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Background/Objective : Penile cancer is aggressive and rapidly progressive. Early recognition is paramount for overall survival. However, many men delay presentation due to a lack of awareness and social stigma. This pilot study aims to develop a convolutional neural network (CNN) model to differentiate penile cancer from precancerous and benign penile lesions. Methods: The CNN was developed using 136 penile lesion images sourced from peer-reviewed open access publications. These images included 65 penile squamous cell carcinoma (SCC), 44 precancerous lesions, and 27 benign lesions. The dataset was partitioned using a stratified split into training (64%), validation (16%), and test (20%) sets. The model was evaluated using ten trials of 10-fold internal cross-validation to ensure robust performance assessment. Results: When distinguishing between benign penile lesions and penile SCC, the CNN achieved an Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.94, with a sensitivity of 0.82, specificity of 0.87, positive predictive value of 0.95, and negative predictive value of 0.72. The CNN showed reduced discriminative capability in differentiating precancerous lesions from penile SCC, with an AUROC of 0.74, sensitivity of 0.75, specificity of 0.65, PPV of 0.45, and NPV of 0.88. Conclusion: These findings demonstrate the potential of artificial intelligence in identifying penile SCC. Limitations of this study include the small sample size and reliance on photographs from publications. Further refinement and validation of the CNN using real-life data are needed.

Background: Genital skin conditions are rare and pose a diagnostic challenge due to their diverse pathology. Patient anxiety and referral decisions add complexity for primary caregivers. Demographics and overlapping symptoms complicate diagnosis, causing anxiety for both patients and clinicians. Social stigma and apprehension to seek healthcare might delay treatment. Accurate differentiation between benign and potentially serious conditions is crucial., Objective: We aim to provide clinicians with a clear and concise framework to assist them in risk stratification, treatment decisions and referral pathways for common genital skin conditions., Discussion: Differentiating normal variations is crucial to minimise unnecessary investigations and alleviate patient anxiety. Circumcision status, pigmentation and genetics influence disease presentation. We highlight benign conditions for reassurance. Inflammatory genital lesions might arise from various causes. Biopsies remain essential for accurately diagnosing uncertain cases. Sexually transmitted infections (STIs) should be promptly diagnosed and treated. Neoplastic conditions can evolve rapidly, requiring an urgent specialist referral.

Purpose: Racial and ethnic healthcare disparities require innovative solutions. Patient portals enable online access to health records and clinician communication and are associated with improved health outcomes. Nevertheless, a digital divide in access to such portals persist, especially among people of minoritized race and non-English-speakers. This study assesses the impact of automatic enrollment (autoenrollment) on patient portal activation rates among adult patients at the University of California, San Francisco (UCSF), with a focus on disparities by race, ethnicity, and primary language., Materials and Methods: Starting March 2020, autoenrollment offers for patient portals were sent to UCSF adult patients aged 18 or older via text message. Analysis considered patient portal activation before and after the intervention, examining variations by race, ethnicity, and primary language. Descriptive statistics and an interrupted time series analysis were used to assess the intervention's impact., Results: Autoenrollment increased patient portal activation rates among all adult patients and patients of minoritized races saw greater increases in activation rates than White patients. While initially not statistically significant, by the end of the surveillance period, we observed statistically significant increases in activation rates in Latinx (3.5-fold, p = < 0.001), Black (3.2-fold, p = 0.003), and Asian (3.1-fold, p = 0.002) patient populations when compared with White patients. Increased activation rates over time in patients with a preferred language other than English (13-fold) were also statistically significant (p = < 0.001) when compared with the increase in English preferred language patients., Conclusion: An organization-based workflow intervention that provided autoenrollment in patient portals via text message was associated with statistically significant mitigation of racial, ethnic, and language-based disparities in patient portal activation rates. Although promising, the autoenrollment intervention did not eliminate disparities in portal enrollment. More work must be done to close the digital divide in access to healthcare technology., (© 2024. The Author(s).)

Objective: To describe the demographic factors of owners and their dogs associated with owner feeding choices and the regularity with which those diets were fed to a US-based population of dogs., Methods: This cross-sectional analysis examined 40,367 initial survey responses from US dog owners participating in the Dog Aging Project. The surveys were collected from January 2, 2020, to December 31, 2022, and included primary and secondary diet component types and dog and owner demographic variables. Each demographic variable was compared across diet type choices with a χ2 test of independence., Results: Most owners (82%) fed a commercially prepared extruded dry diet (kibble) as the primary diet component. Most owners (89%) reported that they fed their dogs a consistent diet over time. Owner demographic factors (income, education level) were less correlated with difference in diet choices than dog demographic factors (size, neuter status, purebred status, activity level), but owner age did correlate with choice: younger owners tended to feed kibble more compared to older owners. Home-cooked diets were most often consumed by small (< 30-lb) dogs, purebred dogs in poorer health status, and dogs with owners aged 45 years or older. Raw diets were more commonly fed to purebred, intact, and highly active dogs. Ten percent of service dogs were reportedly fed a raw diet of some sort., Conclusions: Demographic variables are associated with statistically significant differences in diet types selected. Nutrition studies examining health outcomes associated with the feeding of different diet types should account for these factors during design or analysis in order to avoid bias. An epidemiological tool, the directed acyclic graph, is presented., Clinical Relevance: This information will help clinicians in their discussions with clients about pet nutrition.

