 30 patients), were included in this prospective study. Ileal samples were collected during surgery (controls) and by random mucosal biopsies 6, 12, 24, 36 and 48 months later. Histological (villi height, crypts depth and eosinophil cell count), proliferation (Ki67), and apoptotic (Bcl-2, TUNEL) parameters were assessed.During the 4 year follow up, we recorded progressive villi area, height and crypt depth reduction, mucosa flattening, inflammatory and eosinophilic infdtration in both groups. Villi height: crypt depth ratio showed a statistically significant difference (p<0.05) between the two groups from the 6th month. Bcl-2 values showed a progressive increase until 24 months in surgery (controls) and by random mucosal biopsies 6, 12, 24, 36 and 48 months later. Histological (villi height, crypts depth and eosinophil cell count), proliferation (Ki67), and apoptotic (Bcl-2, TUNEL) parameters were assessed.During the 4 year follow up, we recorded progressive villi area, height and crypt depth reduction, mucosa flattening, inflammatory and eosinophilic infdtration in both groups. Villi height: crypt depth ratio showed a statistically significant difference (p<0.05) between the two groups from the 6th month. Bcl-2 values showed a progressive increase until 24 months in group A and 12 months in group B followed by a decline thereafter. Ki-67 values showed a progressive increase after the 6 months in group A and an increase until 24 months followed by a decline thereafter in group B. TUNEL showed two peaks, in 24 and 48 months respectively. Dysplasia or neoplasia was not observed in either group. Histological adaptation was revealed in both groups, statistically more prominent in the orthotopic neobladder group. Relevant modifications of Bcl-2, Ki-67 and TUNEL were revealed, suggesting that proliferative and apoptotic pathways are implicated.In conclusion, histological adaptation was revealed in both ileal conduits and orthotopic neobladders, statistically more prominent in the orthotopic neobladder group. Both proliferative and apoptotic pathways are implicated in the observed alterations as demonstrated by relevant modifications of Bcl-2, Ki-67, and TUNEL, in accordance with the histological adaptation. Further research is warranted necessitated in order to enrich our knowledge regarding the underlying molecular interactions of the histological adaptation in bladder substitution. Our study is ongoing, trying to light on towards this way.Ο σκοπός αυτής της διατριβής ήταν η προοπτική μελέτη των ιστολογικών μεταβολών, καθώς και του αποπτοτικού και αναγεννητικού μηχανισμού του ειλεϊκού βλεννογόνου, τόσο στις ορθότοπες εγκρατείς νεοκύστες, όσο και στις μη εγκρατείς ετερότοπες νεοκύστες (conduits).Στα πλαίσια αυτά λοιπόν, πενήντα ασθενείς (46 άνδρες και 4 γυναίκες), ηλικίας 52 έως 78 ετών, υποβλήθηκαν σε ριζική κυστεκτομή με συνοδό εκτροπή ούρων. Στην πρώτη ομάδα, σε 20 ασθενείς δημιουργήθηκε ορθότοπη εγκρατής νεοκύστη, ενώ στην δεύτερη ομάδα, σε 30 ασθενείς δημιουργήθηκε μη εγκρατής ετερότοπη νεοκύστη (conduit). Σε όλους αυτούς τους ασθενείς ελήφθη διεγχειρητικά ιστοτεμάχιο ειλεού που χρησιμοποιήθηκε στη συνέχεια ως μάρτυρας, ενώ στη συνέχεια ελήφθησαν τυχαία βιοπτικά τεμάχια ειλεού 6, 12, 24, 36 και 48 μήνες μετά το χειρουργείο. Στα ιστοτεμάχια αυτά μελετήθηκαν ιστολογικές (ύψος λαχνών, βάθος κρυπτών, ηωσινοφιλική διήθηση), αναγεννητικές (Ki-67) και αποπτωτικές (Bcl-2, TUNEL) παράμετροι.Κατά τη διάρκεια των 4 ετών της μετεγχειρητικής παρακολούθησης, παρατηρήσαμε μια προοδευτική ελάττωση της έκτασης του λαχνωτού βλεννογόνου, καθώς και του ύψους των λαχνών και του βάθους των κρυπτών, παράλληλα με ηωσινοφιλική και φλεγμονώδη διήθηση και στις δύο ομάδες ασθενών. Ο λόγος ύψος λαχνών / βάθος κρυπτών έδειξε μια στατιστικά σημαντική διαφορά (ρ<0.05) μεταξύ των δύο ομάδων μετά τους πρώτους 6 μήνες. To Bcl-2 παρουσίασε προοδευτική αύξηση μέχρι τους 24 μήνες στην πρώτη ομάδα της ορθότοπης εγκρατούς εκτροπής, ενώ αυτό παρατηρήθηκε στους πρώτους 12 μήνες στη δεύτερη ομάδα, κάτι που ακολουθήθηκε από πτώση στη συνέχεια. Το Κΐ-67 παρουσίασε προοδευτική αύξηση μετά τον 6° μήνα στην πρώτη ομάδα, ενώ στη δεύτερη ομάδα παρουσίασε αύξηση μέχρι τον 24° μήνα και πτώση στη συνέχεια. To TUNEL έδειξε δύο κορυφές, αντίστοιχα στους 24 και 48 μήνες από το χειρουργείο. Σε καμιά από τις δύο ομάδες δεν παρατηρήθηκε δυσπλασία ή νεοπλασία.Σαν συμπέρασμα λοιπόν, θα μπορούσε να ειπωθεί, πως τόσο στα conduits όσο και στις ορθότοπες εγκρατείς νεοκύστες με χρήση ειλεού, παρατηρείται μια ιστολογική «προσαρμογή» του βλεννογόνου του ειλεού στο καινούριο περιβάλλον. Σε σύγκριση μεταξύ τους, η προσαρμογή αυτή είναι εντονότερη στις ορθότοπες εγκρατείς νεοκύστες, έχοντας στατιστικά σημαντική διαφορά συγκρινόμενη με αυτή που παρατηρείται στα conduits. Τόσο η αναγεννητική ικανότητα όσο και ο αποπτωτικός μηχανισμός επηρεάζονται επίσης, όπως καταδεικνύεται από τις μεταβολές των Ki-67, bcl-2 και TUNET, με ρυθμούς αντίστοιχους των ιστολογικών μεταβολών. Θα πρέπει όμως να γίνουν περαιτέρω έρευνες στην κατεύθυνση αυτή, ώστε να εμπλουτισθούν οι γνώσεις μας σχετικά με τις υποκείμενες μοριακές μεταβολές στον εντερικό βλεννογόνο των νεοκύστεων

