Function of NEK2 in clear cell renal cell carcinoma and its effect on the tumor microenvironment.

BACKGROUND: Previous studies have revealed the critical functions of NEK2 in controlling the cell cycle which is linked to poor prognosis in multiple tumor types, but less research has been devoted to clear cell renal cell carcinoma (ccRCC). METHODS: We downloaded clinical data from the gene expression omnibus (GEO) and TCGA databases together with transcriptional and mutational datasets. Strongly coexpressed genes with NEK2 were extracted from TCGA-KIRC cohort, and were submitted to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional analyses. According to NEK2 levels, the survival status, mutational characteristics, response to immunotherapy and sensitivity to drugs of the patients were studied. The potential correlations between NEK2 levels and immune cell state as well as immune cell infiltration were examined using the GEPIA, TIMER and TISIDB databases. Double immunofluorescence (IF) was performed to identify the NEK2 overexpression and relationship with CD8 in ccRCC. RESULTS: The NEK2 gene was overexpressed and would enhance the nuclear division and cell cycle activities in ccRCC. ccRCC patients with high NEK2 expression had worse clinical outcomes, higher mutation burden and better therapeutic response. Moreover, NEK2 gene overexpression was positively related to various immune cell marker sets, which was also proved by validation cohort, and more infiltration of various immune cells. CONCLUSION: ccRCC patients with NEK2 high expression have a poorer prognosis than those with NEK2 low expression, resulting from its function of promoting proliferation, accompanied by increased infiltration of CD8 + T cells and Tregs and T-cell exhaustion and will respond better to proper treatments.

Modulation of Potential-Limiting Steps in Lithium-Sulfur Batteries by Catalyst Synergy.

Electrocatalysis is considered to be an effective method to solve the sluggish kinetics of lithium-sulfur batteries. However, a single catalyst cannot simultaneously catalyze multi-step sulfur reductions. And once the catalyst surface is covered by the initially deposited solid products, the subsequent catalytic activity will significantly deteriorate. Here, microporous ZIF-67 and its derivative nano-metallic Co0 are used as dual-catalyst aiming to address these drawbacks. The dual catalytic center effectively cooperates the adsorption and electron transfer for multi-steps of sulfur reductions, transforming the potential-limited step (Li2S4→Li2S2/Li2S) into a thermodynamic spontaneous reaction. ZIF-67 first adsorbs soluble Li2S4 to form a coordination structure of ZIF-Li2S4. Then nano-metallic Co0 attracts uncoordinated S atoms in ZIF-Li2S4 and facilitates the breaking of S-S bonds to form transient reductive ZIF-Li2S2 and Co-S2 via. spontaneous electron transfer. These intermediates facilitate continuous conversion to Li2S with reduced formation energy, which is beneficial to the regeneration of the catalyst. As a result, the cathode with ZIF@CNTs/Co@CNFs synergetic catalyst achieves initial areal capacity of 4.7 mAh cm-2 and maintains 3.5 mAh cm-2 at low electrolyte/sulfur ratio (E/S) of 5 µL mg-1. This study provides valuable guidance for improving the electrochemical performance of lithium-sulfur batteries through catalyst synergistic strategies for multi-step reactions.

Biocompatible Gallium Nanodots against Drug-Resistant Bacterial Pneumonia and Liver Abscess.

Resistant bacterial infection remains a severe public health threat, and conventional antibiotic drugs work poorly in effectively treating infectious diseases. Here, we developed gallium-based nanodots (Ga NDs), consisting of specific disruption of bacterial iron ability, to treat multidrug-resistant (MDR) Gram-negative bacteria-infected diseases. The Ga NDs significantly suppress the proliferation of two typical MDR bacteria strains (P. aeruginosa and ESBL E. coli) compared with clinically used antibacterial drugs, including penicillin and levofloxacin. Ga NDs could also disrupt the biofilms of these two bacterial strains. In P. aeruginosa infected pneumonia and ESBL E. coli infected acute liver abscess models, the Ga NDs enable substantial inhibition of bacterial growth and reduce the organs' inflammation that resulted in significant improvement of survival. Further, the Ga NDs demonstrated excellent biocompatibility and biosafety characteristics. Together, we believe that our gallium containing nanotherapeutics are expected to be developed into promising alternative therapies to combat drug-resistant bacterial infection.

A Case of Primary Lymphoepithelioma-Like Carcinoma of the Bladder With Review.

Lymphoepithelioma-like carcinoma (LELC) was characterized by epithelial neoplastic cells developing in solid or incohesive sheets mixed with a noticeable lymphoid infiltration. Lymphoepithelioma-like carcinoma of the bladder (LELCB), which was first described by Zukerberg, is a rare variant of LELC. Here we reported a new case of LELCB occurring in a 70-year-old woman presenting with hematuria. Computed tomography (CT) and cystoscopy revealed a tumor on the left upper wall of the bladder. A partial cystectomy was finally performed. Pathological and immunohistochemical analysis revealed LELCB. After receiving systemic adjuvant chemotherapy, the patient conducted a 25-month follow-up without experiencing a recurrence.

