Search

Prostate cancer (PCa) is a multifocal disease characterized by genomic and phenotypic heterogeneity within a single gland. In this study, Visium spatial transcriptomics (ST) analysis was applied to PCa tissues with different histological structures to infer the molecular events involved in Gleason score (GS) progression. The spots in tissue sections were classified into various groups using Principal Component Analysis (PCA) and Louvain clustering analysis based on transcriptome data. Anotation of the spots according to GS revealed notable similarities between transcriptomic profiles and histologically identifiable structures. The accuracy of macroscopic GS determination was bioinformatically verified through malignancy-related feature analysis, specifically inferred copy number variation (inferCNV), as well as developmental trajectory analyses, such as diffusion pseudotime (DPT) and partition-based graph abstraction (PAGA). Genes related to GS progression were identified from the differentially expressed genes (DEGs) through pairwise comparisons of groups along a GS gradient. The proteins encoded by the representative oncogenes UQCRB and LBH were found to be highly expressed in advanced-stage PCa tissues. Knockdown of their mRNAs significantly suppressed PCa cell proliferation and invasion. These findings were validated using The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset, as well as through histological and cytological experiments. The results presented here establish a foundation for ST-based evaluation of GS progression and provide valuable insights into the GS progression-related genes UQCRB and LBH., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Background: Uric acid may play a critical role in protection against cancer by the suppression of inflammation. The association between serum uric acid (SUA) levels and prostate cancer risk is debatable yet has received little attention in the American population. Therefore, we used data from the National Health and Nutrition Examination Survey (NHANES) to determine their correlation., Methods: Using information from NHANES 1999-2010, a total of 62,160 individuals from the general population were included in this cross-sectional study. Additionally, a number of covariates were acquired. Prostate cancer was used to divide the participants into two groups: prostate cancer group (n=315) and non-prostate cancer group (n=7,545). A weighted adjusted logistic regression analysis was conducted to examine the potential correlation between SUA and prostate cancer., Results: Our study comprised a total of 7,860 participants. After full adjustment for confounders, SUA was not significantly associated with prostate cancer [odds ratio (OR) 0.91, 95% confidence interval (CI): 0.82-1.00, P=0.058]. In participants aged 60 years and above (≥60 years), a higher SUA was significantly associated with a lower risk of prostate cancer (OR 0.88, 95% CI: 0.80-0.96, P=0.003). However, among those younger than 60 years (<60 years), there was no association between SUA and prostate cancer risk (OR 1.29, 95% CI: 0.69-2.42, P=0.42). In addition, in the subgroup analysis stratified by body mass index, hypertension and diabetes, there was no significant correlation between SUA and prostate cancer., Conclusions: SUA is negatively associated with the risk of prostate cancer in older men, especially for those 60 years of age and beyond., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-46/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Objectives: The association of migraine with the risk of certain cancer has been reported. The aim of this pilot study was to examine the associations between migraine and the onset of head and neck cancers (HNC)., Materials and Methods: A total of 1755 individuals were identified through a nationwide population-based cohort registry in Taiwan between 2000 and 2013. The primary end point variable was new-onset head and neck cancers in patients with migraine versus non-migraine controls. Cox proportional hazard regression was used to derive the risk of HNC. Subgroup analyses were performed to determine subpopulations at risk of migraine-associated HNC. Sub-outcome analyses were carried out to provide the subtypes of migraine-associated HNC. Propensity score matching was utilized to validate the findings., Results: A total of four patients out of 351 patients with migraine and seven out of 1404 non-migraine controls developed HNC. The incidence of HNC was higher in patients with migraine than that in non-migraine controls (108.93 vs. 48.77 per 100,000 person-years) (adjusted hazard ratio, aHR = 2.908, 95% CI = 0.808-10.469; p = 0.102). The risk of HNC in patients with migraine with aura (aHR = 5.454, 95% CI = 0.948-26.875; p = 0.264) and without aura (aHR = 2.777, 95% CI = 0.755-8.473; p = 0.118) was revealed. The incidence of non-nasopharyngeal HNC secondary to migraine (112.79 per 100,000 person-years) was higher than that of nasopharyngeal cancer secondary to migraine (105.33 per 100,000 person-years)., Conclusion: A higher incidence of HNC was observed in a small sample of patients with migraine, especially in those with migraine with aura. Migraine-associated HNC included non-nasopharyngeal HNC. Studies with a larger sample are needed to confirm the finding of the high risk of HNC in people with migraine., (© 2023 Wiley Periodicals LLC.)

Context: In men with prostate cancer, urinary incontinence is one of the most common long-term side effects of radical prostatectomy (RP). The recovery of urinary continence in patients is positively influenced by preserving the integrity of the neurovascular bundles (NVBs). However, it is still unclear if bilateral nerve sparing (BNS) is superior to unilateral nerve sparing (UNS) in terms of post-RP urinary continence. The aim of this study is to systematically compare the differences in post-RP urinary continence outcomes between BNS and UNS., Methods: The electronic databases of PubMed and Web of Science were comprehensively searched. The search period was up to May 31, 2023. English language articles comparing urinary continence outcomes of patients undergoing BNS and UNS radical prostatectomy were included. Meta-analyses were performed to calculate pooled relative risk (RR) estimates with 95% confidence intervals for urinary continence in BNS and UNS groups at selected follow-up intervals using a random-effects model. Sensitivity analyses were performed in prospective studies and robotic-assisted RP studies., Results: A meta-analysis was conducted using data from 26,961 participants in fifty-seven studies. A meta-analysis demonstrated that BNS improved the urinary continence rate compared to UNS at all selected follow-up points. RRs were 1.36 (1.14-1.63; p = 0.0007) at ≤ 1.5 months (mo), 1.28 (1.08-1.51; p = 0.005) at 3-4 mo, 1.12 (1.03-1.22; p = 0.01) at 6 mo, 1.08 (1.05-1.12; p < 0.00001) at 12 mo, and 1.07 (1.00-1.13; p = 0.03) at ≥ 24 mo, respectively. With the extension of the follow-up time, RRs decreased from 1.36 to 1.07, showing a gradual downward trend. Pooled estimates were largely heterogeneous. Similar findings were obtained through sensitivity analyses of prospective studies and robotic-assisted RP studies., Conclusion: The findings of this meta-analysis demonstrate that BNS yields superior outcomes in terms of urinary continence compared to UNS, with these advantages being sustained for a minimum duration of 24 months. It may be due to the real effect of saving the nerves involved. Future high-quality studies are needed to confirm these findings., (© 2024. The Author(s).)

Neural style transfer is an algorithm that transfers the style of one image to another image and converts the style of the second image while preserving its content. In this paper, we propose a style transfer approach for sand painting generation based on convolutional neural networks. The proposed approach aims to improve sand painting generation via neural style transfer, which can address the problem of blurred objects. Furthermore, it can reduce background noise caused by neural style transfers. First, we segment the main objects from the content image. Subsequently, we perform close-open filtering operations on the content image to obtain smooth images. Subsequently, we perform Sobel edge detection to process the images and obtain edge maps. Based on these edge maps and the input style image, we perform neural style transfer to generate sand painting images. Finally, we integrate the generated images to obtain the final stylized sand painting image. The results show that the proposed approach yields good visual effects from sand paintings. Moreover, the proposed approach achieves better visual effects for sand painting than the previous method.

