A pilot study of performance enhancement coaching for newly appointed urology registrars.

OBJECTIVES: To assess the feasibility of performance enhancement coaching (PEC) for newly appointed Urology registrars (ST3s), specifically: whether the concept appealed, and which areas beyond technical skills acquisition were felt to be most relevant or useful. SUBJECTS AND METHODS: All delegates on the Urology Bootcamp 2023 were invited to take part in an online survey before and after a 2-hour PEC workshop, collecting: basic demographic data, performance challenges, and the important aspects to include in, and consider with, a coaching programme. The workshop was delivered by a surgeon with a professional coaching qualification, to groups of four delegates at a time over 4 days. Ten pre-defined areas were offered during the session. RESULTS: On a scale of 1 (poor) to 10 (excellent), the 62 participants' overall health was reported as a median of 8/10 (physical) and 7/10 (mental). Anxiety during performance was the most common concern (63%) and was accompanied by a tremor in 55%. The next most popular concerns, with 19% of responses each, were: sleep, insufficient operative skill or expertise, and worry about relationships with trainers. The commonest topics discussed were 'the inner critic' (100%), 'autonomic modulation' (69%), 'not working, well' (13%) and 'optimising study' (6%). Seventy-seven per cent were unaware of PEC for practising surgeons. All respondents felt that they would benefit from PEC to some extent (80% ≥8/10 where 10/10 was 'very useful'), ideally at the ST3 level. Sixty-two percent of respondents said there should be a fee for trainees, whereas 38% thought it should be free and paid for by their training authorities. CONCLUSION: The concept of PEC is acceptable to ST3 Urology trainees, with particular interest in techniques to mitigate negative self-talk and autonomic modulation techniques. Existing barriers to coaching for the surgical community would need to be addressed in designing an acceptable coaching programme.

Targeting brain tumors with innovative nanocarriers: bridging the gap through the blood-brain barrier.

Background: Glioblastoma multiforme (GBM) is recognized as the most lethal and most highly invasive tumor. The high likelihood of treatment failure arises from the presence of the blood-brain barrier (BBB) and stem cells around GBM, which avert the entry of chemotherapeutic drugs into the tumor mass. Objective: Recently, several researchers have designed novel nanocarrier systems like liposomes, dendrimers, metallic nanoparticles, nanodiamonds, and nanorobot approaches, allowing drugs to infiltrate the BBB more efficiently, opening up innovative avenues to prevail over therapy problems and radiation therapy. Methods: Relevant literature for this manuscript has been collected from a comprehensive and systematic search of databases, for example, PubMed, Science Direct, Google Scholar, and others, using specific keyword combinations, including "glioblastoma," "brain tumor," "nanocarriers," and several others. Conclusion: This review also provides deep insights into recent advancements in nanocarrier-based formulations and technologies for GBM management. Elucidation of various scientific advances in conjunction with encouraging findings concerning the future perspectives and challenges of nanocarriers for effective brain tumor management has also been discussed.

A Pilot Study Evaluating a Virtual Reality-Based Nontechnical Skills Training Application for Urology Trainees: Usability, Acceptability, and Impact.

OBJECTIVE: This study aimed to develop and evaluate a virtual reality (VR)-based nontechnical skills (NTS) training application for urology trainees and assess its effectiveness in improving their skills and confidence. DESIGN: A mixed-methods study was conducted to develop and evaluate a VR-based NTS training application for 32 urology trainees. The development process involved collaboration with 5 urology experts, 2 medical education specialists, and a human factors researcher. The study evaluated the application's usability, acceptability, and efficacy through 3 phases: scenario development with expert feedback integration, storyboarding and creation processes with facilitators and urology trainees, and a final evaluation by trainees. SETTING: The data were collected during a 4-day urology boot camp in October 2022. PARTICIPANTS: Thirty-two urology trainees participated in the study and completed 2 VR scenarios designed to enhance their NTS skills RESULTS: The System Usability Scale (SUS) showed a moderate usability score of 66. The Training Evaluation Inventory (TEI) and additional feedback demonstrated positive effects on trainees' learning and confidence in their NTS abilities. Most participants found the application easy to use, and effective and they expressed interest in using similar VR applications for other aspects of surgical training. CONCLUSIONS: VR-based NTS training applications show potential for enhancing urology trainees' nontechnical skills. The integration of expert feedback and immersive technology offers a promising, accessible, and cost-effective solution to the challenges of delivering NTS training. Future research should explore the long-term impact of VR-based NTS training on trainees' performance and patient outcomes and consider incorporating advanced AI technologies for personalized and dynamic learning experiences.

