Clinical Validation of the Proenkephalin (PENK) Methylation Urine Test for Monitoring Recurrence of Non-muscle-invasive Bladder Cancer.

Background and objective: To assess the effectiveness of a urine-based proenkephalin (PENK) methylation test using linear target enrichment-quantitative methylation-specific polymerase chain reaction (mePENK test) for detection of non-muscle-invasive bladder cancer (NMIBC) recurrence compared to cytology and the NMP22 test. Methods: We first conducted a retrospective case-control study involving 54 patients with primary BC and 29 healthy individuals. We then prospectively enrolled 186 patients (January to December 2022) undergoing cystoscopy surveillance after transurethral resection of bladder tumor, of whom 59 had recurrent tumors. We analyzed voided urine samples for PENK methylation levels in urinary DNA. Cystoscopy with histology was used as the reference standard for assessing the diagnostic accuracy of the mePENK test in detecting BC recurrence. We calculated the sensitivity and specificity using receiver operating characteristic curve analysis. Survival differences were determined using the Kaplan-Meier method and Cox proportional-hazards model. A p < 0.05 was considered statistically significant. Key findings and limitations: In the case-control study, the PENK test had sensitivity of 83.3% and specificity of 100%. For NMIBC patients undergoing cystoscopy surveillance, the sensitivity was 76.3% (95% confidence interval [CI] 63.4-86.4%) and the specificity was 85% (95% CI 77.6-90.7%), outperforming cytology (sensitivity: 28.8%, 95% CI 17.8-42.1%; p < 0.001; specificity: 97.6%, 95% CI 93.2-99.5%) and the NMP22 test (sensitivity: 54.2%, 95% CI 40.7-67.2%; p = 0.016; specificity 81.9%, 95% CI 74.1-88.2%). In the high-risk group, the mePENK test had sensitivity of 89.7% (95% CI 75.8-97.1%) and a negative predictive value of 96.9%. For the group with low/intermediate risk, the sensitivity was 41.7%. In the group with negative cystoscopy, recurrence-free survival was shorter for patients with positive than for those with negative mePENK results (245 vs 503 d), with a hazard ratio of 9.4 (p < 0.001). The main study limitation is the small sample size. Conclusions and clinical implications: The mePENK test showed good performance for detection of NMIBC recurrence and has potential for use for prognosis and prediction. Patient summary: We found that a test used to analyze urine samples showed good performance in detecting recurrence of NMIBC. This noninvasive mePENK test may help in personalized follow-up care for patients with NMIBC.

The diverse influences of relaxin-like peptide family on tumor progression: Potential opportunities and emerging challenges.

Relaxin-like peptide family exhibit differential expression patterns in various types of cancers and play a role in cancer development. This family participates in tumorigenic processes encompassing proliferation, migration, invasion, tumor microenvironment, immune microenvironment, and anti-cancer resistance, ultimately influencing patient prognosis. In this review, we explore the mechanisms underlying the interaction between the RLN-like peptide family and tumors and provide an overview of therapeutic approaches utilizing this interaction.

LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells.

The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.

Predictable incorporation of nitrogen into carbon dots: insights from pinacol rearrangement and iminium ion cyclization.

Nitrogen-doped carbon dots (CDs) have attracted considerable attention across various research areas and applications due to their enhanced optical properties and photostability. However, the mechanism of nitrogen incorporation in CDs remains elusive, hampering the precise control over nitrogen-incorporated structures and the investigation of the effects of nitrogen on the electronic structure and optical properties of CDs. In this study, we employed a rational design approach, utilizing glucosamine and ethylene glycol as the carbon source and co-reagent, respectively, to synthesize N-doped CDs. Our synthesis strategy involved pinacol rearrangement and iminium ion cyclization reactions, enabling the reliable formation of N-doped CDs. Notably, the resulting CDs exhibited distinctive emissive states attributed to heteroatomic defect structures, including oxygenic and nitrogenic polycyclic aromatic hydrocarbons. To gain further insights into their energy levels and electronic transitions, we conducted comprehensive investigations, employing extended Hückel calculations and pump-probe spectroscopy. The synthesized CDs displayed great promise as bioimaging and photodynamic therapy agents, highlighting their potential for biomedical applications. Moreover, our study significantly contributes valuable insights into the rational design of N-doped CDs with controllable chemical and electronic structures, thereby paving the way for advancements in their diverse range of applications.

