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    Integrative analysis of deoxyribonuclease 1-like 3 as a potential biomarker in renal cell carcinoma
    (AME, 2023) Ge, Minghuan; Zhu, Hengcheng; Song, Huajie; Schmeusser, Benjamin N.; Ng, Keng Lim; Zeng, Yan; Liu, Ting; Yang, Kang; Urology, School of Medicine
    Background: Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), is insensitive to radiotherapy and chemotherapy after surgery. Deoxyribonuclease 1-like 3 (DNASE1L3), an endonuclease that cleaves both membrane-encapsulated single- and double-stranded DNA, suppresses cell cycle progression, proliferation and metabolism in hepatocellular carcinoma cells. There is currently no established link between DNASE1L3 and RCC inhibition. We are gonging to explored the mechanism underlying the relationship between DNASEL1L3 and RCC. Methods: RNA sequencing data for RCC tissue and peritumoral tissue were downloaded from The Cancer Genome Atlas database and analyzed. The expression levels of DNASE1L3 in RCC and normal samples were verified using the Gene Expression Omnibus (GEO) database, Human Protein Atlas database and western blotting. The role and potential mechanism of DNASE1L3 were investigated by analysis of immune-related databases and wound healing, invasion, cell counting kit 8 and immunofluorescence assays. Results: We revealed that DNASE1L3 expression was downregulated in RCC group compared with control group [The Cancer Genome Atlas (TCGA): 7.98 vs. 10.87, P<0.001]. Meanwhile, DNASE1L3 expression correlated with the clinical characteristics of patients. Patients with low DNASE1L3 expression had worse survival (P<0.001) and larger (r=-0.32, P<0.001) and heavier tumors (r=-0.17, P<0.001). DNASE1L3 overexpression inhibited the proliferation (786-O: 0.135±0.014 vs. 0.322±0.027, P<0.001) and invasion (786-O: 1,479±134 vs. 832±67, P<0.05) of RCC cells. The expression of DNASE1L3 was significantly correlated with the tumor immune microenvironment and drug sensitivity in ccRCC. Moreover, the level of the key phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway protein P-AKT was decreased in the group of cells transfected with DNASE1L3. Conclusions: This study strongly suggest that DNASE1L3 may be a promising potential biomarker for the diagnosis and treatment of ccRCC patients.
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    Sensor-based indicators of performance changes between sessions during robotic surgery training
    (Elsevier, 2021) Wu, Chuhao; Cha, Jackie; Sulek, Jay; Sundaram, Chandru P.; Wachs, Juan; Proctor, Robert W.; Yu, Denny; Urology, School of Medicine
    Training of surgeons is essential for safe and effective usage of robotic surgery, yet current assessment tools for learning progression are limited. The objective of this study was to measure changes in trainees’ cognitive and behavioral states as they progressed in a robotic surgeon training curriculum at a medical institution. Seven surgical trainees in urology who had no formal robotic training experience participated in the simulation curriculum. They performed 12 robotic skills exercises with varying levels of difficulty repetitively in separate sessions. EEG (electroencephalogram) activity and eye movements were measured throughout to calculate three metrics: engagement index (indicator of task engagement), pupil diameter (indicator of mental workload) and gaze entropy (indicator of randomness in gaze pattern). Performance scores (completion of task goals) and mental workload ratings (NASA-Task Load Index) were collected after each exercise. Changes in performance scores between training sessions were calculated. Analysis of variance, repeated measures correlation, and machine learning classification were used to diagnose how cognitive and behavioral states associate with performance increases or decreases between sessions. The changes in performance were correlated with changes in engagement index (rrm = −.25, p < .001) and gaze entropy (rrm = −.37, p < .001). Changes in cognitive and behavioral states were able to predict training outcomes with 72.5% accuracy. Findings suggest that cognitive and behavioral metrics correlate with changes in performance between sessions. These measures can complement current feedback tools used by medical educators and learners for skills assessment in robotic surgery training.