Urethral sphincter insufficiency following radical prostatectomy (RP) is a common cause of non-neurogenic stress urinary incontinence (SUI). Artificial urinary sphincter (AUS) insertion remains the standard of care for fit patients with SUI refractory to non-operative interventions. The proximal urethra is a common location for uncomplicated AUS placement. However, previous failed AUS, urethroplasty, or pelvic radiotherapy (RT) may compromise urethral tissue requiring technique modifications that optimise outcomes. In these situations, transcorporal cuff (TC) placement has been well described to facilitate continence restoration in men where there is no other feasible option other than urinary diversion or permanent incontinence. In the traditional TC approach, the procedure may be complicated by haematoma due to difficulty in completely closing the corporal defects behind the urethra. This narrated video demonstrates the tunical flap (TF) modification for transcorporal AUS implantation via a perineal and penoscrotal approach in patients with prior failed AUS placements secondary to urethral erosion. The TF technique for transcorporal AUS insertion provides circumferential reinforcement with tunica albuginea from the corpora cavernosa. Here, we show how this technique provides additional urethral support for compromised urethral tissue to help prevent cuff erosion. The TF preserves the corporal volume and does not limit candidacy for future penile prosthesis implantation. In our early results, there have been no postoperative haematoma formation with this technique., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-641/coif). The authors have no conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect multiparametric magnetic resonance imaging (mpMRI)-invisible prostate tumours and improve the sensitivity of detection of prostate cancer (PCa) in comparison to mpMRI alone. Numerous risk calculators have been validated as tools for stratification of men at risk of being diagnosed with clinically significant (cs)PCa., Objective: To develop a novel risk calculator using clinical parameters and imaging parameters from mpMRI and PSMA PET/CT in a cohort of patients undergoing mpMRI and PSMA PET/CT before biopsy., Design Setting and Participants: A total of 291 men from the PRIMARY prospective trial underwent mpMRI and PSMA PET/CT before transperineal prostate biopsy with sampling of systematic and targeted cores., Outcome Measurements and Statistical Analysis: Novel risk calculators were developed using multivariable logistic regression analysis to predict detection of overall PCa (International Society of Urological Pathology grade group [GG] ≥1) and csPCa (GG ≥2). The risk calculators were then compared with the European Randomised Study of Screening for Prostate Cancer risk calculator incorporating mpMRI (ERSPC-MRI). Resampling methods were used to evaluate the discrimination and calibration of the risk calculators and to perform decision curve analysis., Results and Limitations: Age, prostate-specific antigen, prostate volume, and mpMRI Prostate Imaging-Reporting and Data System scores were included in the MRI risk calculator, resulting in area under the receiver operating characteristic curve (AUC) values of 0.791 for overall PCa (GG ≥1) and 0.812 for csPCa (GG ≥2). Addition of the maximum standardised uptake value (SUVmax) on PSMA PET/CT for the prostate lesion, and of SUVmax for the mpMRI lesions for the MRI-PSMA risk calculator resulted in AUCs of 0.831 for overall PCa and 0.876 for csPCa (≥ISUP2).The ERSPC-MRI risk calculator had AUCs of 0.758 ( p  = 0.02) for overall PCa and 0.805 ( p  = 0.001) for csPCa. Both the MRI and MRI-PSMA risk calculators were superior to the ERSPC-MRI for both overall PCa and csPCa., Conclusions: These novel risk calculators incorporate clinical and radiological parameters for stratification of men at risk of csPCa. The risk calculator including PSMA PET/CT data is superior to a calculator incorporating mpMRI data alone., Patient Summary: We evaluated a new risk calculator that uses clinical information and results from two types of scan to predict the risk of clinically significant prostate cancer on prostate biopsy. This risk model can guide patients and clinicians in shared decision-making and may help in avoiding unnecessary prostate biopsies., (© 2023 The Authors.)