Objectives: Signet ring cell carcinoma (SRCC) of the urinary bladder is a rare and highly aggressive form of bladder cancer, with no widely agreed-upon treatment strategy. The aim of this study was to identify important factors influencing patient prognosis and to assess how various treatment approaches affect survival outcomes., Methods: A retrospective study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) Program, including patients with bladder primary SRCC who were presented between 2000 and 2017. Univariate and multivariate Cox regression models were used to examine the impact of various factors on cancer-specific survival (CSS) and overall survival (OS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were applied to homogenize both groups. The impact of different treatment regimens on patient CSS and OS was analyzed using the Kaplan-Meier method., Results: A total of 33 cases of non-muscular invasive SRCC and 210 cases of muscular invasive SRCC were included in this study. Multivariate analysis identified race, TNM stage, and surgical method as independent variables influencing both OS and CSS. In non-muscle invasive bladder SRCC patients, radical cystectomy showed no CSS benefit compared to transurethral resection of bladder tumors ( P = 0.304). For muscle invasive SRCC, patients who underwent partial cystectomy had better OS and CSS compared to those who underwent radical cystectomy ( P = 0.019, P = 0.024). However, after conducting a PSM analysis, the differences between the two surgical outcomes were not statistically significant ( P = 0.504, P = 0.335). Lymphadenectomy, chemotherapy, and radiation did not show any benefit to the prognosis of patients., Conclusion: This study identified race, TNM stage, and surgical approach as significant independent predictors for SRCC outcomes. Simple radical cystectomy and partial cystectomy proved to be effective treatments for SRCC. The optimal treatment option still needs to be supported by a number of prospective research trials., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Prostate cancer (PCa) frequently presents as a multifocal disease within a single gland. Herein, the transcriptome-wide profiles of glandular epithelial (GE) cells of four PCa tissues with various Gleason scores (GSs) are analyzed with Visium spatial transcriptomics (ST). The genetic classifications across PCa section sites generally matched the spatial patterns of histological structures with different GSs. Average inferred copy number variation (inferCNV) values gradually increased during GS development. Developing trajectories during GS upgrading were assessed, and differentially expressed genes (DEGs) during GS progression were analyzed which exhibited heterogeneity among individual patients with PCa. Several crucial genes, such as NANS, PABPC1L, PILRB, PPFIA2, and SESN3, were associated with GS upgrading. Enrichment analysis showed that biological functions, such as cadherin binding, Golgi vesicle transport, protein folding, and cell adhesion molecules were related to GS progression. In conclusion, this study provides insight into ST-based transcriptome-wide expression patterns during GS progression., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Author(s).)

Nephrolithiasis is highly prevalent and associated with the increased risk of kidney cancer. The tumor suppressor von Hippel-Lindau (VHL) is critical for renal cancer development, however, its role in kidney stone disease has not been fully elucidated until now. Here we reported VHL expression was upregulated in renal epithelial cells upon exposure to crystal. Utilizing Vhl +/mu mouse model, depletion of VHL exacerbated kidney inflammatory injury during nephrolithiasis. Conversely, overexpression of VHL limited crystal-induced lipid peroxidation and ferroptosis in a BICD2-depdendent manner. Mechanistically, VHL interacted with the cargo adaptor BICD2 and promoted itsd K48-linked poly-ubiquitination, consequently resulting in the proteasomal degradation of BICD2. Through promoting STAT1 nuclear translocation, BICD2 facilitated IFNγ signaling transduction and enhanced IFNγ-mediated suppression of cystine/glutamate antiporter system X c - , eventually increasing cell sensitivity to ferroptosis. Moreover, we found that the BRAF inhibitor impaired the association of VHL with BICD2 through triggering BICD2 phosphorylation, ultimately causing severe ferroptosis and nephrotoxicity. Collectively, our results uncover the important role of VHL/BICD2/STAT1 axis in crystal kidney injury and provide a potential therapeutic target for treatment and prevention of renal inflammation and drug-induced nephrotoxicity., (© 2023. The Author(s).)

N-cadherin (cadherin-2 [CDH2]) is widely known as the promoter of prostate cancer (PCa) invasion and castration resistance. However, the biological mechanism of N-cadherin in PCa progression is unclear. In this study, we overexpressed N-cadherin in LNCaP cells and downregulated N-cadherin in PC3 cells by lentiviral transduction. Then, differentially expressed genes (DEGs) and dysregulated biological functions were investigated through RNA sequencing (RNA-seq) analyses. We found 13 long noncoding RNA (lncRNA) transcripts, 72 messenger RNA (mRNA) transcripts, and 3 integrated genes were dysregulated by N-cadherin. In the disease enrichment, bone cancer, and neurodegenerative and nervous system diseases were associated with N-cadherin in the circular RNA (circRNA; PC3 versus [vs.,/] LNCaP [PC3/LNCaP] comparison) and DEG analysis (LNCaP&#95;oe&#95;CDH2 vs. LNCaP&#95;oe&#95;NC [LNCaP&#95;oe&#95;CDH2/NC] comparison). Epigenetic reprogramming, such as nucleic acid binding, and chromatin and histone modifications, was enriched in Gene Ontology (GO) analysis (DEGs in LNCaP&#95;oe&#95;CDH2/NC and PC3&#95;sh&#95;NC/CDH2, and host genes of circRNA in PC3/LNCaP). Transcriptional misregulation in cancer, post-translational protein modification, gene expression, and generic transcription pathways were dysregulated in the pathway enrichment analysis (host genes of circRNA in PC3/LNCaP, and DEGs in LNCaP&#95;oe&#95;CDH2/NC and PC3&#95;sh&#95;NC/CDH2). Verifying DEGs through TCGA-PRAD dataset revealed six oncogenes (ARHGEF1, GRAMD1A, GTF2H4, MAPK8IP3, POLD1, and PTBP1) that were commonly upregulated by N-cadherin and in advanced PCa stages. In summary, we identified several oncogenes and biological functions associated with N-cadherin expression in PCa cells. N-cadherin may trigger epigenetic reprogramming in PCa cells to promote tumor progression.

Prostate cancer (PCa) is a pernicious tumor with high heterogeneity, which creates a conundrum for making a precise diagnosis and choosing an optimal treatment approach. Multiparametric magnetic resonance imaging (mp-MRI) with anatomical and functional sequences has evolved as a routine and significant paradigm for the detection and characterization of PCa. Moreover, using radiomics to extract quantitative data has emerged as a promising field due to the rapid growth of artificial intelligence (AI) and image data processing. Radiomics acquires novel imaging biomarkers by extracting imaging signatures and establishes models for precise evaluation. Radiomics models provide a reliable and noninvasive alternative to aid in precision medicine, demonstrating advantages over traditional models based on clinicopathological parameters. The purpose of this review is to provide an overview of related studies of radiomics in PCa, specifically around the development and validation of radiomics models using MRI-derived image features. The current landscape of the literature, focusing mainly on PCa detection, aggressiveness, and prognosis evaluation, is reviewed and summarized. Rather than studies that exclusively focus on image biomarker identification and method optimization, models with high potential for universal clinical implementation are identified. Furthermore, we delve deeper into the critical concerns that can be addressed by different models and the obstacles that may arise in a clinical scenario. This review will encourage researchers to design models based on actual clinical needs, as well as assist urologists in gaining a better understanding of the promising results yielded by radiomics.