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    Sexual Function in Men Undergoing Androgen Deprivation Therapy
    (Mary Ann Liebert, Inc., 2022-10-22) Gryzinski, Gustavo M.; Fustok, Judy; Raheem, Omer A.; Bernie, Helen L.; Urology, School of Medicine
    With an increase in the use of androgen deprivation therapy (ADT) in men diagnosed with prostate cancer, there are several adverse effects that accompany its utilization. Among these, sexual dysfunction has contributed to significant deleterious effects on quality of life (QoL) and overall satisfaction. This has prompted clinicians to pursue modalities of ADT that may mitigate these adverse sexual effects, which include continuous versus intermittent ADT, changes in the duration of ADT, and novel methods of cyclical androgen exposure during treatment. Importantly, this must not come at the expense of oncological outcomes. In addition, some men treated with ADT experience persistent hypogonadism and side effects from these medications that linger well after treatment is completed. In this systematic review we discuss the pharmaceutical, mechanical, and psychological methods that play an important role in the mitigation of these sexual side effects, including erectile dysfunction and decreased libido, and their uses and benefits are further discussed. Ultimately, the benefits of ADT and the possible morbidity that these men may experience from use of ADT, as well as options to minimize their side effects need to be discussed with the patient and their partner to make an informed decision and ensure patient autonomy while providing the most up-to-date evidence. Given the prevalence of prostate cancer in the aging male population, this systematic review aims to further explain the different ADT regimens and options for men, as well as discuss the sexual side effects that accompany these treatments and ways in which to mitigate these side effects to improve patient QoL.
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    Sexual activity and function of adult men with spina bifida
    (Elsevier, 2023-06) Szymanski, Konrad M.; Roth, Joshua D.; Hensel, Devon J.; Wiener, John S.; Younsi, Nina; Stein, Raimund; Whittam, Benjamin; Kaefer, Martin; Rink, Richard C.; Cain, Mark P.; Misseri, Rosalia; Urology, School of Medicine
    Objective Data on sexual function of men with spina bifida (SB) is limited. We aimed to assess sexual activity and erectile dysfunction (ED) in a large international sample of men with SB. Methods Men with SB (≥18yo) were recruited in an international online survey via clinics and social media. We collected data on demographics, ambulation (Hoffer classification), penile rigidity (Erection Hardness Score), sexual activity and ED (International Index of Erectile Function). Non-parametric tests were used. Results A total of 162 men (median age 35, 62% shunted, 38% community ambulators) reported sexual desire similar to the general population (p = 0.82), but 55% were dissatisfied with their sex life (Summary Table). Overall, 36% reported full penile rigidity with erections, more commonly with better ambulation (p = 0.01), 69% had ever experienced orgasm and 84% ejaculated. In 44 men (27%) attempting sexual intercourse in the last 4 weeks, 59% had ED (11% severe, 7% moderate, 14% mild-moderate, 27% mild). In this group, 91% of men reporting less than full penile rigidity had ED, compared to 30% with full penile rigidity (p = 0.001). Overall, partnered non-genital contact in the last 3 months was reported by 56%, solo masturbation: 62%, partnered intercourse: 48% (31% vaginal). Of 54 men who used phosphodiesterase type 5 inhibitors (PDE5I), 80% reported improved erections, 56% improved intercourse. Overall, 40% reported non-genital erogenous zones as most pleasurable, especially with poorer ambulation (p = 0.002, chest/nipples: 73%). Comment Strengths of this study include anonymous, voluntary, online participation maximizing participation of a heterogenous, international population. Whenever available, we compared findings to published values for the general population. Since romantic and sexual activity is a complex intersection of interest, opportunity and ability, a more comprehensive assessment was beyond the study's scope. Future work will focus on the interplay with issues like incontinence. Conclusions ED was frequent among men with SB, especially in men with poorer ambulation. PDE5 inhibitors may be beneficial. Partnered sexual activity was reported by half of the men, although it may not involve penetrative intercourse.
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    A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera
    (Wiley, 2020) Jack, Sherwin; Madhivanan, Kayalvizhi; Ramadesika, Swetha; Subramanian, Sneha; Edwards, Daniel F., II; Elzey, Bennett D.; Dhawan, Deepika; McCluskey, Andrew; Kischuk, Erin M.; Loftis, Alexander R.; Truex, Nicholas; Santos, Michael; Lu, Mike; Rabideau, Amy; Pentelute, Bradley; Collier, John; Kaimakliotis, Hristos; Koch, Michael; Ratliff, Timothy L.; Knapp, Deborah W.; Aguilar, Ruben C.; Urology, School of Medicine
    Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF–anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer.