Finasteride competitively inhibits 5α-reductase (5-AR) isoenzymes, which blocks dihydrotestosterone (DHT) production, thereby reducing DHT. Finasteride is used in the management of benign prostatic hyperplasia (BPH) and androgenic alopecia. Amid patient reports of suicidal ideation (SI), the Post Finasteride Syndrome advocacy group has petitioned for either a stop to selling of the drug or advertisement of stronger warnings. The US Food and Drug Administration recently added SI to the adverse effects listed for finasteride. Here we provide a brief but comprehensive review of the literature on the psychological side effects of 5-AR inhibitors (5-ARIs) to provide an opinion to help in guiding treating urologists. Most of the current evidence, obtained from the literature on dermatology, suggests that 5-ARI users experience a higher rate of depressive symptoms. However, given the lack of comprehensive randomised studies, the causal link between finasteride and SI remains unclear. Urologists prescribing 5-ARIs should be aware of the recent addition of suicide and SI risk to the list of side effects. A mental health screen should be performed and appropriate resources provided to patients commencing treatment. Furthermore, a review should be arranged with the general practitioner to assess new-onset mental health or SI symptoms., Patient Summary: We provide recommendations for urologists who prescribe finasteride for the treatment of benign prostate enlargement. Urologists should be aware of the recent addition of suicidal ideation to the list of side effects for this drug. Finasteride prescription should be continued; however, we recommend a detailed medical history to screen for prior mental health and personality disorders, with discontinuation of the medication in patients with new onset of depression or suicidal symptoms. Close liaison with the patient's general practitioner is vital for management of depressive or suicidal symptoms., (© 2023 The Author(s).)

Purpose of Review: This article presents a critical review of the current literature to provide a brief update on the contemporary advances in diagnosing and managing N1 penile cancer., Recent Findings: Penile squamous cell carcinoma (pSCC) has evolved from being an orphan field for cancer innovation. Advances in the understanding tumour biology have enabled sophisticated diagnostics and predictive modelling to better characterize inguinal disease. Minimally invasive inguinal lymph node dissection is emerging as a technique that reduces morbidity while maintaining oncological safety. Furthermore, robust clinical trials are underway ,which will provide level one evidence to guide treatment decisions. Exciting advances in the field of immune-oncology offer promise as adjuvant therapies. International collaboration and centralisation of care will be essential to driving translational research and equitable evidence-based care., Summary: Improving outcomes for men with pSCC remains a global challenge. Radical inguinal lymph node dissection remains the gold standard for diagnosing and curing N1 disease. Although many promising developments are on the horizon, high-level evidence is required to guide therapy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Early detection and management of prostate cancer has evolved over the past decade, with a focus now on harm minimisation and reducing overdiagnosis and overtreatment, given the proven improvements in survival from randomised controlled trials. Multiparametric magnetic resonance imaging (mpMRI) is now an important aspect of the diagnostic pathway in prostate cancer, improving the detection of clinically significant prostate cancer, enabling accurate localisation of appropriate sites to biopsy, and reducing unnecessary biopsies in most patients with normal magnetic resonance imaging scans. Biopsies are now performed transperineally, substantially reducing the risk of post-procedure sepsis. Australian-led research has shown that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior accuracy in the staging of prostate cancer than conventional imaging (CT and whole-body bone scan). Localised prostate cancer that is low risk (International Society for Urological Pathology [ISUP] grade 1, Gleason score 3 + 3 = 6; and ISUP grade group 2, Gleason score 3 + 4 = 7 with less than 10% pattern 4) can be offered active surveillance, reducing harms from overtreatment. Prostatectomy and definitive radiation remain the gold standard for localised intermediate and high risk disease. However, focal therapy is an emerging experimental treatment modality in Australia in carefully selected patients. The management of advanced prostate cancer treatment has evolved to now include several novel agents both in the metastatic hormone-sensitive and castration-resistant disease settings. Multimodal therapy with androgen deprivation therapy, additional systemic therapy and radiotherapy are often recommended. PSMA-based radioligand therapy has emerged as a treatment option for metastatic castration-resistant prostate cancer and is currently being evaluated in earlier disease states., (© 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Objectives: To demonstrate an operative standard for dynamic sentinel lymph node biopsy (DSLNB). Long-term survival in men with penile squamous cell carcinoma (SCC) depends on accurately staging lymph node metastases. European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines recognize DSLNB as a standard for staging men with intermediate to high-risk tumors and clinically absent inguinal lymphadenopathy. DSLNB accuracy has been linked with pre-operative planning and surgical technique, yet no peer-reviewed video exists to establish an operative standard. Here we present a narrated video of our technique and discuss the accuracy of this approach using retrospective patient data., Methods: Ethics approval and patient consent was obtained. Retrospective analysis was performed on patients undergoing DSLNB for inguinal lymph node staging of histologically proven penile SCC. Data was included from 2 experienced uro-oncologists with subspecialty training in penile cancer working in Victoria, Australia between January 2015 and July 2021. Variables collected included Primary tumour histology, DSLNB pathology, progression to radical inguinal lymph node dissection (RILND) and recurrence patterns. DSLNB sensitivity and proportion of groins spared RILND is calculated., Results: DSLNB was performed on 127 groins (64 patients) during the study period. Within the cohort, 44% (n = 28) of patients had a pre-operative lymphoscintigraphy with single-photon emission computed tomography (SPECT/CT). Analysis of primary tumor intervention demonstrates that 82.8% (n = 53) of men underwent penile sparing surgery. Tumor histology in 88% of patients (n = 56) demonstrated pT1-pT2 disease. Overall n = 19 groins undergoing DSLNB were positive for malignancy and n = 108 were negative. 36 groins progressed to RILND during a mean follow up of 29 months. Only 2 groins that previously had a negative DSLNB were positive on RILND, one in the groin and one in the pelvis. We observed a false negative rate of 1.9% and a sensitivity of 90.5%. In our cohort DSLNB allowed 71.7% of groins to proceed for surveillance instead of prophylactic radical ILND., Conclusions: DSLNB is a safe and accurate method for assessing inguinal lymphadenopathy in men with intermediate to high-risk penile SCC and impalpable groins. This video study establishes an operative standard for DSLNB with oncological outcomes are consistent with international expectations. Standardized use of DSLNB by an experienced team will reduce morbidity while maintaining oncological safety for men with intermediate to high-risk penile cancer and cN0 disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Penile squamous cell carcinoma (SCC) is a rare malignancy, which is known to invade local inguinal lymph nodes prior to progressing to the pelvis. Dynamic sentinel lymph node biopsy (DSLNB) is a standard for the minimally invasive assessment of lymphadenopathy in patients with subclinical groin metastasis. Hybrid 99m Tc Single-Photon Emission Computed Tomography (SPECT-CT) has been shown to increase the accuracy of identifying first draining "sentinel" nodes (SN). Unilateral inguinal visualization on SPECT-CT is a rare presentation, which may increase the likelihood of a false negative SN biopsy. Retrospective analysis from three-penile cancer uro-oncologists in Melbourne, Australia identified 78 groins undergoing DSLNB for intermediate/high risk primary disease. Unilateral SPECT-CT results were observed in four patients suggesting a functional pattern of lymph diversion. Analysis confirmed malignancy ( n = 2), sarcoidosis ( n = 1), and evidence of local inflammation in SPECT-CT negative groins. Findings re-iterate the role of SPECT-CT a pre-operative adjunct. Experienced multimodal groin assessment using palpation, SPECT-CT, lymphoscintigraphy, and blue dye tracking remains paramount. Unilateral SN on pre-operative SPECT-CT in men with intermediate/high-risk penile SCC should elicit a higher degree of clinical suspicion. We recommend a low threshold for recommending radical inguinal lymph node dissection (ILND) for groins refractory to minimally invasive assessment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 O'Brien, Teh, Kelly, Chen, Manning, Furrer, Chee and Lawrentschuk.)