Background: Racial/ethnic disparities in prostate cancer are reported in the United States (US). However, long-term trends and contributors of racial/ethnic disparities in all-cause and cause-specific death among patients with prostate cancer remain unclear. We analysed the trends and contributors of racial/ethnic disparities in prostate cancer survivors according to the cause of death in the US over 25 years., Methods: In this retrospective, population-based longitudinal cohort study, we identified patients diagnosed with first primary prostate cancer between 1995 and 2019, with follow-up until Dec 31, 2019, using population-based cancer registries' data from the Surveillance, Epidemiology, and End Results (SEER) Program. We calculated the cumulative incidence of death for each racial/ethnic group (Black, white, Hispanic, Asian or Pacific Islander [API], and American Indian or Alaska Native [AI/AN] people), by diagnostic period and cause of death. We quantified absolute disparities using rate changes for the 5-year cumulative incidence of death between racial/ethnic groups and diagnostic periods. We estimated relative (Hazard ratios [HR]) racial/ethnic disparities and the percentage of potential factors contributed to racial/ethnic disparities using Cox regression models., Findings: Despite a decreasing trend in the cumulative risk of death across five racial/ethnic groups, AI/AN and Black patients consistently had the highest rate of death between 1995 and 2019 with an adjusted HR of 1.48 (1.40-1.58) and 1.40 (1.38-1.42) respectively. The disparities in all-cause mortality between AI/AN and white patients increased over time, with adjusted HR 1.32 (1.17-1.49) in 1995-1999 and 1.95 (1.53-2.49) in 2015-2019. Adjustment of stage at diagnosis, initial treatment, tumor grade, and household income explained 33% and 24% of the AI/AN-white and Black-white disparities in all-cause death among patients with prostate cancer., Interpretation: The enduring racial/ethnic disparities in patients with prostate cancer, call for new interventions to eliminate health disparities. Our study provides important evidence and ways to address racial/ethnic inequality., Funding: National Key R&D Program of China, National Natural Science Foundation of China, Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Key Projects of Philosophy and Social Sciences Research, Ministry of Education of China., Competing Interests: We declare no competing interests., (© 2023 The Author(s).)

Background: Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes are suboptimal. Camrelizumab, a PD-1 blockade, has shown benefits in several tumors. This study aimed to investigate the efficacy and safety of neoadjuvant camrelizumab in combination with gemcitabine plus cisplatin (GC) followed by RC for MIBC patients., Methods: This was a multi-center, single-arm study that enrolled MIBC patients with a clinical stage of T2-4aN0-1M0, and scheduled for RC. Patients received three 21-day cycles of camrelizumab 200 mg on day 1, gemcitabine 1000 mg/m 2 on day 1 and 8, and cisplatin 70 mg/m 2 on day 2, followed by RC. The primary endpoint was pathologic complete response (pCR, pT0N0)., Results: From May 2020 to July 2021, 43 patients were enrolled and received study medications at nine centers in China. Three of them were deemed ineligible and excluded from efficacy analysis but included in safety analysis. In total 10 patients were unevaluable as they declined RC (two due to adverse events [AEs] and eight due to patient's willingness). Among 30 evaluable patients, 13 patients (43.3%) achieved pCR, and 16 patients (53.3%) achieved pathologic downstaging. No AEs leading to death were observed. The most common AEs were anemia (69.8%), decreased white blood cell count (65.1%), and nausea (65.1%). Immune-related AEs were all grade 1 or 2. Pathologic response was not correlated with PD-L1 expression status or tumor mutation burden. Individual genes as a biomarker for pathologic response were not identified., Conclusions: Neoadjuvant treatment with camrelizumab and GC regimen demonstrated preliminary anti-tumor activity for MIBC patients with manageable safety profiles. The study met its primary endpoint, and the following randomized trial is ongoing., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Epigenetic reprogramming through dysregulated histone lysine methylation (HLM) plays a crucial role in prostate cancer (PCa) progression. This study aimed to comprehensively evaluate HLM modification patterns in PCa microenvironment infiltration., Materials and Methods: Ninety-one HLM regulators in The Cancer Genome Atlas (TCGA) dataset were analyzed using bioinformatics. Differentially expressed genes (DEGs) and survival analyses were performed using TCGA-PRAD clinicopathologic and follow-up information. Consensus clustering analysis divided patients into subgroups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Tumor mutation burden (TMB) and tumor microenvironment (TME) cell infiltration were evaluated in different HLM clusters. Quantitative real-time PCR (qPCR) analysis assessed HLM regulators in clinical PCa tissues., Results: The tumor vs. normal (TN), Gleason score (GS) > 7 vs. GS < 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS > 7, pT3, HR > 1, and TP53 mutation) (P < 0.05) and verified in clinical PCa tissues. Consensus clustering analysis revealed three distinct HLM modification patterns (HLMclusters). However, no significant differences in recurrence-free survival (RFS) rates were found among the groups (P > 0.05). We screened 189 HLM phenotype-related genes that overlapped in the pairwise comparisons of HLMclusters and P < 0.01 in the Cox regression analysis. Three distinct subgroups (geneClusters) were revealed based on the 189 genes, in which cluster A involved the most advanced PCa (PSA > 10, T3-4, GS8-10, and biochemical recurrence) and the poorest RFS. The HLM score (HLMscore) was calculated by principal component analysis (PCA) of HLM phenotype-related genes that have positive predictive value for RFS (P < 0.001) and immune therapy responses (in the CTLA4-positive and -negative responses accompanied by a PD1-negative response)., Conclusion: We comprehensively evaluated HLM regulators in the PCa microenvironment using TCGA-PRAD, revealing a nonnegligible role of HLM patterns in PCa complexity and heterogeneity. Elucidating the effects of HLM regulators in PCa may enhance prognostics, aggressiveness assessments, and immunotherapy strategies., 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 Quan, Zhang, Wang and Ping.)

Objective: Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men. The transforming growth factor beta 1 (TGFβ1) plays an important role in the proliferation and differentiation of BPH stroma. However, it is not clear yet which important pathways and key genes are the downstream of TGFβ1 acting on prostatic stromal cells. Methods: GSE132714 is currently the newer, available, and best high-throughput sequencing data set for BPH disease and includes the largest number of BPH cases. We examined the TGFβ1 expression level in BPH and normal prostate (NP) by analyzing the GSE132714 data set as well as carrying out immunohistochemistry of 15 BPH and 15 NP samples. Primary prostatic stromal cells (PrSCs) were isolated from five fresh BPH tissues. RNA sequencing and bioinformatics analysis were used to reveal important pathways and hub genes associated with TGFβ1 stimulation on PrSCs. Results: TGFβ1 was upregulated in BPH stroma compared to NP stroma. A total of 497 genes (244 upregulated and 253 downregulated) were differentially expressed in PrSCs with and without TGFβ1 stimulation. The Gene Ontology revealed that differentially expressed genes (DEGs) were mainly enriched in progesterone secretion, interleukin-7 receptor binding, and CSF1-CSF1R complex. The Wnt signaling pathway, PI3K-Akt signaling pathway, JAK-STAT signaling pathway, and Hippo signaling pathway were screened based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. FN1, SMAD3, CXCL12, VCAM1, and ICAM1 were selected as hub genes according to the degree of connection from the protein-protein interaction (PPI) network. Conclusion: This study sheds some new insights into the role of TGFβ1 in BPH stroma and provides some clues for the identification of potential downstream mechanisms and targets., 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 Xiang, Du, Wang, Liu, Yan, Hao, Liu, Guan and Ping.)

Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and diabetic. An adrenalectomy was performed to investigate the relationship between steroid hormone and liraglutide. To investigate the effect of central liraglutide infusion on blood glucose in rats, rats were intracerebroventricularly administrated with liraglutide with or without HPA axis inhibitors such as berberine and dexamethasone. The results showed that a single injection of liraglutide caused a temporary increase in blood glucose in healthy rats. Another GLP-1R agonist, Exendin-4 (Ex-4), increased blood sugar in a manner similar to that of liraglutide. The effects of liraglutide were also blocked by guanethidine pretreatment and vanished in normal rats with adrenalectomy. Additionally, central infusion of liraglutide via intracerebroventricular (icv) injection into normal rats also causes a temporary increase in blood glucose that was blocked by GLP-1R antagonists or the inhibitors such as berberine and dexamethasone. Similarly, central liraglutide treatment causes temporary increases in plasma glucose, adrenocorticotropic hormone (ACTH), and cortisol levels, which were reversed by inhibitors for the hypothalamic-pituitary-adrenal (HPA) axis. In normal rats, the temporary glucose-increasing effect of liraglutide was gradually eliminated during consecutive daily treatments, indicating tolerance formation. Additionally, liraglutide and Ex-4 cross-tolerance was also discovered in normal rats. Liraglutide was more effective in diabetic rats than in normal rats in activating GLP-1R gene expression in the isolated adrenal gland. Interestingly, the effect of liraglutide on glycemic control varied depending on whether the rats were diabetic or not. In normal rats, bolus injection of liraglutide, such as Ex-4, may stimulate the HPA axis, resulting in hyperglycemia. The cross-tolerance of liraglutide and Ex-4 provided a novel perspective on GLP-1R activation.

Background and Purpose: The pathogenesis of diabetic gastroparesis due to visceral neuropathy involves multidimensional mechanisms with limited exploration of gastric mucosal innervation. This study aimed to examine quantitatively this topic and its relationship with gastroparesis symptoms and gastric emptying in diabetes., Methods: We prospectively enrolled 22 patients with type 2 diabetes and gastroparesis symptoms and 25 age- and gender-matched healthy controls for comparison. The assessments included: (i) neuropathology with quantification of gastric mucosal innervation density (MID) on endoscopic biopsy; (ii) clinical manifestations based on the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire; and (iii) functional tests of gastric emptying scintigraphy (GES)., Results: In patients with diabetes, stomach fullness, bloating and feeling excessively full after meals constituted the most common GCSI symptoms. Seven patients with diabetes (32%) had prolonged gastric emptying patterns. In diabetes, gastric MID was significantly lower in all the regions examined compared with the controls: antrum (294.8 ± 237.0 vs. 644.0 ± 222.0 mm/mm 3 ; p < 0.001), body (292.2 ± 239.0 vs. 652.6 ± 260.9 mm/mm 3 ; p < 0.001), and fundus (238.0 ± 109.1 vs. 657.2 ± 332.8 mm/mm 3 ; p < 0.001). Gastric MID was negatively correlated with gastroparesis symptoms and total scores on the GCSI (p < 0.001). Furthermore, gastric MID in the fundus was negatively correlated with fasting glucose and glycated hemoglobin levels. Gastric emptying variables, including half emptying time and gastric retention, were prolonged in patients with diabetes, and gastric retention at 3 h was correlated with fasting glucose level., Conclusion: In diabetes, gastric MID was reduced and GES parameters were prolonged. Both were correlated with gastroparesis symptoms and glycemic control. These findings provide pathology and functional biomarkers for diabetic visceral neuropathy of gastroparesis and underlying pathophysiology., (© 2022 European Academy of Neurology.)

This work investigated the effect of oxidized beef tallow on the volatile compositions and sensory properties of soybean meal-based Maillard reaction products (MRPs). Various tallow oxidation methods included thermal treatment (TT), enzymatic hydrolysis (ET) and enzymatic hydrolysis combined with mild thermal (ETT) treatment. Results showed that all these oxidized tallow contained more types of volatile compounds than those of untreated tallow. Moreover, the composition of almost all types of volatile substances was greatly increased with the addition of the oxidized beef tallow into the hydrolyzed soybean meal-based Maillard reaction system. More importantly, the composition of oxygen-containing heterocycles (63.89 μg/mL), sulfur-containing compounds (76.64 μg/mL), and nitrogen-containing heterocycles (19.81 μg/mL) that contribute positively to sensory properties in ETT-MRPs was found to be the highest among all the MRPs. Correlation assessment revealed that ETT was closely related to the most typical volatile products and sensory attributes, indicating this approach can effectively enhance the sensory and flavor of hydrolyzed soybean meal derived MRPs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Epigenetic reprogramming reportedly has a crucial role in prostate cancer (PCa) progression. RNA modification is a hot topic in epigenetics, and N6-methyladenosine (m6A) accounts for approximately 60% of RNA chemical modifications. The aim of this study was to evaluate the m6A modification patterns in PCa patients and construct a risk prediction model using m6A RNA regulators., Materials and Methods: Analyses were based on the levels of 25 m6A regulators in The Cancer Genome Atlas (TCGA). Differentially expressed gene (DEG) and survival analyses were performed according to TCGA-PRAD clinicopathologic and follow-up information. To detect the influences of m6A regulators and their DEGs, consensus clustering analysis was performed, and tumor mutational burden (TMB) estimation and tumor microenvironment (TME) cell infiltration were assessed. mRNA levels of representative genes were verified using clinical PCa data., Results: Diverse expression patterns of m6A regulators between tumor and normal (TN) tissues were detected regarding Gleason score (GS), pathological T stage (pT), TP53 mutation, and survival comparisons, with HNRNPA2B1 and IGFBP3 being intersecting genes. HNRNPA2B1 was upregulated in advanced stages (GS > 7, pT3, HR > 1, and TP53 mutation), as verified using clinical PCa tissue. Three distinct m6A modification patterns were identified through consensus clustering analysis, but no significant difference was found among these groups in recurrence-free survival (RFS) analysis. Six DEGs of m6A clusters (m6Aclusters) were screened through univariate Cox regression analysis. MMAB and PAIAP2 were intersecting genes for the five clinical factors. MMAB, which was upregulated in PCa compared with TN, was verified using clinical PCa samples. Three distinct subgroups were established according to the 6 DEGs. Cluster A involved the most advanced stages and had the poorest RFS. The m6A score (m6Ascore) was calculated based on the 6 genes, and the low m6Ascore group showed poor RFS with a negative association with infiltration for 16 of 23 immune-related cells., Conclusion: We screened DEGs of m6Aclusters and identified 6 genes (BAIAP2, TEX264, MMAB, JAGN1, TIMM8AP1, and IMP3), with which we constructed a highly predictive model with prognostic value by dividing TCGA-PRAD into three distinct subgroups and performing m6Ascore analysis. This study helps to elucidate the integral effects of m6A modification patterns on PCa progression., (© 2022. The Author(s).)

Purpose: Subconjunctival hemorrhage (SCH) is usually a benign ocular disorder that causes painless, redness under the conjunctiva. However, since SCH and acute coronary syndrome (ACS) share many vascular risk factors, studies have suggested that these two disorders may be significantly associated with each other, and evaluate the concomitance of ACS in patients with SCH. Methods: This population-based cohort study, enrolled 35,260 Taiwanese patients, and used the Taiwan National Health Insurance Research Database to identify patients with ACS and SCH. Outcomes were compared between the with and without SCH groups. The study population was followed until the date of ACS onset, the date of withdrawal, death, or December 31st 2013, whichever came first. Results: Of the 85,925 patients identified with SCH between 1996 and 2013, 68,295 were excluded based on the study's exclusion criteria, and a total of 17,630 patients with SCH who were diagnosed by ophthalmologists between 2000 and 2012 were eligible for analysis. After 1:1 propensity score matching for 5-year age groups, gender, and the index year, the results showed that SCH was more common in the 40-59 age group (53.82%) and females (58.66%). As for the ACS-related risk factors, patients with diabetes mellitus (aHR = 1.58, 95% CI = [1.38, 1.81]), hypertension (aHR = 1.71, 95% CI = [1.49, 1.96]) and patients taking aspirin (aHR = 1.67, 95% CI = [1.47, 1.90]) had a notably higher risk of ACS. However, it was found that there were no significant differences in the occurrence of ACS between the non-SCH and SCH patients. Conclusion: This results of this study regarding the risk factors and epidemiology of SCH and ACS were in keeping with previously reported findings. However, the results revealed no significant association between SCH and ACS., 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 © 2021 Chiang, Lai, Chiang, Hu, Hsu and Wei.)