Giant genital warts

Key Clinical Message Genital warts are quite common and should be treated early with nonaggressive conservative or invasive methods. When they are severely neglected patients may be submitted to amputative surgical management. Preoperatively malignant transformation of the tumors cannot be excluded

Profile of Enfortumab Vedotin in the Treatment of Urothelial Carcinoma: The Evidence to Date

Nowadays the therapeutic landscape for advanced and metastatic urothelial carcinoma continues to evolve. The recent regulatory approval of enfortumab vedotin (EV) for the treatment of advanced urothelial cancer confirms the evolving role of antibody-drug conjugates. EV demonstrates a favorable profile in heavily pretreated patients with locally advanced or metastatic urothelial carcinoma. Early survival reports demonstrate a significant antitumor effectiveness along with a rather acceptable safety profile in a difficult-to-treat population

The Impact of COVID-19 Disease on Urology Practice

The diagnosis and timely treatment of cancer patients should not be compromised during an infectious disease pandemic. The pandemic of coronavirus disease 2019 (COVID-19) has serious implications on urology practice and raises particular questions for urologists about the management of different conditions. It was recommended to cancel most of the elective urological surgeries. Urological cancers surgeries that should be prioritized are radical cystectomy for selective tumors, orchiectomy for suspected testicular tumors, nephrectomy for c T3+, nephroureterectomy for high-grade disease, and radical adrenalectomy for tumors &gt;6 cm or adrenal carcinoma. Most prostatectomies can be delayed without compromising the survival rate of patients. Urological emergencies should be treated adequately even during this pandemic. There is a potential risk of coronavirus diffusion during minimally invasive procedures performed. It is crucial to use specific precautions when urologists performed those type of surgeries. It was also recommended to suspend the kidney transplantation program during the COVID-19 pandemic except for specific cases. In this review, we discussed the triage of urological surgeries, the risk of minimally invasive urological procedure, the kidney transplantation challenges, the systemic therapies, intravesical instillation of Bacillus Calmette-Guerin (BCG), endourology, teleconferencing, and telemedicine application in urology during the COVID-19 pandemic