Metastatic spread of testicular cancer has been well documented, with 95% of cases involving para-aortic retroperitoneal lymph nodes. Mesenteric lymphatic basins do not lie within the canonical drainage pathway of the testes and represent a rare site of metastasis. Various mechanisms of spread to the mesentery have been described, including direct extension and haematogenous dissemination. We present a case of a previously-well 43-year-old man who presented with right scrotal discomfort and intermittent lower back pain, who was found to have mesenteric metastases from a non-seminomatous germ cell tumour of the testis. Managing lymphadenopathy that lies outside of standard resection templates remains a complex surgical challenge. Here we present the first case in the English medical literature with co-existing supradiaphragmatic axillary and mediastinal nodal disease., (© 2020 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

PSI4 is a free and open-source ab initio electronic structure program providing implementations of Hartree-Fock, density functional theory, many-body perturbation theory, configuration interaction, density cumulant theory, symmetry-adapted perturbation theory, and coupled-cluster theory. Most of the methods are quite efficient, thanks to density fitting and multi-core parallelism. The program is a hybrid of C++ and Python, and calculations may be run with very simple text files or using the Python API, facilitating post-processing and complex workflows; method developers also have access to most of PSI4's core functionalities via Python. Job specification may be passed using The Molecular Sciences Software Institute (MolSSI) QCSCHEMA data format, facilitating interoperability. A rewrite of our top-level computation driver, and concomitant adoption of the MolSSI QCARCHIVE INFRASTRUCTURE project, makes the latest version of PSI4 well suited to distributed computation of large numbers of independent tasks. The project has fostered the development of independent software components that may be reused in other quantum chemistry programs.

Purpose: Three-dimensional (3D) printing was invented in 1983 but has only just begun to influence medicine and surgery. Conversion of digital images into physical models demonstrates promise to revolutionize multiple domains of surgery. In the field of uro-oncology, researchers and clinicians have recognized the potential of this technology and are working towards making it an integral part of urological practice. We review current literature regarding 3D printing and other 3D technology in the field of urology., Method: A comprehensive assessment of contemporary literature was performed according to a modified PRISMA analysis for the purposes of this narrative review article. Medical databases that were searched included: Web of Science, EMBASE and Cochrane databases. Articles assessed were limited only to English-language peer-reviewed articles published between 1980 and 2017. The search terms used were "3D", "3-dimensional", "printing", "printing technology", "urology", "surgery". Acceptable articles were reviewed and incorporated for their merit and relevance with preference given for articles with high impact, original research and recent advances., Results: Thirty-five publications were included in final analysis and discussion., Conclusions: The area of 3D printing in Urology shows promising results, but further research is required and cost reduction must occur before clinicians fully embrace its use. As costs continue to decline and diversity of materials continues to expand, research and clinical utilization will increase. Recent advances have demonstrated the potential of this technology in the realms of education and surgical optimization. The generation of personalized organs using 3D printing scaffolding remains the 'holy grail' of this technology.