Purpose: This study aimed to identify differentially expressed genes (DEGs) and pathways in benign prostatic hyperplasia (BPH) by comprehensive bioinformatics analysis., Methods: Data of the gene expression microarray (GSE6099) were downloaded from GEO database. DEGs were obtained by GEO2R. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein-protein interaction network was constructed through STRING. Anterior gradient 2 (ARG2) and lumican (LUM) staining in paraffin-embedded specimens from BPH and normal prostate (NP) were detected by immunohistochemistry (IHC). Differences between groups were analyzed by the Student's t test., Results: A total of 24 epithelial DEGs and 39 stromal DEGs were determined. The GO analysis results showed that epithelial DEGs between BPH and NP were enriched in biological processes of glucose metabolic process, glucose homeostasis and negative regulation of Rho protein signal transduction. For DEGs in stroma, enriched biological processes included response to ischemia, antigen processing and presentation, cartilage development, T cell costimulation and energy reserve metabolic process. ARG2, as one of the epithelial DEGs, was mainly located in epithelial cells of prostate. In addition, LUM is primarily expressed in the stroma. We further confirmed that compared with NP, the BPH have the lower ARG2 protein level (p = 0.029) and higher LUM protein level (p = 0.003) using IHC., Conclusions: Our study indicated that there are possible differentially expressed genes in epithelial and stromal cells, such as ARG2 and LUM, which may provide a novel insight for the pathogenesis of BPH., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

The dysregulation of androgen receptor ( AR ) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 ( NDRG1 ) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro . Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 ( DNMT1 ) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Adipose-derived cytokines may contribute to the inflammation that occurs in metabolic syndrome (MetS). The Takeda G protein-coupled receptor (TGR5) regulates energy expenditure and affects the production of pro-inflammatory biomarkers in metabolic diseases. Etanercept, which acts as a tumor necrosis factor (TNF)-α antagonist, can also block the inflammatory response. Therefore, the interaction between TNF-α and TGR5 expression was investigated in rats with high-fat diet (HFD)-induced obesity. Heart tissues isolated from the HFD-induced MetS rats were analyzed. Changes in TGR5 expression were investigated with lithocholic acid (LCA) as the agonist. Betulinic acid (BA) was used to activate TGR5 in urinary bladders. LCA was more effective in the heart tissues of HFD-fed rats, although etanercept alleviated the function of LCA. STAT3 activation and higher TGR5 expression were observed in the heart tissues collected from HFD-fed rats. Thus, cardiac TGR5 expression is promoted by HFD through STAT3 activation in rats. Moreover, the urinary bladders of female rats fed a HFD showed a low response, which was reversed by etanercept. Relaxation by BA in the bladders was more marked in HFD-fed rats. The high TGR5 expression in HFD-fed rats was characterized using a mRNA assay, and the increased cAMP levels were found to be stimulated by BA in the isolated bladders. Therefore, TGR5 expression increases with a HFD in both the hearts and urinary bladders. Collectively, cytokine-medicated TGR5 activation was observed in the hearts and urinary bladders of rats.

Objective: To investigate the efficacy and safety of prostatic artery embolization (PAE) vs. transurethral resection of the prostate (TURP) in patients affected by benign prostatic hyperplasia (BPH). We also reviewed mean changes from baseline in PAE at selected follow-up points., Methods: PubMed, Web of Science, and Embase were searched up to May 1, 2020. Randomized controlled trials on PAE were collected according to specific inclusion and exclusion criteria. Meta-analyses were performed using RevMan 5.3, STATA 14, and GraphPad Prism 8. Pooled patient-reported scores and functional outcomes were calculated by using a fixed or random-effect model., Results: Eleven articles met our selection criteria and ten independent patient series were included in the final analysis. Pooled estimates suggested no significant difference between TURP and PAE for patient-reported outcomes including International Prostate Symptom Score (2.32 (- 0.44 to 5.09)) and quality of life (0.18 (- 0.41 to 0.77)) at 12 months. PAE was less effective regarding improvements in most functional outcomes such as maximum flow rate, prostate volume, and prostate-specific antigen. Moreover, PAE may be associated with relatively fewer complications, lower cost, and shorter hospitalization. After the PAE procedure, the overall weighted mean differences for all outcomes except sexual health scores were significantly improved from baseline during follow-up to 24 months., Conclusion: PAE is non-inferior to TURP with regard to improving patient-reported outcomes, though most functional parameters undergo more changes after TURP than after PAE. Moreover, PAE can significantly continue to relieve symptoms for 24 months without causing serious complications., Key Points: • PAE is as effective as TURP in improving subjective symptom scores, with fewer complications and shorter hospitalization times. • PAE is inferior to TURP in the improvement of most functional outcomes. • Improvements due to PAE are durable during follow-up to 24 months.

Circulation tumor cells (CTCs) play an important role in metastasis and highly correlate with cancer progression; thus, CTCs could be considered as a powerful diagnosis tool. Our previous studies showed that the number of CTCs could be utilized for recurrence prediction in colorectal cancer (CRC); however, the odds ratio was still lower than five. To improve prognosis in CRC patients, we analyzed CTC clusters/microemboli, CTC numbers, and carcinoembryonic antigen (CEA)/carbohydrate antigen 19-9 (CA19-9) levels using a self-assembled cell array (SACA) chip system for recurrence prediction. In CRC patients, the presence of CTC clusters/microemboli may have higher correlation in metastasis when compared to the high number of CTCs. Additionally, when both the number of CTCs and serum CEA levels are high, very high odds ratios of 24.4 and 17.1 are observed in patients at all stages and stage III of CRC, respectively. The high number of CTCs and CTC clusters/microemboli simultaneously suggests the high chance of relapse (odds ratio 8.4). Overall, the characteristic of CTC clusters/microemboli, CEA level, and CTC number have a clinical potential to enhance CRC prognosis.

Ribosome-binding protein 1 (RRBP1) is a marker for colorectal, lung, esophageal and prostate cancer. However, the association between RRBP1 and bladder cancer is not completely understood. The present study aimed to evaluate the expression and function of RRBP1 in bladder cancer. The association between RRBP1 expression and clinicopathological characteristics, as well as the prognosis of bladder cancer was analyzed. RRBP1 expression was further analyzed in bladder cancer cell lines via reverse transcription-quantitative PCR and western blotting. RRBP1 knockdown was established using short hairpin RNAs to investigate the function of RRBP1 in T24 cells. Compared with healthy bladder tissue, RRBP1 expression levels were significantly upregulated in bladder cancer tissue. High RRBP1 expression was associated with tumor stage, lymph node metastasis and shorter overall survival time. RRBP1 protein was highly expressed in bladder cancer cell lines compared with normal SV-HUC-1 cells. Compared with the control group, RRBP1 knockdown inhibited T24 migration and invasion by downregulating the expression of C-C chemokine receptor type 7 (CCR7) protein. In conclusion, the present study indicated that RRBP1 was associated with bladder cancer migration, invasion and prognosis, and CCR7 might serve a role in the process., (Copyright: © Wang et al.)