Circulating Tumor DNA Analysis on Metastatic Prostate Cancer with Disease Progression.

The positivity rate of circulating tumor DNA (ctDNA) next-generation sequencing (NGS) varies among patients with metastatic prostate cancer (mPC), complicating its incorporation into regular practice. This retrospective study analyzed the ctDNA sequencing results of 100 mPC patients from May 2021 to March 2023 to identify the factors associated with positive ctDNA. Three custom gene panels were used for sequencing. Overall, 63% of the patients exhibited tier I/II somatic alterations, while 12% had pathogenic/likely pathogenic germline alterations. The key genes that were altered included AR, TP53, RB1, PTEN, and APC. Mutations in BRCA1/2, either germline or somatic, were observed in 21% of the patients. Among the metastatic castration-resistant prostate cancer (mCRPC) patients, the ctDNA-positive samples generally showed higher median prostate-specific antigen (PSA) levels and were more likely to be at the radiographic and clinical progressive disease stages, although they were not significantly associated with PSA progression. Our results suggest that ctDNA analysis could detect meaningful genetic changes in mPC patients, especially during disease progression.

Prediction of Postoperative Creatinine Levels by Artificial Intelligence after Partial Nephrectomy.

Background and Objectives: Multiple factors are associated with postoperative functional outcomes, such as acute kidney injury (AKI), following partial nephrectomy (PN). The pre-, peri-, and postoperative factors are heavily intertwined and change dynamically, making it difficult to predict postoperative renal function. Therefore, we aimed to build an artificial intelligence (AI) model that utilizes perioperative factors to predict residual renal function and incidence of AKI following PN. Methods and Materials: This retrospective study included 785 patients (training set 706, test set 79) from six tertiary referral centers who underwent open or robotic PN. Forty-four perioperative features were used as inputs to train the AI prediction model. XG-Boost and genetic algorithms were used for the final model selection and to determine feature importance. The primary outcome measure was immediate postoperative serum creatinine (Cr) level. The secondary outcome was the incidence of AKI (estimated glomerular filtration rate (eGFR) < 60 mL/h). The average difference between the true and predicted serum Cr levels was considered the mean absolute error (MAE) and was used as a model evaluation parameter. Results: An AI model for predicting immediate postoperative serum Cr levels was selected from 2000 candidates by providing the lowest MAE (0.03 mg/dL). The model-predicted immediate postoperative serum Cr levels correlated closely with the measured values (R2 = 0.9669). The sensitivity and specificity of the model for predicting AKI were 85.5% and 99.7% in the training set, and 100.0% and 100.0% in the test set, respectively. The limitations of this study included its retrospective design. Conclusions: Our AI model successfully predicted accurate serum Cr levels and the likelihood of AKI. The accuracy of our model suggests that personalized guidelines to optimize multidisciplinary plans involving pre- and postoperative care need to be developed.

One-Pot Fabrication of Nanocomposites Composed of Carbon Nanotubes and Alumina Powder Using a Rotatable Chemical Vapor Deposition System.

The fabrication of multi-dimensional nanocomposites has been extensively attempted to achieve synergistic performance through the uniform mixing of functional constituents. Herein, we report a one-pot fabrication of nanocomposites composed of carbon nanotubes (CNTs) and Al2O3 powder. Our strategy involves a synthesis of CNTs on the entire Al2O3 surface using a rotatable chemical vapor deposition system (RCVD). Ehylene and ferritin-induced nanoparticles were used as the carbon source and wet catalyst, respectively. The RCVD was composed of a quartz reaction tube, 5.08 cm in diameter and 150 cm in length, with a rotation speed controller. Ferritin dissolved in deionized water was uniformly dispersed on the Al2O3 surface and calcinated to obtain iron nanoparticles. The synthesis temperature, time, and rotation speed of the chamber were the main parameters used to investigate the growth behavior of CNTs. We found that the CNTs can be grown at least around 600 °C, and the number of tubes increases with increasing growth time. A faster rotation of the chamber allows for the uniform growth of CNT by the tip-growth mechanism. Our results are preliminary at present but show that the RCVD process is sufficient for the fabrication of powder-based nanocomposites.

Phosphodiesterase-5 Inhibitor Use in Robot Assisted Radical Prostatectomy Patients Is Associated with Reduced Risk of Death: A Propensity Score Matched Analysis of 1,058 Patients.