Potential of nanoemulsions for accelerated wound healing: innovative strategies.

Wounds represent various significant health concerns for patients and also contribute major costs to healthcare systems. Wound healing comprises of overlapped and various coordinated steps such as homeostasis, inflammation, proliferation, and remodeling. In response to the failure of many strategies in delivering intended results including wound closure, fluid loss control, and exhibiting properties such as durability, targeted delivery, accelerated action, along with histocompatibility, numerous nanotechnological advances have been introduced. To understand the magnitude of wound therapy, this systematic and updated review discussing the effectiveness of nanoemulsions has been undertaken. This review portrays mechanisms associated with wound healing, factors for delayed wound healing, and various technologies utilized to treat wounds effectively. While many strategies are available, nanoemulsions have attracted the tremendous attention of scientists globally for the research in wound therapy due to their long-term thermodynamic stability and bioavailability. Nanoemulsions not only aid in tissue repair, but are also considered as an excellent delivery system for various synthetic and natural actives. Nanotechnology provides several pivotal benefits in wound healing, including improved skin permeation, controlled release, and stimulation of fibroblast cell proliferation. The significant role of nanoemulsions in improved wound healing along with their preparation techniques has also been highlighted with special emphasis on mechanistic insights. This article illustrates recent research advancements for the utilization of nanoemulsions in wound treatment. An adequate literature search has been conducted using the keywords 'Nanoemulsions in wound healing', 'Wound therapy and nanoemulsions', 'Herbal actives in wound therapy', 'Natural oils and wounds treatment' etc., from PubMed, Science Direct, and Google Scholar databases. Referred and original publications in the English language accessed till April 2022 has been included, whereas nonEnglish language papers, unpublished data, and nonoriginal papers were excluded from the study.

Mechanistic Insights into the Pharmacological Significance of Silymarin.

Medicinal plants are considered the reservoir of diverse therapeutic agents and have been traditionally employed worldwide to heal various ailments for several decades. Silymarin is a plant-derived mixture of polyphenolic flavonoids originating from the fruits and akenes of Silybum marianum and contains three flavonolignans, silibinins (silybins), silychristin and silydianin, along with taxifolin. Silybins are the major constituents in silymarin with almost 70-80% abundance and are accountable for most of the observed therapeutic activity. Silymarin has also been acknowledged from the ancient period and is utilized in European and Asian systems of traditional medicine for treating various liver disorders. The contemporary literature reveals that silymarin is employed significantly as a neuroprotective, hepatoprotective, cardioprotective, antioxidant, anti-cancer, anti-diabetic, anti-viral, anti-hypertensive, immunomodulator, anti-inflammatory, photoprotective and detoxification agent by targeting various cellular and molecular pathways, including MAPK, mTOR, ß-catenin and Akt, different receptors and growth factors, as well as inhibiting numerous enzymes and the gene expression of several apoptotic proteins and inflammatory cytokines. Therefore, the current review aims to recapitulate and update the existing knowledge regarding the pharmacological potential of silymarin as evidenced by vast cellular, animal, and clinical studies, with a particular emphasis on its mechanisms of action.

Ethnopharmacological perspectives of glucokinase activators in the treatment of diabetes mellitus.