Context: Recently, prostatic urethral lift (PUL) is being used to treat lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Although preliminary clinical studies on PUL are increasing, the long-term efficacy and safety of this procedure are still not well evaluated., Objective: The objective of our study is to synthesize the existing literature evidence, and make a comprehensive and long-term systematic review for the PUL procedure., Evidence Acquisition: A systematic search was performed from the electronic databases including PubMed, Embase, and OVID. The search period was up to January 1, 2020. Comprehensive retrospective and prospective studies on PUL were collected in accordance with specific inclusion and exclusion criteria. Pooled prostatic symptom scores, sexual health scores, and functional outcomes were calculated by using a fixed or random-effect model., Evidence Synthesis: Nineteen articles meet our determined inclusion and exclusion criteria, and 11 independent patient series were included in the final analysis. Meta-analysis results indicated improvement after the PUL procedure, including International Prostate Symptom Score improvement of 9.73-12.16 points, BPH Impact Index improvement of 3.74-4.50 points, maximum flow rate improvement of 3.44-4.26 ml/s, and quality of life improvement of 2.20-2.55 points. Postvoid residual volume at most of the intervals was not significantly variable. Data regarding sexual function remained stable or improved slightly during the 24-mo follow-up period. Pooled estimates were largely heterogeneous except for sexual function., Conclusions: PUL can continue to relieve prostatic symptoms for 24 mo without causing serious complications. The extremely important advantage of the PUL procedure is that it can preserve or slightly improve sexual function. Longer-term and more comprehensive clinical trials are still needed to further clarify the functional outcomes and cost effectiveness of PUL., Patient Summary: Prostatic urethral lift is an attractive option for selected patients who seek rapid and durable relief of lower urinary tract symptoms with complete preservation of sexual function., (© 2020 Published by Elsevier B.V. on behalf of European Association of Urology.)

Prostate cancer (PCa) is one of the most prevalent malignancies in men. However, the molecular mechanism controlling the transformation of androgen-dependent PCa (ADPC) to castration-resistant PCa (CRPC) is largely unknown. Androgen receptor (AR) signaling has been reported to play a key role in this process; thus, searching for the novel AR co-activator is important for identifying the mechanism underlying PCa progression. In this study, we focused on the function of mixed lineage leukemia-5α (MLL5α), an epigenetic regulator that exhibits aberrant expression in PCa. MLL5α was the primary expressed form of MLL5 protein in PCa cells and it significantly suppressed proliferation, invasion, and migration in PCa cell lines. Upon stimulation with dihydrotestosterone (DHT), knockdown of MLL5α significantly suppressed N-myc downstream regulated gene 1 (NDRG1) and Kallikrein-related peptidase 3 (KLK3) expression. MLL5α directly bound with AR on the androgen response elements (AREs) and recruited H3K4me3 to the promoters of NDRG1 and KLK3. Downregulation of NDRG1 partially restored the cell invasion and migration suppressed by MLL5α. As evaluated by the proliferation of PCa cells, overexpression of MLL5α synergistically promoted sensitivity to enzalutamide (ENZ) treatment. In PCa patients, MLL5α expression was lower in the high Gleason score (GS) (GS > 7) group than in the low GS (GS < 7) group. In conclusion, suppression of AR/NDRG1 signaling via androgen deprivation therapy (ADT) may be a potential mechanism of CRPC progression. MLL5α significantly suppressed PCa progression by promoting AR/NDRG1 signaling, indicating that regulating MLL5α expression may be a potential treatment approach for patients with advanced PCa., Competing Interests: None., (AJCR Copyright © 2020.)