Background: This study aims to review current laboratory reporting strategies across Australia and New Zealand with a view to propose a more useful template for reporting serum testosterone in the context of prostate cancer., Materials and Methods: Registered pathology laboratories in Australia and New Zealand were enrolled into the current study. An electronic or a phone survey was utilized to collect data from each participating laboratory. Obtained information included assay utilized, units reported, reference intervals, lowest reported value, and lowest detectable value. To identify recommendations for testosterone testing, a systematic search was performed across Web of Science (including MEDLINE), EMBASE, and Cochrane libraries., Results: Assessment of national pathology laboratories identified significant heterogeneity in the reporting methods. Reports typically used a "normal healthy male of 35 years of age" as a comparator but did not refer to optimal castrate levels, the lowest level that their assay was able to detect, nor did they include appended clinical guidelines relating to the prostate cancer patient cohort., Conclusions: Across Australia and New Zealand, various methods for testing and reporting serum testosterone exist, while international guidelines remain vague. The fashion in which serum testosterone levels are displayed should be re-evaluated to address the relevant clinical population and reflect an agreed-upon castrate threshold in patients undergoing androgen deprivation therapy.

A 64-year-old man presented with a 2 week history of progressive phimosis and painful ulcer on his penile meatus. He underwent penile preserving excision, and subsequent pathological examination confirmed T-cell non-Hodgkin lymphoma with immunohistochemical features of large cell transformation of mycosis fungoides. The penis was further treated with local external beam radiotherapy consisting of 27 Gy in 15 fractions and systemic mini-CHOP chemotherapy. An organ-preserving tissue response has since been achieved. This case is the first of its kind in the literature and firmly highlights the role of multidisciplinary management for this rare malignancy.

Background: Toxicity of airborne particulate matter (PM) is difficult to assess because PM composition is complex and variable due to source contribution and atmospheric transformation. In this study, we used an in vitro toxicoproteomic approach to identify the toxicity mechanisms associated with different subfractions of Ottawa urban dust (EHC-93)., Methods: A549 human lung epithelial cells were exposed to 0, 60, 140 and 200 μg/cm 2 doses of EHC-93 (total), its insoluble and soluble fractions for 24 h. Multiple cytotoxicity assays and proteomic analyses were used to assess particle toxicity in the exposed cells., Results: The cytotoxicity data based on cellular ATP, BrdU incorporation and LDH leakage indicated that the insoluble, but not the soluble, fraction is responsible for the toxicity of EHC-93 in A549 cells. Two-dimensional gel electrophoresis results revealed that the expressions of 206 protein spots were significantly altered after particle exposures, where 154 were identified by MALDI-TOF-TOF-MS/MS. The results from cytotoxicity assays and proteomic analyses converged to a similar finding that the effects of the total and insoluble fraction may be alike, but their effects were distinguishable, and their effects were significantly different from the soluble fraction. Furthermore, the toxic potency of EHC-93 total is not equal to the sum of its insoluble and soluble fractions, implying inter-component interactions between insoluble and soluble materials resulting in synergistic or antagonistic cytotoxic effects. Pathway analysis based on the low toxicity dose (60 μg/cm 2 ) indicated that the two subfractions can alter the expression of those proteins involved in pathways including cell death, cell proliferation and inflammatory response in a distinguishable manner. For example, the insoluble and soluble fractions differentially affected the secretion of pro-inflammatory cytokines such as MCP-1 and IL-8 and distinctly altered the expression of those proteins (e.g., TREM1, PDIA3 and ENO1) involved in an inflammatory response pathway in A549 cells., Conclusions: This study demonstrated the impact of different fractions of urban air particles constituted of various chemical species on different mechanistic pathways and thus on cytotoxicity effects. In vitro toxicoproteomics can be a valuable tool in mapping these differences in air pollutant exposure-related toxicity mechanisms.