Traditional medicinal plants have wide-reaching utilisation in the treatment of diabetes especially in developing countries where medical resources are meagre. Traditionally used anti-diabetic plants act by numerous mechanisms, however, only a few of them act through activation of the glucokinase enzyme. Glucokinase is a key regulatory enzyme in glucose metabolism thereby controls glucose homeostasis and insulin secretion. The present review significantly analyses the knowledge about various plant-based glucokinase activators including numerous phytochemicals which modulate the activity and gene expression of glucokinase and would provide data support and perspective regarding future research in the discovery and development of different plant-derived glucokinase activators.

Synthesis, Molecular Docking, and Biological Evaluation of Some Novel 2- (5-Substituted 1,3,4-oxadiazole-2-yl)-1,3-benzothiazole Derivatives as Anticonvulsant Agents.

BACKGROUND: Benzothiazole is an organosulfur heterocyclic compound that has a considerable place in drug discovery due to significant pharmacological actions. OBJECTIVE: The main objective of the present study was to synthesize some novel 2-(5-substituted 1,3,4-oxadiazole-2-yl)-1,3-benzothiazole derivatives and evaluate them for their anticonvulsant activity using in silico and in vivo methods. METHODS: A set of sixteen 2-(5-substituted 1, 3, 4-oxadiazole-2-yl)-1, 3-benzothiazole derivatives were prepared using multi-step reactions starting from o-amino-thiophenol and characterized by suitable spectral techniques. The synthesized compounds were evaluated for anticonvulsant activity using in silico and in vivo methods. In silico molecular docking study was performed using Molegro Virtual Docker software to analyze binding modes of compounds with the internal ligand of PDB ID: 1OHY and 1OHV; and in vivo pharmacological activities were tested for both generalized tonic-clonic seizures and generalized absence (petit mal) seizures using Maximal Electrical Shock and PTZ-induced seizure models, respectively. RESULTS: Some new 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3- benzothiazole (5a-5p) were successfully synthesized by finally refluxing 1, 3-benzothiazole-2-carboxyhydrazide with different aromatic acids in phosphoryl chloride. Docking results showed that compounds 5c, 5j, and 5m were found to have the highest number of H-bond interactions; i.e. 4, 4, and 7 respectively with target proteins 1OHY and 6, 3, and 4 respectively with target protein 1OHV, whereas phenytoin showed only two H-bonding with both proteins. In the Maximal electroshock seizure method, the synthesized compounds 5h, 5k and 5o demonstrated potent anticonvulsant activity against the tonic seizure with a significant decrease in tonic hind leg extension period with a mean duration of 7.9, 7.4, and 7.0 sec respectively, as compared to the other synthesized compounds. In contrast, in the PTZ-induced seizure model, compounds 5c, 5h, and 5m showed protection against clonic convulsion with significant elevation in the onset time of clonic convulsion at 311.2, 308.0, and 333.11 sec, respectively. CONCLUSION: Thus, from the results, it can be concluded that compound 5h, a benzothiazole derivative endowed with an oxadiazole ring, can be developed as a potential anticonvulsant agent.

Identification of potential therapeutic targets in prostate cancer through a cross-species approach.

Genetically engineered mouse models of cancer can be used to filter genome-wide expression datasets generated from human tumours and to identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB-Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer-associated gene expression changes that are conserved between the two species. To identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we revealed a functional role for the kinase MELK as a driver and potential therapeutic target in prostate cancer. We found that MELK expression was required for cell survival, affected the expression of genes associated with prostate cancer progression and was associated with biochemical recurrence.

Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.

Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.

Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer.