PURPOSE: We investigated whether the use of a phosphodiesterase-5 inhibitor (PDE5i) after robot assited radical prostatectomy has a survival benefit over non-use patients because there are controversial results on the association between PDE5i use and survival outcomes for prostate cancer patients in literature. MATERIALS AND METHODS: We designed a retrospective, matched, large-sample cohort study of 5,545 patients who underwent robot assisted radical prostatectomy (RARP) during 2013-2021 in a single institute. The exclusion criteria was patients who were aged >70 years at surgery, American Society of Anesthesiologists (ASA) physical status classification grade 4 or 5, history of other malignancies, patients who started PDE5i 6 months after survery and patients with follow up period less than 24 months after surgery. Among the 1,843 included patients, 1,298 were PDE5i users, and 545 were PDE5i non-users. We performed propensity score matching (PSM) of PDE5i users (n=529) with non-users (n=529) by adjusting for the variables of age, Gleason grade group, pathological T stage, preoperative ASA physical status grade, and International Index of Erectile Function score. RESULTS: There were no significant difference in patient characteristics according to PSM. Kaplan-Meier curve revealed the difference of overall survival for PDE5i users and non-users (clustered log-rank test p<0.05). In a stratified Cox regression analysis, PDE5i use after RARP was associated with improved overall survival and reduced risk of death (hazard ratio 0.43; confidence interval 0.24-0.79; p=0.007). The limitation of this study was that the indication for the prescription of PDE5i was not given. CONCLUSIONS: PDE5i administration after RARP were associated with overall survival of patients with prostate cancer. A further randomized control trial may reveal whether routine use of PDE5i after prostatectomy can improve survival of prostate cancer patient.

Noninvasive studies may have potential to replace cystoscopy in non-muscle invasive bladder cancer follow-up.

Bladder cancer has a high recurrence rate which requires frequent follow-up. Cystoscopy is currently the gold standard for follow-up which is invasive and undesirable procedure for patients. We aimed to investigate the feasibility of noninvasive studies for follow-up of non-muscle invasive bladder cancer. This retrospective study was done for non-muscle invasive bladder cancer patients with abnormal lesion at follow up cystoscopy, therefore those needed transurethral resection of bladder tumor (TUR-BT). Inclusion criteria was patients who had preoperative bladder magnetic resonance imaging (MRI) within 1 month to TUR-BT and urine cytology results. MRI, urine cytology, and surgical pathology results were analyzed for sensitivity, specificity, positive and negative predictive values, accuracy, diagnostic odds ratio, and number needed to misdiagnose for the diagnostic performance of non-invasive studies. From total of 2,258 TUR-BT cases, 1,532 cases of primary TUR-BT and 481 cases which bladder MRI were not done was excluded. Finally, 245 cases of TUR-BT were included. Combined urine cytology and bladder MRI showed 96% sensitivity, 43% specificity, 89% positive and 67% negative predictive values, 87% accuracy, 16.2 diagnostic odds ratio, and 7.4 number needed to misdiagnose values. Among nine false-negative cases, three (1.2%) were missed by the radiologist, two (0.8%) had an empty bladder during magnetic resonance imaging, and three (1.2%) had gross hematuria which needed cystoscopy despite of bladder MRI or urine cytology result. Only one case (0.4%) was missed based on symptoms and noninvasive tests. However, none of the false-negative cases showed rapid extensive progression requiring radical or partial cystectomy. The combination of bladder MRI and urine cytology was comparable to cystoscopy for the follow-up of recurred lesions in non-muscle invasive bladder cancer patients for sensitivity, but not for specificity. However, it may reduce the need for cystoscopy and allowing patients to have choices for follow up diagnostic methods. Also, additional imaging tests to evaluate kidney, ureter and peri-vesical lesions can be reduced.

Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.

Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.

In Vivo Feasibility Test of a New Flexible Ureteroscopic Robotic System, easyUretero, for Renal Stone Retrieval in a Porcine Model.