Multiparametric magnetic resonance imaging (mpMRI) has added to the armamentarium for the diagnosis and surveillance for organ-confined prostate cancer. Atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia (HGPIN) are premalignant prostatic lesions. The management of such lesions remains contentious, and the addition of mpMRI introduces further uncertainty, given its ability to pick up indolent lesions and its use in targeted biopsy. We aimed to perform a comprehensive review of current evidence regarding atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and mpMRI to ascertain a consensus for a current management algorithm., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Purpose: In penile cancer, the optimal diagnostics and management of metastatic lymph nodes are not clear. Advances in minimally invasive staging, including dynamic sentinel lymph node biopsy, have widened the diagnostic repertoire of the urologist. We aimed to provide an objective update of the recent trends in the management of penile squamous cell carcinoma, and inguinal and pelvic lymph node metastases., Materials and Methods: We systematically reviewed several medical databases, including the Web of Science® (with MEDLINE®), Embase® and Cochrane databases, according to PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines. The search terms used were penile cancer, lymph node, sentinel node, minimally invasive, surgery and outcomes, alone and in combination. Articles pertaining to the management of lymph nodes in penile cancer were reviewed, including original research, reviews and clinical guidelines published between 1980 and 2016., Results: Accurate and minimally invasive lymph node staging is of the utmost importance in the surgical management of penile squamous cell carcinoma. In patients with clinically node negative disease, a growing body of evidence supports the use of sentinel lymph node biopsies. Dynamic sentinel lymph node biopsy exposes the patient to minimal risk, and results in superior sensitivity and specificity profiles compared to alternate nodal staging techniques. In the presence of locoregional disease, improvements in inguinal or pelvic lymphadenectomy have reduced morbidity and improved oncologic outcomes. A multimodal approach of chemotherapy and surgery has demonstrated a survival benefit for patients with advanced disease., Conclusions: Recent developments in lymph node management have occurred in penile cancer, such as minimally invasive lymph node diagnosis and intervention strategies. These advances have been met with a degree of controversy in the contemporary literature. Current data suggest that dynamic sentinel lymph node biopsy provides excellent sensitivity and specificity for detecting lymph node metastases. More robust long-term data on multicenter patient cohorts are required to determine the optimal management of lymph nodes in penile cancer., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

In this study, we used cytotoxicity assays, proteomic and gene expression analyses to examine the difference in response of A549 cells to two silica particles that differ in physical properties, namely cristobalite (CR) and α-quartz (Min-U-Sil 5, MI). Cytotoxicity assays such as lactate dehydrogenase release, 5-bromo-2'-deoxyuridine incorporation and cellular ATP showed that both silica particles could cause cell death, decreased cell proliferation and metabolism in the A549 human lung epithelial cells. While cytotoxicity assays revealed little difference between CR and MI exposures, proteomic and gene expression analyses unveiled both similar and unique molecular changes in A549 cells. For instance, two-dimensional gel electrophoresis data indicated that the expression of proteins in the cell death (e.g., ALDH1A1, HTRA2 and PRDX6) and cell proliferation (e.g., FSCN1, HNRNPAB and PGK1) pathways were significantly different between the two silica particles. Reverse transcription-polymerase chain reaction data provided additional evidence supporting the proteomic findings. Preliminary assessment of the physical differences between CR and MI suggested that the extent of surface interaction between particles and cells could explain some of the observed biological effects. However, the differential dose-response curves for some other genes and proteins suggest that other physical attributes of particulate matter can also contribute to particulate matter-related cellular toxicity. Our results demonstrated that toxicoproteomic and gene expression analyses are sensitive in distinguishing subtle toxicity differences associated with silica particles of varying physical properties compared to traditional cytotoxicity endpoints. Copyright © 2016 Her Majesty the Queen in Right of Canada. Journal of Applied Toxicology published by John Wiley & Sons, Ltd., (Copyright © 2016 Her Majesty the Queen in Right of Canada. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.)

The likelihood of environmental and health impacts of silicon dioxide nanoparticles (SiNPs) has risen, due to their increased use in products and applications. The biological potency of a set of similarly-sized amorphous SiNPs was investigated in a variety of cells to examine the influence of physico-chemical and biological factors on their toxicity. Cellular LDH and ATP, BrdU incorporation, resazurin reduction and cytokine release were measured in human epithelial A549, human THP-1 and mouse J774A.1 macrophage cells exposed for 24 h to suspensions of 5-15, 10-20 and 12 nm SiNPs and reference particles. The SiNPs were characterized in dry state and in suspension to determine their physico-chemical properties. The dose-response data were simplified into particle potency estimates to facilitate the comparison of multiple endpoints of biological effects in cells. Mouse macrophages were the most sensitive to SiNP exposures. Cytotoxicity of the individual cell lines was correlated while the cytokine responses differed, supported by cell type-specific differences in inflammation-associated pathways. SiNP (12 nm), the most cytotoxic and inflammogenic nanoparticle had the highest surface acidity, dry-state agglomerate size, the lowest trace metal and organics content, the smallest surface area and agglomerate size in suspension. Particle surface acidity appeared to be the most significant determinant of the overall biological activity of this set of nanoparticles. Combined with the nanoparticle characterization, integration of the biological potency estimates enabled a comprehensive determination of the cellular reactivity of the SiNPs. The approach shows promise as a useful tool for first-tier screening of SiNP toxicity.