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    Data-Independent Acquisition Phosphoproteomics of Urinary Extracellular Vesicles Enables Renal Cell Carcinoma Grade Differentiation
    (Elsevier, 2023) Hadisurya, Marco; Lee, Zheng-Chi; Luo, Zhuojun; Zhang, Guiyuan; Ding, Yajie; Zhang, Hao; Iliuk, Anton B.; Pili, Roberto; Boris, Ronald S.; Tao, W. Andy; Urology, School of Medicine
    Translating the research capability and knowledge in cancer signaling into clinical settings has been slow and ineffective. Recently, extracellular vesicles (EVs) have emerged as a promising source for developing disease phosphoprotein markers to monitor disease status. This study focuses on the development of a robust data-independent acquisition (DIA) using mass spectrometry to profile urinary EV phosphoproteomics for renal cell cancer (RCC) grades differentiation. We examined gas-phase fractionated library, direct DIA (library-free), forbidden zones, and several different windowing schemes. After the development of a DIA mass spectrometry method for EV phosphoproteomics, we applied the strategy to identify and quantify urinary EV phosphoproteomes from 57 individuals representing low-grade clear cell RCC, high-grade clear cell RCC, chronic kidney disease, and healthy control individuals. Urinary EVs were efficiently isolated by functional magnetic beads, and EV phosphopeptides were subsequently enriched by PolyMAC. We quantified 2584 unique phosphosites and observed that multiple prominent cancer-related pathways, such as ErbB signaling, renal cell carcinoma, and regulation of actin cytoskeleton, were only upregulated in high-grade clear cell RCC. These results show that EV phosphoproteome analysis utilizing our optimized procedure of EV isolation, phosphopeptide enrichment, and DIA method provides a powerful tool for future clinical applications.
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    Development and validation of an objective scoring tool to evaluate surgical dissection: Dissection Assessment for Robotic Technique (DART)
    (American Urological Association Education and Research, Inc., 2021) Vanstrum, Erik B.; Ma, Runzhuo; Maya-Silva, Jacqueline; Sanford, Daniel; Nguyen, Jessica H.; Lei, Xiaomeng; Chevinksy, Michael; Ghoreifi, Alireza; Han, Jullet; Polotti, Charles F.; Powers, Ryan; Yip, Wesley; Zhang, Michael; Aron, Monish; Collins, Justin; Daneshmand, Siamak; Davis, John W.; Desai, Mihir M.; Gerjy, Roger; Goh, Alvin C.; Kimmig, Rainer; Lendvay, Thomas S.; Porter, James; Sotelo, Rene; Sundaram, Chandru P.; Cen, Steven; Gill, Inderbir S.; Hung, Andrew J.; Urology, School of Medicine
    Purpose: Evaluation of surgical competency has important implications for training new surgeons, accreditation, and improving patient outcomes. A method to specifically evaluate dissection performance does not yet exist. This project aimed to design a tool to assess surgical dissection quality. Methods: Delphi method was used to validate structure and content of the dissection evaluation. A multi-institutional and multi-disciplinary panel of 14 expert surgeons systematically evaluated each element of the dissection tool. Ten blinded reviewers evaluated 46 de-identified videos of pelvic lymph node and seminal vesicle dissections during the robot-assisted radical prostatectomy. Inter-rater variability was calculated using prevalence-adjusted and bias-adjusted kappa. The area under the curve from receiver operating characteristic curve was used to assess discrimination power for overall DART scores as well as domains in discriminating trainees (≤100 robotic cases) from experts (>100). Results: Four rounds of Delphi method achieved language and content validity in 27/28 elements. Use of 3- or 5-point scale remained contested; thus, both scales were evaluated during validation. The 3-point scale showed improved kappa for each domain. Experts demonstrated significantly greater total scores on both scales (3-point, p< 0.001; 5-point, p< 0.001). The ability to distinguish experience was equivalent for total score on both scales (3-point AUC= 0.92, CI 0.82-1.00, 5-point AUC= 0.92, CI 0.83-1.00). Conclusions: We present the development and validation of Dissection Assessment for Robotic Technique (DART), an objective and reproducible 3-point surgical assessment to evaluate tissue dissection. DART can effectively differentiate levels of surgeon experience and can be used in multiple surgical steps.