PURPOSE: Using a new robotic endoscopic platform system developed for retrograde intrarenal surgery (RIRS) called easyUretero (ROEN Surgical Inc.), we evaluated the feasibility and safety of renal stone retrieval in a porcine model. MATERIALS AND METHODS: Six female pigs were used for our in vivo study. First, 0.3-cm-sized phantom stones were inserted into the kidneys of each pig via the ureteral access sheath. Next, renal stone retrieval was attempted using manual RIRS in three pigs and robotic RIRS in three pigs. Three surgeons performed extraction of 10 stones in each session. RESULTS: The mean stone retrieval time by manual RIRS was significantly shorter than that by robotic RIRS (399.9±185.4 sec vs. 1127.6±374.5 sec, p=0.001). In contrast, the questionnaire regarding usability showed high satisfaction in the surgeons' fatigue category for surgeons using robotic RIRS. The radiation exposure dose was also lower in robotic RIRS than in manual RIRS (0.14 µSv vs. 45.5 µSv). Postoperative ureteral injury assessment revealed Grade 0 in manual RIRS cases and Grades 0, 1, and 2 in robotic RIRS cases. CONCLUSION: The easyUretero system is a new robotic RIRS system that was developed in Korea. The results of the present study suggest that using easyUretero for stone retrieval during RIRS is safe and ergonomic.

Optical genome mapping identifies clinically relevant genomic rearrangements in prostate cancer biopsy sample.

BACKGROUND: Prostate cancer (PCa) is characterized by complex genomic rearrangements such as the ETS oncogene family fusions, yet the clinical relevance is not well established. While paneled genetic tests of DNA repair genes are recommended in advanced PCa, conventional genomic or cytogenetic tools are not ideal for genome-wide screening of structural variations (SVs) such as balanced translocation due to cost and/or resolution issues. METHODS: In this study, we tested the feasibility of whole-genome optical genomic mapping (OGM), a newly developed platform for genome-wide SV analysis to detect complex genomic rearrangements in consecutive unselected PCa samples from MRI/US-fusion targeted biopsy. RESULTS: We tested ten samples, and nine (90%) passed quality check. Average mapping rate and coverage depth were 58.1 ± 23.7% and 157.3 ± 97.7×, respectively (mean ± SD). OGM detected copy number alterations such as chr6q13 loss and chr8q12-24 gain. Two adjacent tumor samples were distinguished by inter/intra-chromosomal translocations, revealing that they're from the same ancestor. Furthermore, OGM detected large deletion of chr13q13.1 accompanied by inter-chromosomal translocation t(13;20)(q13.1;p13) occurring within BRCA2 gene, suggesting complete loss of function. CONCLUSION: In conclusion, clinically relevant genomic SVs were successfully detected in PCa samples by OGM. We suggest that OGM can complement panel sequencing of DNA repair genes BRCA1/2 or ATM in high-risk PCa.

Feasibility of Laser Lithotripsy for Midsize Stones Using Robotic Retrograde Intrarenal Surgery System easyUretero in a Porcine Model.

Purpose: To test the safety and feasibility of laser lithotripsy for midsize renal stones using a newly developed robotic retrograde intrarenal surgery (RIRS) system (easyUretero) in a porcine model. Materials and Methods: Three urologic surgeons representing three different RIRS experience levels (beginner, intermediate, and expert) participated. Four female pigs (aged 6 months) underwent manual or robotic RIRS. Under general anesthesia, a nephrostomy tract was created ventrally, and calcium stones (diameter, 1.0-1.5 cm) were inserted at renal calices. For manual RIRS, surgeons operated a flexible ureteroscope. For robotic RIRS, the ureteroscope was attached to the robotic slave device. The Auriga XL™ Holmium laser was used for lithotripsy. Lasering and stone retrieval time were measured. Kidneys and ureters were inspected for injury at the end of each session. Results: For the expert, both lasering and stone retrieval by manual RIRS were quicker than by robotic RIRS (22.8 ± 11.0 s/stone vs 234.5 ± 102.5 s/stone, p = 0.02; 41.5 ± 0.5 s/stone vs 79.3 ± 8.1 s/stone, p = 0.02). For the intermediate and beginner, lasering and stone retrieval times were not significantly different between manual and robotic procedures (127.8 ± 93.2 s/stone vs 284.8 ± 112.3 s/stone, p = 0.08; 86.0 ± 30.5 s/stone vs 84.1 ± 21.4 s/stone, p = 0.92). All stones were removed. Grade 1 ureteral and renal injuries occurred in both manual RIRS and robotic RIRS. Conclusions: The laser lithotripsy using the easyUretero robotic system is safe and feasible in a porcine model, even for less-experienced surgeons.

Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis.

Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.

p53 Immunohistochemistry and Mutation Types Mismatching in High-Grade Serous Ovarian Cancer.