Natural products are invaluable historic sources of drugs for infectious diseases; however, the discovery of novel antimicrobial chemical scaffolds has waned in recent years. Concurrently, there is a pressing need for improved therapeutics to treat fungal infections. We employed a co-culture screen to identify ibomycin, a large polyketide macrolactone that has preferential killing activity against Cryptococcus neoformans. Using chemical and genome methods, we determined the structure of ibomycin and identified the biosynthetic cluster responsible for its synthesis. Chemogenomic profiling coupled with cell biological assays link ibomycin bioactivity to membrane function. The preferential activity of ibomycin toward C. neoformans is due to the ability of the compound to selectively permeate its cell wall. These results delineate a novel antifungal agent that is produced by one of the largest documented biosynthetic clusters to date and underscore the fact that there remains significant untapped chemical diversity of natural products with application in antimicrobial research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Tubular particles presenting heterogeneous regions of chemistry on the tube-ends versus the side are fabricated and are shown to control the particle orientation on the surface of live lymphocytes. Controlling the orientation of anisotropic microparticles on cell surfaces is of interest for biomedical applications and drug delivery in particular, since it can be used to promote or resist particle internalization., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment.

Prosaposin, the precursor of saposins or saps, is an injury-repair protein that acts on both neurons and glia. Previous studies identified the prosaposin gene as one of differentially expressed genes following nerve injury. In the present study, we investigated expression of prosaposin mRNA in injured brain utilizing rat models of focal cerebral ischemia and cortical stab wound in order to explore the significance of prosaposin in nerve injury. In ischemic brain, the level of prosaposin mRNA was elevated greater than 400% over controls within 5 days after ischemic insults. Importantly, this induction was accompanied by a 9-base splicing consistent with the alternative Exon-8 splicing of human prosaposin mRNA. In normal brain, two prosaposin mRNA species with and without the 9-base insertion were expressed at a ratio of 85:15; however, this equilibrium reverted to 5:95 following ischemic injury. Similar inductions were observed in stab wound brains. Immunohistochemical staining and in situ hybridization demonstrated an enhanced signal distribution of prosaposin mRNA and injury-induced prosaposin protein around the lesion. The data suggest the expression and processing of prosaposin mRNA may be crucially regulated not only for cerebral homeostasis but also during nerve regenerative and degenerative processes.

Recently, TX14(A), a prosaposin-derived neurotrophic peptide, was shown to prevent both large and small fiber deficits in streptozotocin diabetes. Here, the efficacy of TX14(A) in reversing established nerve conduction disorders in streptozotocin diabetes, a model of insulin deficiency, and preventing them in galactose feeding, an insulin-replete model of polyol pathway flux, was investigated. Following streptozotocin injection (50 mg/kg ip), TX14(A) treatment (1 mg/kg ip thrice weekly) was initiated in half of the animals. After 8 wk, treatment was begun in half of the untreated animals and discontinued in half of the treated animals, and the experiment continued for 6 wk. TX14(A) reversed established motor and sensory nerve conduction deficits in streptozotocin-diabetic rats and the impact of previous treatment was still evident 3 wk after withdrawal. With the onset of 40% galactose feeding, the same dose of TX14(A) was given to half of the control and half of the galactose-fed animals for 16 wk. TX14(A) was without effect in control animals but it attenuated motor and sensory nerve conduction deficits in galactose-fed rats, an effect associated with amelioration of axonal dwindling in the sciatic nerve. These observations extend the therapeutic utility of TX14(A) and highlight its potential in treating established diabetic neuropathy.

Prosaposin is the precursor of the saposins and has both neurotrophic and myelinotrophic activity in vitro and in vivo. Using an antibody specific for the holoprotein, an immunocytochemical survey demonstrated intense staining of adult rat skeletal, cardiac, and smooth muscle cells. Prosaposin immunoreactivity in muscle appears dependent on innervation, as denervated adult rat skeletal muscles showed decreased immunostaining that returned to normal levels after reinnervation. TX14(A), a peptide derived from the neurotrophic sequence of prosaposin, attenuated the decline in muscle mass loss following nerve injury induced by a constricting ligature. In vitro, both L6 myoblasts and primary chick-embryo myoblasts showed similar prosaposin immunopositivity, mainly in myotubes. TX14(A) induced a threefold increase in L6 myoblast fusion during early stages of differentiation without affecting cell proliferation. The fusion process was decreased in vitro in a dose-dependent fashion by addition of a neutralizing anti-prosaposin antibody. These data suggest that, in addition to neurotrophic and myelinotrophic activities, prosaposin has myotrophic properties., (Copyright 2001 John Wiley & Sons, Inc.)

The myelinotrophic action of Prosaptide D5 was investigated in developing rats. Sulfatide concentrations in brain and sciatic nerve were determined to assess the development of myelination. Subcutaneous D5-injection significantly increased sulfatide concentrations in both brain and sciatic nerve by 250 and 150% over controls, respectively. D5 promoted ERK phosphorylation in iSC Schwann cells similar to prosaposin. The results showed that D5 treatment stimulated a myelination process in developing rat.