We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an in vivo metastasis model. hSef stable expressing cells (PC3M-hSef) or empty vector controls (PC3M-EV) were injected subcutaneously into the lateral thoracic walls of NOD-SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M-EV xenografts had definitive lung micro-metastasis whilst only 1/6 PC3M-hSef xenografts exhibited metastasis recapitulating the clinical scenario (p = 0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over-expression and silencing reciprocally altered E-Cadherin expression (p = <0.001) amongst other EMT markers. Immunohistochemistry of excised tumors from the xenografts also confirmed the effect of hSef in suppressing E-Cadherin expression at the protein level. Phosphokinase arrays further demonstrated a role for hSef in attenuating signaling of not only ERK-MAPK but also the JNK and p38 pathways as well. Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumor dissemination of prostate cancer through alteration of EMT. Detection of downregulated hSef, along with other negative regulators, may therefore be a useful biomarker heralding a transition to a metastatic phenotype and warrants further exploration in this context.

Transperineal prostate biopsies for diagnosis of prostate cancer are well tolerated: a prospective study using patient-reported outcome measures.

We aimed to determine short-term patient-reported outcomes in men having general anesthetic transperineal (TP) prostate biopsies. A prospective cohort study was performed in men having a diagnostic TP biopsy. This was done using a validated and adapted questionnaire immediately post-biopsy and at follow-up of between 7 and 14 days across three tertiary referral hospitals with a response rate of 51.6%. Immediately after biopsy 43/201 (21.4%) of men felt light-headed, syncopal, or suffered syncope. Fifty-three percent of men felt discomfort after biopsy (with 95% scoring <5 in a 0-10 scale). Twelve out of 196 men (6.1%) felt pain immediately after the procedure. Despite a high incidence of symptoms (e.g., up to 75% had some hematuria, 47% suffered some pain), it was not a moderate or serious problem for most, apart from hemoejaculate which 31 men suffered. Eleven men needed catheterization (5.5%). There were no inpatient admissions due to complications (hematuria, sepsis). On repeat questioning at a later time point, only 25/199 (12.6%) of men said repeat biopsy would be a significant problem despite a significant and marked reduction in erectile function after the procedure. From this study, we conclude that TP biopsy is well tolerated with similar side effect profiles and attitudes of men to repeat biopsy to men having TRUS biopsies. These data allow informed counseling of men prior to TP biopsy and a benchmark for tolerability with local anesthetic TP biopsies being developed for clinical use.

Robotic assisted laparoscopic radical prostatectomy following transrectal compared to transperineal prostate biopsy: surgical, oncological and functional outcomes.

BACKGROUND: To assess if transperineal prostate (TP) biopsy affects th e outcome of robotic-assisted laparoscopic prostatectomy (RALP), with particular reference to perioperative complications, oncological results and functional outcomes in the early postoperative setting. METHODS: We identified 61 men who had undergone RALP after TP biopsies, from June 2012 to June 2014 and a control group of 120 men who had undergone RALP after conventional TRUS biopsy in the same period. Data was compared from the pre-operative biopsy, peri- and postoperative period, procedural outcomes including histological, oncological and functional outcomes between the groups. RESULTS: The groups had comparable demographics, with matched median ages and PSA levels. There was a higher incidence of Gleason 6 disease detected in the TRUS group (P=0.01). Mean operative time (146 minutes TRUS vs. 158 minutes TP, P=0.133), blood loss (250 mL TRUS vs. 288 mL TP, P=0.462) and intraoperative complications were not significantly different between groups. Median length of stay (1 day) and median catheter duration (7 days) were identical in both cohorts. PSA failure rate at 6 months was similar (11.7% TRUS vs. 9.8% TP, P=0.904). There were no differences in functional outcomes (potency or continence) between groups at 6 month s follow-up. CONCLUSIONS: RALP is safe after TP biopsy with no adverse impact on oncological or short-term functional outcomes.

The influence of environmental conditions on the incidence of renal colic in Rome.