Docetaxel is the first-line chemotherapy agent for metastatic prostate cancer. However, the emergence of resistance diminishes its efficacy and limits the survival benefit. Quercetin is a dietary flavonoid which has been shown to have multiple anti-cancer effects. Also, quercetin has been reported to reverse chemo-resistance in many other cancers. This study was to determine whether quercetin could reverse docetaxel resistance in prostate cancer cells and xenograft models, thereby exploring the underlying mechanism. Depending on the docetaxel-resistant cells (LNCaP/R, PC-3/R) which were established from docetaxel-sensitive cells (LNCaP, PC-3), it was demonstrated that quercetin could reverse docetaxel resistance in prostate cancer on proliferation, colony formation, migration, invasion and apoptosis. Although single docetaxel application had little effect on docetaxel-resistant cells, combining docetaxel with quercetin was significantly effective. Combination therapy could maximally inhibited PI3K/Akt pathway and promoted apoptosis. As shown by in-vivo study, xenograft tumors treated by docetaxel with quercetin had poorest growth. Then, to investigate the underlying mechanisms, the differences among parental cells, docetaxel-resistant subclones and quercetin treated resistant subclones were evaluated. It was found that docetaxel-resistant subclones had stronger activation of androgen receptor and PI3K/Akt pathway, more remarkable mesenchymal and stem-like cell phenotypes, and more P-gp expression than that of parental cells. Interestingly, quercetin could reverse these transformations. Our data revealed that quercetin had docetaxel-resistance reversal effect both in vitro and in vivo and provided in-depth support for clinical use of quercetin in docetaxel-resistant prostate cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To examine the association of kidney stones with new-onset hypertension, diabetes and obesity., Participants and Methods: This prospective cohort study included participants in the Qingdao Port Cardiovascular Health Study who were aged ≥18 years and had abdominal ultrasonography results in 2013 that were negative for kidney stones. Multivariable Cox regression models with time-dependent covariates were used to estimate the effects of new-onset hypertension, diabetes and obesity on the incidence of kidney stones., Results: There were 9667 participants without kidney stones in 2013 (mean age 46.2 years; 75.6% men). During a mean (range) follow-up of 33.5 (6-42) months, 676 (7.0%) incident cases of kidney stones were identified. Kidney stones were more frequent among those who had new-onset of a metabolic factor vs those who did not (hypertension: 7.7 vs 6.0%; diabetes: 8.4 vs 6.6%; obesity: 7.4 vs 6.8%). Adjusted Cox models identified that increased risk of kidney stones was associated with new-onset hypertension (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.25-2.27), new-onset diabetes (HR 1.78, 95% CI 1.07-2.96), and new-onset obesity (HR 1.78, 95% CI 1.15-2.74)., Conclusions: New-onset of hypertension, diabetes and obesity were all strongly associated with an increased risk of kidney stones in this prospective cohort study. Results suggest that a substantial proportion of kidney stones are potentially preventable by appropriate control of these metabolic risk factors., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Background: Emerging preclinical evidence suggests a critical role for androgen-mediated androgen receptor (AR) signaling in bladder cancer progression. However, researchers have not determined whether autophagy modulates the efficacy of an enzalutamide (ENZ) treatment in subjects with advanced bladder cancer. In this study, we investigated the synergistic effect of ENZ and autophagy inhibitors on bladder cancer., Methods: ENZ was used as an anti-AR drug, and chloroquine (CQ), 3-methyladenine (3-MA), and bafilomycin A1 (BAF) were used as autophagy inhibitors. J82, T24, and UMUC3 cell lines were used as models of bladder cancer. A bifluorescence autophagy system with the mRFP-GFP-LC3 plasmid was used to evaluate autophagy flux. Protein and mRNA levels were detected using Western blotting and qPCR, respectively. A Cell Counting Kit-8 (CCK-8) assay, colony assay, and flow cytometry analysis were used to evaluate cell proliferation and apoptosis. Four-week-old BALB/c athymic nude mice were used in the in vivo assay., Results: Based on the results obtained using the bifluorescence autophagy system, ENZ (10-20 μM) significantly facilitated the accumulation of autophagosomes and autolysosomes in the cytoplasm of J82 and T24 cells. Additionally, ENZ significantly increased the expression of autophagy-related genes (AMP-dependent protein kinase (AMPK), autophagy-related gene 5 (ATG5), microtubule-associated protein light chain 3B (LC3B), and UNC-51-like kinase 1 (ULK1)) and proteins (microtubule-associated protein 1 light chain 3-II/I (LC3-II/I), ATG5, and phosphorylated AMP-dependent protein kinase α (p-AMPKα)). The administration of ENZ monotherapy (10-20 μM) to J82 and T24 cells failed to alter proliferation and apoptosis. Concurrent treatment with ENZ and autophagy inhibitors distinctly triggered apoptosis and inhibited proliferation. Genetic inhibition of autophagy by specifically blocking ATG5 with siRNA also increased ENZ-induced apoptosis in J82 and T24 cells. In vivo, concurrent treatment with ENZ (25 mg/kg/day) and CQ (10 mg/kg/day) improved the therapeutic sensitivity by decreasing tumor growth and apoptosis. Additionally, overexpression of AR suppressed ENZ-induced autophagy-related genes (LC3-II/I, ATG5, and p-AMPKα) in T24 cells, and CQ exerted synergistic effects with ENZ to suppressed AR-responsive genes expression (KLK2 and KLK3) in bladder cancer. In UMUC3 cells, ENZ monotherapy directly induced anticancer effects, and concurrent treatment with ENZ and CQ also had a synergistic effect on proliferation and apoptosis., Conclusions: Autophagy may be a potential mechanism underlying ENZ-resistant bladder cancer. Blockade of autophagy significantly increased ENZ-induced apoptosis in bladder cancer. Thus, concurrent treatment with autophagy inhibitors and ENZ may be a novel therapeutic strategy for bladder cancer., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Routinely, after receiving prostate specific antigen (PSA) testing and digital rectum examination, patients with suspected prostate cancer are required to undergo prostate biopsy. However, the ability of ultrasound-guided prostate biopsy to detect prostate cancer is limited. Nowadays, a variety of diagnostic methods and more sensitive diagnostic methods, such as multi-parameter prostate magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) can be applied clinically. Furthermore, laparoscopic/robot-assisted prostatectomy is also a safe and effective procedure for the treatment of benign prostatic hyperplasia. So maybe it is time to reconsider the necessary to perform prostate biopsy before radical prostatectomy., Aim: To explore the feasibility of radical prostatectomy without prostate biopsy in the era of new imaging technology and minimally invasive techniques., Methods: From June 2014 to November 2018, 11 cases of laparoscopic radical prostatectomy without prostate biopsy were performed at the three tertiary medical centers involved in this study. All patients received prostate magnetic resonance imaging and prostate cancer was suspected, including six patients with positive 68 Ga-PSMA PET/CT results. Laparoscopic radical prostatectomy and pelvic lymph node dissection were performed for all patients., Results: All surgeries were accomplished successfully. The mean age was 69 ± 7.7 year, the mean body mass index was 24.7 ± 1.6 kg/m 2 , the range of serum PSA was 4.3 to >1000 ng/mL, and the mean prostate volume was 40.9 ± 18.3 mL. The mean operative time was 96 ± 23.3 min, the mean estimated blood loss was 90 ± 90.9 mL, and the median duration of catheter placement was 14 d. The final pathology confirmed that all specimens were prostate cancer except one case of benign prostatic hyperplasia. No major complications occurred in 90 d postoperatively., Conclusion: The current practice of mandating a prostatic biopsy before prostatectomy should be reconsidered in the era of new imaging technology and minimally invasive techniques. Radical prostatectomy could be carried out without the evidence of malignancy. Large-sample randomized controlled trials are definitely required to confirm the feasibility of this new concept., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare.

Objective: To study the feasibility of ultrasonography (US) as a replacement for CT during the diagnosis of ureteral calculi (UC)., Materials and Methods: Clinical and imaging data of patients with UC between January 2013 and December 2017 were retrospectively analyzed. According to the imaging method, patients were divided into 3 groups: Group A, CT alone; Group B, CT and US, Group C, US alone. Age, location, and the size of stones were compared among the groups. According to the maximum diameter (MD) measured by using CT in Group B, patients were subdivided into 3 groups (subgroup 1-3): MD <0.5 cm, 0.5 cm ≤ MD ≤1.0 cm, and MD >1.0 cm. The MD measured by US and CT were compared in the subgroups., Results: A total of 1,289 patients with UC were admitted. The use of CT correlated with age (p = 0.000) and stone location (p = 0.004). The sensitivity and specificity of US were 71.3 and 100%. Positive US results correlated with stone size (p = 0.008), but not location (p = 0.861). The mean MDs of the calculi measured by US and CT: in subgroup 1:  0.80 ± 0.31 and 0.35 ± 0.05 cm (p = 0.000); in subgroup 2: 0.94 ± 0.32 and 0.72 ± 0.16 cm (p = 0.000); in subgroup 3: 1.75 ± 0.68 and 1.59 ± 0.52 cm (p = 0.094)., Conclusions: US confirmed that UC do not require confirmatory CT. US can replace CT as the initial imaging examination of UC., (© 2019 S. Karger AG, Basel.)

Objective: To evaluate the clinical effects of plasmakinetic enucleation of the prostate (PKERP) and holmium laser enucleation of the prostate (HoLEP) in the treatment of BPH., Methods: We retrospectively analyzed the clinical data on 78 BPH patients treated by PKERP (n = 38) or HoLEP (n = 40) from January 2016 to October 2017. We recorded the operation time, intraoperative hemoglobin level, catheter-indwelling time, bladder irrigation time, hospital stay, 6-month postoperative IPSS, quality of life (QOL), maximum urinary flow rate (Qmax), postvoid residual urine (PVR), PSA level, International Index of Erectile Function (IIEF) and postoperative complications, and compared the obtained parameters between the two groups and some of them with the baseline., Results: In comparison with the baseline, both the PKERP and HoLEP groups showed statistically significant differences at 6 months after surgery in the QOL score (4.82 ± 0.56 and 4.70 ± 0.67 vs 2.44 ± 0.69 and 2.92 ± 0.49, P < 0.01), IPSS (19.52 ± 4.96 and 19.44 ± 4.08 vs 9.56 ± 2.5 and 9.81 ± 2.5, P < 0.01), Qmax (［4.54 ± 1.86］ and ［4.42 ± 2.89］ ml/s vs ［17.72 ± 3.46］ and ［17.27 ± 4.42］ ml/s, P < 0.01), and PVR (［83.73±55.33］ and ［109.65 ± 89.58］ ml vs ［19.93 ± 11.07］ and ［18.31 ± 15.03］ ml, P < 0.01). Statistically significant differences were also found between the PKERP and HoLEP groups in the reduced hemoglobin level (［21.04 ± 16.96］ vs ［7.88 ± 6.65］ g/dl, P = 0.01), catheter-indwelling time (［7.67 ± 2.27］ vs ［3.93 ± 2.18］ d, P = 0.01), bladder irrigation time (［1.67 ± 0.62］ vs ［1.3 ± 0.54］ d, P = 0.05), hospital stay (［4.22 ± 1.55］ vs ［3.26 ± 0.9］ d, P = 0.01), and 6-month postoperative QOL score (［2.44 ± 0.69］ vs ［2.92 ± 0.49］, P = 0.05), but not in the other parameters., Conclusions: Both PKERP and HoLEP are safe and effective for the treatment of BPH, the former more feasible in primary hospitals, while the latter with the advantages of less bleeding, shorter catheterization and hospital stay, and higher 6-month postoperative QOL score.