High-grade serous carcinoma (HGSCa) of the ovary is featured by TP53 gene mutation. Missense or nonsense mutation types accompany most cases of HGSCa that correlate well with immunohistochemical (IHC) staining results-an all (missense) or none (nonsense) pattern. However, some IHCs produce subclonal or mosaic patterns from which TP53 mutation types, including the wild type of the gene, cannot be clearly deduced. We analyzed a total of 236 cases of ovarian HGSCa and tumors of other histology by matching the results of p53 IHC staining and targeted next-generation sequencing (TruSight Tumor 170 panel). Ambiguous IHCs that do not belong to the conventional "all or none" groups were reviewed to distinguish the true wild type (WT) from potentially pathogenic subclonal or mosaic patterns. There were about 9% of sequencing-IHC mismatching cases, which were enriched by the p53 c-terminal encoding nuclear localization signal and oligomerization domain, in which the subcellular locations of p53 protein were affected. Indeed, mutations in the oligomerization domain of the p53 protein frequently revealed an unmatched signal or cytosolic staining (L289Ffs*57 (Ins), and R342*). We conclude that both mutation types and IHC patterns of p53 are important sources of information to provide a precise diagnosis of HGSCa.

Generation of a human induced pluripotent stem cell line YCMi004-A from a patient with dilated cardiomyopathy carrying a protein-truncating mutation of the Titin gene and its differentiation towards cardiomyocytes.

Dilated cardiomyopathy (DCM) is a heart muscle disease that causes heart failure and is the leading cause for heart transplantation. It is a heart muscle disease resulted from a variety of genetics, toxic, metabolic, and infectious causes. One of the most prevalent genetic causes of DCM is a protein-truncating variant in the Titin gene (TTNtv). We have generated a human-induced pluripotent stem cell (hiPSC) line from patients who underwent heart transplantation due to DCM carrying a TTNtv mutation (c.70051C > T, p.Arg23351Ter) at the age of 20. The generated hiPSCs showed normal karyotype (46, XY) and expression of pluripotency markers, and were differentiated towards cardiomyocytes successfully.

Androgen-Independent Prostate Cancer Is Sensitive to CDC42-PAK7 Kinase Inhibition.

Prostate cancer is a common form of cancer in men, and androgen-deprivation therapy (ADT) is often used as a first-line treatment. However, some patients develop resistance to ADT, and their disease is called castration-resistant prostate cancer (CRPC). Identifying potential therapeutic targets for this aggressive subtype of prostate cancer is crucial. In this study, we show that statins can selectively inhibit the growth of these CRPC tumors that have lost their androgen receptor (AR) and have overexpressed the RNA-binding protein QKI. We found that the repression of microRNA-200 by QKI overexpression promotes the rise of AR-low mesenchymal-like CRPC cells. Using in silico drug/gene perturbation combined screening, we discovered that QKI-overexpressing cancer cells are selectively vulnerable to CDC42-PAK7 inhibition by statins. We also confirmed that PAK7 overexpression is present in prostate cancer that coexists with hyperlipidemia. Our results demonstrate a previously unseen mechanism of action for statins in these QKI-expressing AR-lost CRPCs. This may explain the clinical benefits of the drug and support the development of a biology-driven drug-repurposing clinical trial. This is an important finding that could help improve treatment options for patients with this aggressive form of prostate cancer.

Prostate epithelial genes define therapy-relevant prostate cancer molecular subtype.

BACKGROUND AND OBJECTIVES: Transcriptomic landscape of prostate cancer (PCa) shows multidimensional variability, potentially arising from the cell-of-origin, reflected in serum markers, and most importantly related to drug sensitivities. For example, Aggressive Variant Prostate Cancer (AVPC) presents low PSA per tumor burden, and characterized by de novo resistance to androgen receptor signaling inhibitors (ARIs). Understanding PCa transcriptomic complexity can provide biological insight and therapeutic guidance. However, unsupervised clustering analysis is hindered by potential confounding factors such as stromal contamination and stress-related material degradation. MATERIALS AND METHODS: To focus on prostate epithelial cell-relevant heterogeneity, we defined 1,629 genes expressed by prostate epithelial cells by analyzing publicly available bulk and single- cell RNA sequencing data. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival. Serum markers PSA and PAP was analyzed to predict response to docetaxel chemotherapy in metastatic setting. RESULTS: We identified two luminal subtypes and two aggressive variant subtypes of PCa: luminal A (Adipogenic/AR-active/PSA-high) (30.0%); luminal S (Secretory/PAP-high) (26.0%); AVPC-I (Immune-infiltrative) (14.7%), AVPC-M (Myc-active) (4.2%), and mixed (25.0%). AVPC-I and AVPC-M subtypes predicted to be resistant to ARI and have low PSA per tumor burden. Luminal A and AVPC-M predicted to be resistant to docetaxel and have high PSA/PAP Ratio. Metastatic PCa patients with high PSA/PAP ratio (>20) had significantly shorter progression-free survival than those with low ratio (≤20) following docetaxel chemotherapy. CONCLUSION: We propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents.