DeepTAP: An RNN-based method of TAP-binding peptide prediction in the selection of tumor neoantigens.

The transport of peptides from the cytoplasm to the endoplasmic reticulum (ER) by transporters associated with antigen processing (TAP) is a critical step in the intracellular presentation of cytotoxic T lymphocyte (CTL) epitopes. The development and application of computational methods, especially deep learning methods and new neural network strategies that can automatically learn feature representations with limited knowledge, provide an opportunity to develop fast and efficient methods to identify TAP-binding peptides. Herein, this study presents a comprehensive analysis of TAP-binding peptide sequences to derive TAP-binding motifs and preferences for N-terminal and C-terminal amino acids. A novel recurrent neural network (RNN)-based method called DeepTAP, using bidirectional gated recurrent unit (BiGRU), was developed for the accurate prediction of TAP-binding peptides. Our results demonstrated that DeepTAP achieves an optimal balance between prediction precision and false positives, outperforming other baseline models. Furthermore, DeepTAP significantly improves the prediction accuracy of high-confidence neoantigens, especially the top-ranked ones, making it a valuable tool for researchers studying antigen presentation processes and T-cell epitope screening. DeepTAP is freely available at https://github.com/zjupgx/deeptap and https://pgx.zju.edu.cn/deeptap.

Giant Adrenal Cyst: A Case Report.

Giant adrenal cysts are rare lesions, most often discovered incidentally. In this case report, a patient presenting with nonspecific abdominal distension is described. Imaging studies revealed a vast cystic mass closely attached to the left adrenal gland. Neither routine laboratory tests nor endocrine function tests revealed abnormalities. By performing open surgery, the cystic mass was completely removed. According to the pathological results, the wall of the cystic mass has an endothelial structure and some vascular components. Comprehensive analysis indicated that this case was an angiomatous adrenal endothelial cyst which was an extremely uncommon form of an adrenal cyst. Over a one-year follow-up, no evidence of recurrence was observed in the patient postoperatively. Through this case, we wish to raise awareness of this disease.

Proteomic Profile of Sperm in Infertile Males Reveals Changes in Metabolic Pathways.

The objective of the present study was to investigate the differences in the proteomic profiles of sperm from infertile males with severe oligoasthenoteratozoospermia requiring intracytoplasmic sperm injection (ICSI) and normal control sperm from fertile males. Isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry was performed for identifying proteins in the sperm of infertile and fertile males. Differentially expressed proteins were analyzed via the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases through the Database for Annotation, Visualization, and Integrated Discovery, and protein-protein networks were produced using the Search Tool for Retrieval of Interacting Genes. Immunofluorescence and western blotting verified the differential expression of Y-box-binding protein 1(YBX1), adenylate kinase 1 (AK1), and aconitase 2, mitochondrial (ACO2) proteins. Altogether, 3444 proteins were identified in the sperm of infertile and fertile males, and 938 were differentially expressed between the two groups. Pairwise comparisons revealed that 226 and 712 proteins were significantly upregulated and downregulated in infertile males, respectively. These proteins were significantly enriched in metabolic pathways as per KEGG enrichment analysis. YBX1 expression was upregulated in the sperm heads of patients requiring ICSI treatment, whereas AK1 and ACO2, which are critical enzymes involved in energy metabolism, were downregulated in the sperm tails of the same patients. This result indicates that metabolism may have a crucial role in maintaining normal sperm function. Overall, our results provide insights that will further help in investigating the pathogenic mechanisms of infertility and possible therapeutic strategies.

Comparison of proteomic profiles from the testicular tissue of males with impaired and normal spermatogenesis.