INTRODUCTION: The aim of this study was to investigate the effect of three major environmental variables (temperature, humidity, air pressure) on the probability of onset of renal colic (RC) in a large cohort of patients in Rome. METHODS: The records of 2682 patients discharged by the Emergency Department (ED) of the University Hospital of Tor Vergata, Rome, from January 2007 to November 2009 with the main diagnosis of reno-ureteric colic associated with a proven calculus, were retrospectively evaluated. The climatic parameters (average humidity, average air pressure and daily minimum, medium and maximum temperature) were recorded in a second, independent database. RC events were grouped by weeks and months and analysed for a total period of 35 months and 153 weeks. RESULTS: Two thousand five hundred and fourteen patients out of 2682 had a proven urolithiasis. RC events were observed more likely in the warmer months, from the second half of June to the first half of September, compared with the colder months. Although the weekly model showed a positive correlation (R2 = 0.134) between the average increase of environmental temperature and RC incidence, the monthly model was much more convincing (R2 = 0.373). We found no statistically significant correlation between humidity and air pressure and the incidence of RC. CONCLUSIONS: This study demonstrates that an increase in average environmental temperature is associated with a significant increase in the number of episodes of RC seen in the ED at both weekly and monthly time intervals. The average humidity and air pressure were not found to be associated with an increased incidence of RC.

Magnetic Resonance and Ultrasound Image Fusion Supported Transperineal Prostate Biopsy Using the Ginsburg Protocol: Technique, Learning Points, and Biopsy Results.

BACKGROUND: Prostate biopsy supported by transperineal image fusion has recently been developed as a new method to the improve accuracy of prostate cancer detection. OBJECTIVE: To describe the Ginsburg protocol for transperineal prostate biopsy supported by multiparametric magnetic resonance imaging (mpMRI) and transrectal ultrasound (TRUS) image fusion, provide learning points for its application, and report biopsy results. The article is supplemented by a Surgery in Motion video. DESIGN, SETTING, AND PARTICIPANTS: This single-centre retrospective outcome study included 534 patients from March 2012 to October 2015. A total of 107 had no previous prostate biopsy, 295 had benign TRUS-guided biopsies, and 159 were on active surveillance for low-risk cancer. SURGICAL PROCEDURE: A Likert scale reported mpMRI for suspicion of cancer from 1 (no suspicion) to 5 (cancer highly likely). Transperineal biopsies were obtained under general anaesthesia using BiopSee fusion software (Medcom, Darmstadt, Germany). All patients had systematic biopsies, two cores from each of 12 anatomic sectors. Likert 3-5 lesions were targeted with a further two cores per lesion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Any cancer and Gleason score 7-10 cancer on biopsy were noted. Descriptive statistics and positive predictive values (PPVs) and negative predictive values (NPVs) were calculated. RESULTS AND LIMITATIONS: The detection rate of Gleason score 7-10 cancer was similar across clinical groups. Likert scale 3-5 MRI lesions were reported in 378 (71%) of the patients. Cancer was detected in 249 (66%) and Gleason score 7-10 cancer was noted in 157 (42%) of these patients. PPV for detecting 7-10 cancer was 0.15 for Likert score 3, 0.43 for score 4, and 0.63 for score 5. NPV of Likert 1-2 findings was 0.87 for Gleason score 7-10 and 0.97 for Gleason score ≥4+3=7 cancer. Limitations include lack of data on complications. CONCLUSIONS: Transperineal prostate biopsy supported by MRI/TRUS image fusion using the Ginsburg protocol yielded high detection rates of Gleason score 7-10 cancer. Because the NPV for excluding Gleason score 7-10 cancer was very high, prostate biopsies may not be needed for all men with elevated prostate-specific antigen values and nonsuspicious mpMRI. PATIENT SUMMARY: We present our technique to sample (biopsy) the prostate by the transperineal route (the area between the scrotum and the anus) to detect prostate cancer using a fusion of magnetic resonance and ultrasound images to guide the sampling.

Defining the learning curve for multiparametric magnetic resonance imaging (MRI) of the prostate using MRI-transrectal ultrasonography (TRUS) fusion-guided transperineal prostate biopsies as a validation tool.