Relationship between the experience of online game genre and high risk of Internet gaming disorder in Korean adolescents.

OBJECTIVES: This study examined the association between high risk of Internet gaming disorder (IGD) and online game genres used by adolescents. METHODS: The data derived from the baseline data of the Internet user Cohort for Unbiased Recognition of gaming disorder in Early Adolescence. A total 1,532 middle school students who use online games included. The participants reported the names of the online games they used during the past year. Game genres were categorized into role playing games (RPGs), shooting, multiplayer online battle arena (MOBA), simulation, arcade, sports and action games. The risk of IGD was measured using the Internet Gaming Use-Elicited symptom Screen. The relationship between the experience of online game genre and high risk of IGD was analyzed using multiple logistic regression model. RESULTS: The game time of a student was longer if he or she had an experience of RPGs, shooting games, MOBA games, simulation games, and action games. The direct and independent association between high risk of IGD in adolescents and the genres of RPGs, simulation games and MOBA were found to be odds ratios 1.52 (95% confidence interval [CI], 1.03 to 2.26); 1.59 (95% CI, 1.03 to 2.45); and 1.51 (95% CI, 1.03 to 2.21), respectively after adjusted the potential confounding variables and the use of other online game genres. CONCLUSIONS: The present cross-sectional study has found an association between online game genres and the risk of IGD in adolescents attending a school. A cohort study should verify the causal association in future.

Gaming patterns and related symptoms in adolescents using cluster analysis: Baseline results from the Internet User Cohort for Unbiased Recognition of Gaming Disorder in Early Adolescence (iCURE) study.

PURPOSE: The risk and protective factors of Internet gaming disorder (IGD) could vary by individual. The identification of more homogeneous subgroups may lead to better understanding of gaming behaviors and their consequences in adolescents. The purpose of this study was to investigate the prevalence of IGD among the subgroups defined by cluster analysis in adolescents. METHODS: A total of 2319 adolescents were enrolled in the Internet User Cohort for Unbiased Recognition of Gaming Disorder in Early Adolescence (iCURE) study at baseline. Self-reported IGD was assessed with a DMS-5 adapted measurement. Smartphone addiction, musculoskeletal discomfort, and dry eye symptoms were evaluated by self-administered questionnaires. Cluster analysis was performed using risk and protective factors of IGD after considering multicollinearity. RESULTS: Three different clusters were identified. Cluster 1 (19.2%) was users with combined potential psychological and social issues. Cluster 2 (32.3%) was users with potential social but no psychological issues. Cluster 3 (45.6%) was users with no potential issues of either a social or psychological nature. Adolescents from both clusters 1 and 2 showed higher degrees of IGD, smartphone addiction, musculoskeletal discomfort, and dry eye symptoms than did those from cluster 3. Also compared with adolescents in cluster 3, those in cluster 1 showed statistically higher risks of IGD (aOR:11.9, 95%CI:7.5-19.9), smartphone addiction (aOR:5.4, 95%CI:4.0-7.2), musculoskeletal discomfort (aOR:2.6, 95%CI:2.1-7.4), and dry eye symptoms (aOR:3.8, 95%CI:3.0-4.9). Those in cluster 2 also showed statistically higher risk of IGD, smartphone addiction, musculoskeletal discomfort, and dry eye symptoms compared with cluster 3 (aOR:4.5, 95%CI:2.8-7.6; aOR:2.8, 95%CI:2.1-3.7; aOR:1.6, 95%CI:1.3-1.9; and aOR:1.9, 95%CI:1.6-2.4, respectively). CONCLUSIONS: Clustering based on the risk and preventive factors of IGD may be suitable for determination of high risk of IGD in adolescents. However, we need to confirm the usefulness and clinical application of the classifications by observing their longitudinal changes.