A protein isolated from the supernatant of cryopreserved rooster sperm was found to increase the capability of cryopreserved rooster sperm to bind in vitro to the perivitelline membrane of a chicken egg and substantially raise fertility after artificial insemination (AI). That activity was partially purified and termed universal primary sperm-egg binding protein (UPSEBP). Insufficient protein remained from 6 x 10(11) sperm, despite retention of bioactivity, to allow sequencing. We deduced that the protein may be related to prosaposin (also termed SGP-1, for sulfated glycoprotein-1), and we used published amino acid sequences of prosaposin as a guide for synthesis of peptides. Certain peptides were found to increase in vitro sperm-egg binding and increase fertility of frozen-thawed or fresh rooster sperm, in a manner similar to semipurified UPSEBP. Active epitopes were in a 60 amino acid sequence, reflecting the intervening sequence between saposins A and B, plus short extensions into saposins A and B. Highest activity was found when this synthetic peptide was oxidized to form a disulfide bond between terminal cysteines. Antibody against a synthetic peptide consisting of 58 of these 60 amino acids bound to a 7-9 kilodalton protein in UPSEBP. Collectively, the data support the conclusion that UPSEBP is a fragment of prosaposin. Because prosaposin is in semen in humans and animals, these observations have broad implications for possible cause and therapy of one type of subfertility.

We report that prosaposin treatment induced extracellular signal-regulated kinases (ERKs) and sphingosine kinase activity, increased DNA synthesis, and prevented cell apoptosis. Prosaposin treatment induced pheochromocytoma cells (PC12) to enter the S phase of the cell cycle; this effect was inhibited by the MEK inhibitor PD98059, indicating that prosaposin-induced ERK phosphorylation is required for stimulation of DNA synthesis. The prosaposin effect was also inhibited by pertussis toxin, indicating that the prosaposin receptor is a G-protein-coupled receptor. Prosaposin rescued PC12 cells from apoptosis induced by staurosporine or ceramide. Sphingosine kinase activity was increased by prosaposin treatment. We propose that this effect is a mechanism underlying the proliferative and anti-apoptotic functions of prosaposin. Prosaposin appears to be a key regulatory factor in the ceramide-S-1-P rheostat, which regulates cell fate.

Background: Short-term diabetes causes sensory disorders in rats ranging from thermal hypoalgesia to exaggerated behavioral responses to other sensory stimuli. As impaired neurotrophic support may promote sensory nerve disorders during diabetes, the authors investigated whether TX14(A), a neurotrophic peptide derived from prosaposin, was able to ameliorate nerve disorders in diabetic rats., Methods: TX14(A) was delivered by intraperitoneal or intrathecal injection to control or streptozotocin-diabetic rats in either single or multiple (three times weekly) dose regimens. Efficacy was measured against diabetes-induced disorders of sensory nerve conduction velocity, paw withdrawal latency to radiant heat, tactile response thresholds to von Frey filaments, and flinching after paw formalin injection., Results: Prolonged TX14(A) treatment of diabetic rats prevented the progressive decline in large sensory fiber conduction velocity in the sciatic nerve, development of paw thermal hypoalgesia, and increased flinching after paw formalin injection. The effect on formalin hyperalgesia persisted for 48 h but not 72 h after injection. No effects were noted in control rats. A single injection of TX14(A) 30 min before testing did not alter thermal response latencies in control or diabetic rats but prevented formalin hyperalgesia in diabetic rats. Tactile allodynia and the prolonged paw thermal hyperalgesia to radiant heat after intrathecal delivery of substance P were also dose-dependently ameliorated in diabetic rats by a single injection of TX14(A), whereas no effects were observed on the responses to these tests in control rats., Conclusions: TX14(A) exhibits both neuroprotective and acute antihyperalgesic properties in diabetic rats without altering normal nociceptive function.

Prosaptide (trademark of Myelos Corporation, San Diego, CA) peptides are based on the 14-amino-acid neurotrophic sequence of human prosaposin and, like the parent protein, have potent neurotrophic and neuroprotective properties. We previously examined the in vivo stability of a series of bioactive Prosaptide peptides and designed peptides with increased enzymatic stability in the central and peripheral nervous systems. In this article, we examined the stability, biological activity, and permeability of the blood-brain barrier to retro-inverso Prosaptide peptidomimetics. Retro-inversion both reverses the primary sequence and replaces L-amino acids with D-amino acids. We examined the bioactivity of five peptidomimetics, Prosaptides D1-D5. Prosaptide D1, a peptide containing all D-amino acids with the primary sequence intact, was inactive. However, four retro-inverso peptidomimetics, Prosaptides D2-D5 retained bioactivity in neurite outgrowth and [(35)S]GTPgammaS binding assays. We focused on Prosaptide D4 as a prototypical retro-inverso Prosaptide peptidomimetic for further study. (125)I-Prosaptide D4 remained intact in brain or serum for 60 min after i.v. administration and was transported across the blood-brain barrier with a unidirectional influx constant of 2.5 x 10(-4) ml. g(-1). min(-1). We conclude that retro-inverso Prosaptide peptidomimetics are excellent candidates for development as therapeutics for central nervous system neurodegeneration.