H 2 S, synthesized by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST), functions as a signalling molecule in mammalian cells. H 2 S serves complex functions in physiological and pathological processes, including in bladder cancer. In the present study, H 2 S production, the expression of the associated enzymes and the effect of H 2 S on human urothelial cell carcinoma of the bladder (UCB) tissue and cell lines were evaluated, and whether decreasing H 2 S levels influenced cell viability and tumour growth following treatment with cisplatin (CDDP) was assessed in UCB cells in vitro and in vivo . H 2 S production and the expression of CBS, CSE and MPST in bladder tissue specimens and the UCB cell lines 5637, EJ and UM-UC-3 were analysed using a sulfur-sensitive electrode and western blotting. UCB cells were subjected to different treatments, and viability and protein expression were determined. H 2 S production was inhibited to examine its influence on EJ cell tumour growth following CDDP treatment in vivo . It was identified that CBS, CSE and MPST protein were up-regulated in UCB tissues and cells. The H 2 S production and enzyme expression levels were the highest in UCB tissue and EJ cells. The inhibition of endogenous H 2 S biosynthesis decreased EJ cell viability and tumour growth in response to CDDP treatment. H 2 S levels and the associated biosynthetic enzymes were increased in human UCB tissue and cells compared with adjacent tissue and normal cells, which may have increased the resistance to CDDP-induced apoptosis in UCB. Therefore, H 2 S and its production may be an alternative therapeutic target for UCB.

The aim of the present study was to investigate the expression and potential roles of CD74 in human urothelial cell carcinoma of the bladder (UCB) in vitro and in vivo . CD74 and macrophage migration inhibitory factor (MIF) were located and assayed in normal and UCB samples and cell lines using immunostaining. CD74 was knocked down using CD74 shRNA lentiviral particles in HT-1376 cells. The proliferative, invasive potential and microvessel density (MVD) of knockdown-CD74 HT-1376 cells were analyzed in vitro or in vivo . The expression of CD74 in an additional high grade UCB J82 cell line was also verified in vivo . All experiments were repeated at least 3 times. The majority of muscle-invasive bladder cancer (MIBC) samples, and only one high grade UCB cell line, HT-1376, expressed CD74, compared with normal, non-muscle-invasive bladder cancer (NMIBC) samples and other cell lines. The levels of proliferation and invasion were decreased in the CD74 knockdown-HT-1376 cells, and western blotting assay indicated that the levels of proteins associated with proliferation, apoptosis and invasion in the cells were affected correspondingly by different treatments in vitro . The tumorigenesis and MVD assays indicated less proliferation and angiogenesis in the knockdown-HT-1376 cells compared with the scramble cells. Notably, J82 cells exhibiting no signal of CD74 in vitro presented the expression of CD74 in vivo . The present study revealed the potential roles of CD74 in the proliferation, invasion and angiogenesis of MIBC, and that it may serve as a potential therapeutic target for UCB, but additional studies are required.

Background: Robot-assisted/laparoscopic intracorporeal ileal conduit (ICIC) has been reported in many experienced centers. Whether laparoscopic ICIC is superior to extracorporeal ileal conduit (ECIC) and whether laparoscopic ICIC should be promoted is still controversial. The aim of the study was to compare surgical and early oncological outcomes between patients undergoing laparoscopic radical cystectomy (LRC) with ICIC and ECIC., Methods: From January 2011 to June 2016, a total of 45 patients with bladder cancer underwent LRC with ileal conduit at our department, of whom 20 patients underwent LRC with ECIC and 25 patients underwent LRC with ICIC. Data of each patient's characteristics, surgical outcomes, and short-term oncological outcomes were collected and analyzed., Results: LRC with ileal conduit was performed successfully on all 45 patients. There were no significant differences in patients' characteristics, mean total operative time, and mean estimated blood loss between the ICIC and ECIC groups. Median time of flatus and oral intake was shorter in the ICIC group compared with the ECIC group (3 vs. 5 days, P = 0.035; 4 vs. 5 days, P = 0.002). The complications rates did not show significant difference between the two groups within the first 90 days postoperatively (P = 0.538). Cancer staging showed 45% of patients in the ECIC group and 36% in the ICIC group had a pathologic stage of T3 or T4, and 50% of patients in the ECIC group and 44% in the ICIC group had a pathologic stage of N1 or N1+. Kaplan-Meier analysis showed no significant difference in overall survival at 24 months (60% vs. 62%, P = 0.857) between the ECIC and ICIC groups., Conclusions: ICIC after LRC may be successful with the benefits of faster recovery time. No significant difference was found in complications and oncological outcomes between ICIC and ECIC. However, larger series with longer follow-up are needed to validate this procedure., Competing Interests: There are no conflicts of interest

Betulin, a natural product isolated from the bark of the birch trees, exhibits multiple anticancer effects. Activation of mTOR signaling pathway has been found in numerous cancers, including renal cell carcinoma (RCC). Here, we attempted to study whether mTOR signaling was essential for betulin to treat RCC. Based on cell survival and colony formation assays, we found that mTOR hyperactive RCC cell line 786-O cells were more sensitive to betulin treatment compared with mTOR-inactive Caki-2 cells. Knockdown of TSC2 in Caki-2 cells had similar results to 786-O cells, and mTOR silencing in 786-O cells rescued the inhibitory effect of betulin, indicating that betulin inhibited RCC cell proliferation in an mTOR-dependent manner. Furthermore, betulin treatment decreases the levels of glucose consumption and lactate production in 786-O cells, while minimal effects were observed in Caki-2 cells. In addition, betulin significantly inhibited the expression of PKM2 and HK2 in 786-O cells. Finally, knockdown of PKM2 or HK2 in 786-O reversed the anti-proliferative effects of betulin, and overexpression of PKM2 or HK2 in Caki-2 cells enhanced the sensitivity to betulin treatment. Taken together, these findings demonstrated the critical role of mTOR activation in RCC cells to betulin treatment, suggesting that betulin might be valuable for targeted therapies in RCC patients with mTOR activation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Competing Interests: There are no conflicts of interest.

IκB kinase (IKK)/nuclear factor κB (NF-κB) pathway activation is a key event in the acquisition of invasive and metastatic capacities in prostate cancer. A potent small-molecule compound, BMS-345541, was identified as a highly selective IKKα and IKKβ inhibitor to inhibit kinase activity. This study explored the effect of IKK inhibitor on epithelial-mesenchymal transition (EMT), apoptosis and metastasis in prostate cancer. Here, we demonstrate the role of IKK inhibitor reducing proliferation and inducing apoptosis in PC-3 cells. Furthermore, BMS345541 inhibited IκBα phosphorylation and nuclear level of NF-κB/p65 in PC-3 cells. We also observed downregulation of the N-cadherin, Snail, Slug and Twist protein in a dose-dependent manner. BMS‑345541 induced upregulation of the epithelial marker E-cadherin and phosphorylated NDRG1 at protein level. Moreover, BMS‑345541 reduced invasion and metastasis of PC-3 cells in vitro. In conclusion, IKK has a key role in both EMT and apoptosis of prostate cancer. IKK inhibitor can reverse EMT and induce cell death in PCa cells. IKK was identified as a potential target structure for future therapeutic intervention in PCa.