OBJECTIVES: To determine the accuracy of multiparametric magnetic resonance imaging (mpMRI) during the learning curve of radiologists using MRI targeted, transrectal ultrasonography (TRUS) guided transperineal fusion biopsy (MTTP) for validation. PATIENTS AND METHODS: Prospective data on 340 men who underwent mpMRI (T2-weighted and diffusion-weighted MRI) followed by MTTP prostate biopsy, was collected according to Ginsburg Study Group and Standards for Reporting of Diagnostic Accuracy standards. MRI data were reported by two experienced radiologists and scored on a Likert scale. Biopsies were performed by consultant urologists not 'blinded' to the MRI result and men had both targeted and systematic sector biopsies, which were reviewed by a dedicated uropathologist. The cohorts were divided into groups representing five consecutive time intervals in the study. Sensitivity and specificity of positive MRI reports, prostate cancer detection by positive MRI, distribution of significant Gleason score and negative MRI with false negative for prostate cancer were calculated. Data were sequentially analysed and the learning curve was determined by comparing the first and last group. RESULTS: We detected a positive mpMRI in 64 patients from Group A (91%) and 52 patients from Group E (74%). The prostate cancer detection rate on mpMRI increased from 42% (27/64) in Group A to 81% (42/52) in Group E (P < 0.001). The prostate cancer detection rate by targeted biopsy increased from 27% (17/64) in Group A to 63% (33/52) in Group E (P < 0.001). The negative predictive value of MRI for significant cancer (>Gleason 3+3) was 88.9% in Group E compared with 66.6% in Group A. CONCLUSION: We demonstrate an improvement in detection of prostate cancer for MRI reporting over time, suggesting a learning curve for the technique. With an improved negative predictive value for significant cancer, decision for biopsy should be based on patient/surgeon factors and risk attributes alongside the MRI findings.

Targeted transperineal biopsy of the prostate has limited additional benefit over background cores for larger MRI-identified tumors.

PURPOSE: To compare histological outcomes in patients undergoing MRI-transrectal ultrasound fusion transperineal (MTTP) prostate biopsy and determine the incremental benefit of targeted cores. METHODS: Seventy-six consecutive patients with 89 MRI-identified targets underwent MTTP biopsy. Separate targeted biopsies and background cores were obtained according to a standardized protocol. Target biopsies were considered of added diagnostic value if these cores showed a higher Gleason grade than non-targeted cores taken from the same sector (Group 1, n = 41). Conversely, where background cores demonstrated an equal or higher Gleason grade, target cores were considered to be non-beneficial (Group 2, n = 48). RESULTS: There was no significant difference in age, PSA, prostate volume, time-to-biopsy, and number of cores obtained between the groups. A greater proportion of target cores were positive for cancer (158/228; 69.3 %) compared to background (344/1881; 18.38 %). The median target volume was 0.54 cm(3) for Group 1 (range 0.09-2.79 cm(3)) and 1.65 cm(3) for Group 2 (0.3-9.07 cm(3)), p < 0.001. The targets in Group 1 had statistically lower diameters for short and long axes, even after correction for gland size. The highest area under the receiver operating characteristic curve was demonstrated when a lesion cutoff value of 1.0 cm in short axis was applied, resulting in a sensitivity of 83.3 % and a specificity of 82.9 %. CONCLUSIONS: When a combined systematic and targeted transperineal prostate biopsy is performed, there is limited benefit in acquiring additional cores from larger-volume targets with a short axis diameter >1.0 cm.

Salt-inducible kinase 2 regulates mitotic progression and transcription in prostate cancer.