The role of 18F-FDG PET/CT scan compared to CT-scan alone for lymph node staging before radical cystectomy in patients with bladder cancer

Background: Accurate Lymph node (LN) staging before radical cystectomy (RC) in patients with bladder cancer (BC) is crucial to improve patient’s management. 18F-fluorodeoxyglucose positron-emission tomography-computed tomography (FDG-PET-CT) become widely used in the loco-regional staging of BC. The diagnostic performance of PET-CT in preoperative LN staging of BC is still unknown due to lacking large trials. Objectives: We aim to evaluate the diagnostic value of PET-CT scan, compared with CT scan alone for preoperative LN staging of BC. Patients and methods: From January 2010 to November 2020, we retrospectively reviewed the records of 300 patients undergoing RC for muscle-invasive BC and high-risk non-muscle-invasive BC. All patients had PET-CT and CT of abdomen and pelvis to assess for pelvic LN metastases before RC. Patients were excluded from analysis if they had neoadjuvant chemotherapy (NAC). Sensitivity, specificity, and accuracy for detecting pelvic LN metastases were determined by comparing the results of the FDG PET-CT and CT alone to the final histopathology reports obtained after RC. Results: LN metastasis was confirmed histology in 134 patients (44.7%). On a patient-based analysis, PET-CT, and CT showed a sensitivity of 40.3% and 13.4 %, respectively, a specificity of 79.5% and 86.7 %, respectively, positive predictive value (PPV) of 61.4% and 45%, respectively, and negative predictive value (NPV) of 62.3% and 55.4%, respectively. The diagnostic accuracy of PET-CT scan depends on multiple preoperative and postoperative factors. Conclusion: PET-CT is more accurate than CT-scan alone for preoperative LN staging in patients with BC. (C) 2021 Elsevier Inc. All rights reserved

Relugolix: A new kid on the block among gonadotrophin-releasing hormone antagonists

Androgen-deprivation therapy (ADT) is the cornerstone of metastatic prostate cancer treatment. ADT can be achieved through surgical castration, or it may be induced either by gonadotrophin-releasing hormone (GnRH) agonists or GnRH antagonists. GnRH antagonists provide a more rapid castration alongside with a safer profile regarding adverse events. Degarelix is the sole GnRH antagonist used in clinical practice. Injection site reactions are the commonest adverse events related to the use of degarelix. Relugolix, a novel molecule, represents the first orally administered United States Food and Drug Administration approved GnRH antagonist, with clinical efficacy equal to that of the established ADT regimens. The main advantages of relugolix are the avoidance of the injection site reactions of GnRH antagonists such as degarelix alongside its patient-friendly oral administration. The aim of the present review article is to present novel data regarding the role of relugolix as ADT for the treatment of prostate cancer

Hyberbaric oxygen as sole treatment for severe radiation - induced haemorrhagic cystitis

ABSTRACT Purpose To examine the safety and efficacy of hyperbaric oxygen as the primary and sole treatment for severe radiation-induced haemorrhagic cystitis. Materials and methods Hyperbaric oxygen was prospectively applied as primary treatment in 38 patients with severe radiation cystitis. Our primary endpoint was the incidence of complete and partial response to treatment, while the secondary endpoints included the duration of response, the correlation of treatment success-rate to the interval between the onset of haematuria and initiation of therapy, blood transfusion need and total radiation dose, the number of sessions to success, the avoidance of surgery and the overall survival. Results All patients completed therapy without complications with a mean follow-up of 29.33 months. Median number of sessions needed was 33. Complete and partial response rate was 86.8% and 13.2%, respectively. All 33 patients with complete response received therapy within 6 months of the haematuria onset. One patient needed cystectomy, while 33 patients were alive at the end of follow-up. Conclusions Our study suggests the early primary use of hyperbaric oxygen for radiation-induced severe cystitis as an effective and safe treatment option