In this study, we aimed to explore the potential differences in proteomic profiles from the testicular tissue of azoospermatic men with impaired spermatogenesis and normal spermatogenesis. Isobaric tags for relative and absolute quantitation (iTRAQ) labeled technology and LC-MS/MS technology were used to identify differentially expressed proteins. Potential functions of differentially expressed proteins were predicted using gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG). Immunohistochemistry (IHC) and western blot (WB) were used to verify the differentially expressed proteins. A protein-protein interaction (PPI) network was built to outline the regulatory network of differentially expressed proteins. A total of 3,945 proteins were identified in men with normal and impaired spermatogenesis. Of these, 116 proteins were differentially expressed in men with impaired spermatogenesis: 39 were upregulated and 77 were downregulated. Furthermore, we found that these differentially expressed proteins were mainly involved in the cellular component, which may be mainly associated with the spliceosome, ribosome, and thyroid hormone synthesis signaling pathways. The spliceosome- and ribosome-associated proteins YBX1, FBL, and HNRNPU were downregulated. And the proteomic profile of testicular tissue in men with impaired spermatogenesis is different from that of men with normal spermatogenesis. For this reason, differentially expressed proteins such as YBX1, FBL and HNRNPU might be involved in the pathology of spermatogenesis dysfunction.Abbreviations: iTRAQ: Isobaric tags for relative and absolute quantitation;GO: Gene ontology; KEGG: Kyoto encyclopedia of genes and genomes; IHC: Immunohistochemistry; WB: Western blot; PPI: Protein-protein interaction; ICSI: Intracytoplasmic sperm injection; BP: Biological process; CC: Cellular components; MF: Molecular function; snoRNA: Small nucleolar RNA; snRNA: Small nuclear RNA; LC-MS/MS: Liquid chromatography and MS/MS analysis; BSA: Bovine serum albumin; SD: Spermatogenic dysfunction; micro-TESE: Testicular microscopic sperm extraction.

Activation of Glucocorticoid Receptor Inhibits the Stem-Like Properties of Bladder Cancer via Inactivating the ß-Catenin Pathway.

Background: Glucocorticoid receptor (GR) signaling pathway has been shown to involve epithelial -to- mesenchymal transition which was implicated in the regulation of bladder cancer stem cells (CSCs) in our previous study. Herein, we aim to figure out how GR affects the stem-like properties of bladder cancer cells. Methods: We used dexamethasone (DEX) treatment or gene-knockdown/-knockout techniques to activate or silence the GR pathway, respectively. Then we applied immunohistochemical staining and flow cytometry to assess the associations between the expression levels of GR and a stem cell surface marker CD44. Stem-like properties were assessed by reactive oxygen species (ROS), sphere-formation and side population assays. The expression levels of cancer stem cell-associated molecules were assessed by quantitative PCR and Western blotting. Tumor growth was compared using mouse xenograft models. Results: In GR-positive bladder cancer cells, DEX significantly reduced the expression of CD44 as well as pluripotency transcription factors including ß-catenin and its downstream target (C-MYC, Snail, and OCT-4), the rate of sphere formation, and the proportion of side populations, and induced the intracellular levels of ROS. By contrast, GR silencing in bladder cancer cells showed the opposite effects. In xenograft-bearing mice, GR silencing resulted in the enhancement of tumor growth. Conclusions: These data suggested that GR activity was inversely associated with the stem-like properties of bladder cancer cells, potentially via inactivating the ß-catenin pathway.

Holmium Laser Enucleation of the Prostate: Modified Two-Lobe Technique versus Traditional Three-Lobe Technique-A Randomized Study.

BACKGROUND: Holmium laser enucleation of the prostate (HoLEP) is considered the standard endoscopic treatment of benign prostatic hyperplasia (BPH), but traditional HoLEP surgery will cause some postoperative complications. This study was attempted to evaluate the safety and efficacy of modified two-lobe technique versus traditional three-lobe technique of HoLEP focusing mainly on incidences of retrograde ejaculation (RE) and urinary incontinence (UI). METHODS: From March 2014 to February 2017, 191 men with BPH were randomly assigned to two groups: 97 underwent modified two-lobe technique; 94 underwent traditional three-lobe technique. All patients were followed up for 12 months. Primary outcomes were incidences of RE and UI, and secondary outcomes were international prostate symptom score (IPSS), quality of life (QOL), maximal urine flowing rate (MFR), and residual urine among the studied patients. RESULTS: Compared with the traditional technique, patients in the modified group had a statistically significant decrease in frequency of UI (1.03% vs 8.51%, p=0.036) and RE in the 6th month (33.33% vs 63.64%, p=0.030) and 12th month (13.33% vs 50%, p=0.034) and a significant increase in ejaculatory volume in the 6th month (p=0.050) and 12th month (p=0.003). Besides, the modified HoLEP was more beneficial to patients according to the change of QoL score at 1 month (p=0.002), 3 months (p=0.004), 6 months (p=0.026), and 12 months (p=0.015). CONCLUSIONS: The modified two-lobe technology of HoLEP reduced the incidence of RE and UI, which improved the quality of life of the patients after surgery compared to the traditional three-lobe technology. This trial is registered with ChiCTR1800018553.

Role of glucocorticoid signaling in urothelial tumorigenesis: Inhibition by prednisone presumably through inducing glucocorticoid receptor transrepression.