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    Randomized Placebo-Controlled Trial of Reloxaliase in Enteric Hyperoxaluria
    (NEJM Group, 2022-05-06) Lieske, John C.; Lingeman, James E.; Ferraro, Pietro M.; Wyatt, Christina M.; Tosone, Christine; Kausz, Annamaria T.; Knauf, Felix; Urology, School of Medicine
    BACKGROUND Enteric hyperoxaluria is caused by increased intestinal oxalate absorption and can lead to kidney stones, chronic kidney disease, and kidney failure. Reloxaliase is an orally administered recombinant enzyme that degrades oxalate along the gastrointestinal tract, thereby preventing its absorption. METHODS We randomly assigned participants with enteric hyperoxaluria to reloxaliase or placebo, three to five times per day with food for 4 weeks. The primary end point was percent change from baseline in 24-hour urinary oxalate (UOx) excretion during weeks 1 to 4. Secondary end points included the proportion of participants with more than a 20% reduction in 24-hour UOx and an efficacy assessment in the bariatric surgery subgroup. RESULTS A total of 115 patients underwent randomization. The 24-hour UOx decreased from a baseline geometric mean of 83.2 to 67.4 mg/24 hr during weeks 1 to 4 in reloxaliase-treated participants. Corresponding data for placebo-treated participants were 84.2 to 78.1 mg/24 hr. Estimates from the mixed-effect model repeated-measures (MMRM) analysis showed a 22.6% reduction in geometric mean UOx during weeks 1 to 4 for reloxaliase and 9.7% for placebo, a difference of 14.3 percentage points (95% confidence interval [CI], 4.9 to 22.8; P=0.004). A 20% or greater reduction in 24-hour UOx was observed in 48.3% of reloxaliase-treated participants and 31.6% of placebo-treated participants (P=0.06). In the bariatric surgery subgroup, MMRM analysis showed a 21.2% reduction in geometric mean UOx for reloxaliase and a 6.0% reduction for placebo, for a difference of 16.2 percentage points (95% CI, 4.2% to 26.7%). Adverse events occurred in 69% of reloxaliase-treated participants versus 53% of individuals taking placebo and were most commonly gastrointestinal. All but one of the adverse events were grade 1 or 2 in severity; no reloxaliase-treated participants discontinued the study. CONCLUSIONS Reloxaliase treatment for 4 weeks reduced UOx excretion in patients with enteric hyperoxaluria; adverse events were relatively common, but not dose-limiting. These data establish the foundation for a clinical trial to determine the impact of reloxaliase on nephrolithiasis in patients with enteric hyperoxaluria. (Funded by Allena Pharmaceuticals; number, NCT03456830.)
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    Early and Midterm Complications of the Continent Catheterizable Indiana Pouch Urinary Diversion: A 7-year Experience
    (Elsevier, 2022-09) Burns, Ramzy; Speir, Ryan; Kern, Sean Q.; Jarvis, Hannah; Schmidt, Jonathan; Cary, Clint; Masterson, Timothy; Gardner, Thomas; Bihrle, Richard; Koch, Michael; Kaimakliotis, Hristos; Urology, School of Medicine
    Objectives To describe the most recent 7 year experience with 137 Indiana pouch patients at a single institution and provide data on complications with this type of urinary diversion during the first postoperative year. Methods We queried our bladder cancer database to identify all patients who underwent cystectomy with continent catheterizable urinary reservoir between 2012 and 2018. Pre-, intra-, and postoperative data were collected. Complications were stratified into early (within 90 days) and midterm (90-365 days). The primary outcomes were postoperative complications, and overall and cancer-specific mortality. Results A total of 137 patients underwent open cystectomy with Indiana pouch creation. Of these, 93% were radical cystectomies. On average, the operation took 422 minutes. There were 53 (39%) patients who experienced any type of complication during the first postoperative year (Clavien II-V). Twenty-five patients (18.2%) readmitted in the early postoperative period vs 18 (13.1%) patients midterm. There were 10 (7.3%) patients that required early reoperation and 11 (8%) in the midterm period. The overall mortality rate was 1.5% early and 3.7% midterm, with the majority of the mortality rate attributed to cancer progression (85.7%). Conclusion Patients undergoing continent catheterizable reservoir urinary diversion appear to have comparable complication rates to other urinary diversions published in the literature. At high-volume urologic institutions, Indiana Pouch creation is a suitable option for select patients desiring a continent diversion.
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    Physiological Metrics of Surgical Difficulty and Multi-Task Requirement during Robotic Surgery Skills
    (MDPI, 2023-04-28) Lim, Chiho; Barragan, Juan Antonio; Farrow, Jason Michael; Wachs, Juan P.; Sundaram, Chandru P.; Yu, Denny; Urology, School of Medicine
    Previous studies in robotic-assisted surgery (RAS) have studied cognitive workload by modulating surgical task difficulty, and many of these studies have relied on self-reported workload measurements. However, contributors to and their effects on cognitive workload are complex and may not be sufficiently summarized by changes in task difficulty alone. This study aims to understand how multi-task requirement contributes to the prediction of cognitive load in RAS under different task difficulties. Multimodal physiological signals (EEG, eye-tracking, HRV) were collected as university students performed simulated RAS tasks consisting of two types of surgical task difficulty under three different multi-task requirement levels. EEG spectral analysis was sensitive enough to distinguish the degree of cognitive workload under both surgical conditions (surgical task difficulty/multi-task requirement). In addition, eye-tracking measurements showed differences under both conditions, but significant differences of HRV were observed in only multi-task requirement conditions. Multimodal-based neural network models have achieved up to 79% accuracy for both surgical conditions.