UNLABELLED: Salt-inducible kinase 2 (SIK2) is a multifunctional kinase of the AMPK family that plays a role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential in ovarian cancer. The expression of this kinase was investigated in prostate cancer clinical specimens. Interestingly, auto-antibodies against SIK2 were increased in the plasma of patients with aggressive disease. Examination of SIK2 in prostate cancer cells found that it functions both as a positive regulator of cell-cycle progression and a negative regulator of CREB1 activity. Knockdown of SIK2 inhibited cell growth, delayed cell-cycle progression, induced cell death, and enhanced CREB1 activity. Expression of a kinase-dead mutant of SIK2 also inhibited cell growth, induced cell death, and enhanced CREB1 activity. Treatment with a small-molecule SIK2 inhibitor (ARN-3236), currently in preclinical development, also led to enhanced CREB1 activity in a dose- and time-dependent manner. Because CREB1 is a transcription factor and proto-oncogene, it was posited that the effects of SIK2 on cell proliferation and viability might be mediated by changes in gene expression. To test this, gene expression array profiling was performed and while SIK2 knockdown or overexpression of the kinase-dead mutant affected established CREB1 target genes; the overlap with transcripts regulated by forskolin (FSK), the adenylate cyclase/CREB1 pathway activator, was incomplete. IMPLICATIONS: This study demonstrates that targeting SIK2 genetically or therapeutically will have pleiotropic effects on cell-cycle progression and transcription factor activation, which should be accounted for when characterizing SIK2 inhibitors.

Investigating the ability of multiparametric MRI to exclude significant prostate cancer prior to transperineal biopsy.

INTRODUCTION: We characterized false negative prostate magnetic resonance imaging (MRI) reporting by using histology derived from MRI-transrectal ultrasound (TRUS)-guided transperineal (MTTP) fusion biopsies. METHODS: In total, 148 consecutive patients were retrospectively reviewed. Men underwent multiparametric MRI (mpMRI), reported by a consultant/attending radiologist in line with European Society of Urogenital Radiology (ESUR) standards. MTTP biopsy of the lesions was performed according to the Ginsburg recommendations. Cases with an MRI-histology mismatch were identified and underwent a second read by an experienced radiologist. A third review was performed with direct histology comparison to determine a true miss from an MRI-occult cancer. Statistical analysis was performed with McNemar's test. RESULTS: False negative lesions were identified in 29 MRI examinations (19.6%), with a total of 46 lesions. Most false negative lesions (21/46) were located in the anterior sectors of the prostate. The second read led to a significant decrease of false-negative lesions with 7/29 further studies identified as positive on a patient-by-patient basis (24.1% of studies, p = 0.016) and 11/46 lesions (23.9%; p = 0.001). Of these, 30 lesions following the first read and 23 lesions after the second read were considered significant cancer according to the University College London criteria. However, on direct comparison with histology, most lesions were MRI occult. CONCLUSION: We demonstrate that MRI can fail to detect clinically relevant lesions. Improved results were achieved with a second read but despite this, a number of lesions remain MRI-occult. Further advances in imaging are required to reduce false negative results.

Definitions of terms, processes and a minimum dataset for transperineal prostate biopsies: a standardization approach of the Ginsburg Study Group for Enhanced Prostate Diagnostics.

OBJECTIVES: To define terms and processes and agree on a minimum dataset in relation to transperineal prostate biopsy procedures and enhanced prostate diagnostics. To identify the need for further evaluation and establish a collaborative research practice. PATIENTS AND METHODS: A 19-member multidisciplinary panel rated 66 items for their appropriateness and their definition to be incorporated into the international databank using the Research and Development/University of California Los Angeles Appropriateness Method. The item list was developed from interviews conducted with healthcare professionals from urology, radiology, pathology and engineering. RESULTS: The panel agreed on 56 items that were appropriate to be incorporated into a prospective database. In total, 10 items were uncertain and were omitted. These items were within the categories: definitions (n = 2), imaging (n = 1), surgical protocols (n = 2) and histology (n = 5). CONCLUSIONS: The components of a minimum dataset for transperineal prostate biopsy have been defined. This provides an opportunity for multicentre collaborative data analysis and technique development. The findings of the present study will facilitate prospective studies into the application and outcome of transperineal prostate biopsies.