Glucocorticoids, including dexamethasone (DEX) and prednisone (PRED), have been prescribed in patients with neoplastic disease as cytotoxic agents or comedications. Nonetheless, it remains uncertain whether they have an impact on the development of bladder cancer. We, therefore, assessed the functional role of the glucocorticoid-mediated glucocorticoid receptor (GR) signaling in urothelial tumorigenesis. Tumor formation was significantly delayed in xenograft-bearing mice with implantation of control bladder cancer UMUC3 cells or nonneoplastic urothelial SVHUC cells undergoing malignant transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA), compared with respective GR knockdown xenografts. Using the in vitro system with MCA-SVHUC cells, we screened 11 GR ligands, including DEX, and found significant inhibitory effects of PRED on their neoplastic transformation. The effects of PRED were restored by a GR antagonist RU486 in GR-positive MCA-SVHUC cells, while PRED failed to inhibit the neoplastic transformation of GR knockdown cells. Significant decreases in the expression levels of oncogenes (c-Fos/c-Jun) and significant increases in those of a tumor suppressor UGT1A were seen in MCA-SVHUC-control cells (vs GR-short hairpin RNA) or PRED-treated MCA-SVHUC-control cells (vs mock). In addition, N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder cancer in all of eight mock-treated mice vs seven (87.5%) of DEX-treated (P = .302) or four (50%) of PRED-treated (P = .021) animals. Finally, DEX was found to considerably induce both transactivation (activation of glucocorticoid-response element mediated transcription and expression of its targets) and transrepression (suppression of nuclear factor-kappa B transactivation and expression of its regulated genes) of GR in SVHUC cells, while PRED more selectively induced GR transrepression. These findings suggest that PRED could prevent urothelial tumorigenesis presumably via inducing GR transrepression.

Tumor Enucleation vs. Partial Nephrectomy for T1 Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

Purpose: Tumor enucleation (TE) and partial nephrectomy (PN) have both become main treatment strategies for T1 renal cell carcinoma (RCC), despite the discrepancy between their safety margin. We performed a meta-analysis on all the relevant trials in order to compare the clinical efficacy and safety of TE with those of PN for RCC treatment. Methods: In this meta-analysis, randomized controlled trials or retrospective studies were included if they compared TE and PN therapy in patients with localized renal cancer. The main outcomes extracted were perioperative data and post-operative outcomes. Subgroups for analyses were undertaken according to tumor size and duration of follow up. Data were pooled using the generic variance method with a fixed or random effects model and expressed as mean differences or odds ratios with 95% CI. Results: A total of 13 studies containing 1,792 patients undergoing TE and 3,068 undergoing PN were identified. Our study showed that the patients received TE had significantly shorter operative time (MD = -28.46, 95% CI = -42.09, -14.83, P < 0.0001), less hospital day (MD = -0.68, 95% CI = -1.04, -0.31, P = 0.0003), less estimate blood loss (MD = -59.90, 95% CI = -93.23, -26.58, P = 0.0004) and smaller change in estimated glomerular filtration rate (fixed effect: MD = 4.66, 95% CI = 1.67, 7.66, P = 0.002), fewer complications (fixed effect: OR = 0.65, 95% CI = 0.50, 0.85, P = 0.001) compared with those received PN. However, there were no significant differences in terms of warm ischemic time, positive margin rates, recurrence rates and survival rates between the two groups. All the subgroup analyses presented consistent results with the overall analyses. Conclusions: Our findings suggested that TE is not only less-traumatizing and beneficial for recovery, but also better for renal function protection. Moreover, it did not show the evidence of an increase relapse rate or mortality rate when compared with PN.

Transurethral resection versus holmium laser enucleation of the prostate: A prospective randomized trial comparing perioperative thrombin generation and fibrinolysis.

OBJECTIVES: The purpose of this study was to compare transurethral resection of the prostate (TURP) versus holmium laser enucleation of the prostate (HoLEP) in patients with benign prostatic hyperplasia (BPH) focusing on perioperative thrombin generation and fibrinolysis. METHODS: Sixty-five BPH patients were prospectively randomly assigned to undergo TURP (n = 32) or HoLEP (n = 33). The prothrombin fragment (PF) 1+2, thrombin-antithrombin complex (TAT), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) were measured preoperatively, at the 1st day and 3rd day after surgery. RESULTS: PF1+2, TAT, t-PA, and PAI-1 significantly elevated at day 1 and day 3 after surgery (P < .05) and remarkedly decreased from the 1st day to the 3rd day (P < .05). The levels of PF1+2 and TAT were higher in TURP group postoperatively than that in HoLEP group (P < .05). There is no significant difference between 2 groups in regard of t-PA and PAI-1 (P > .05). CONCLUSION: The activation of thrombin generation and fibrinolysis system were noticed in BPH patients after TURP or HoLEP. TURP may associate with a higher hypercoagulable thrombotic risk than HoLEP.

Reducing postoperative morbidity of mini-invasive percutaneous nephrolithotomy: Would it help if blood vessels are left unharmed during puncture? A CONSORT-prospective randomized trial.

BACKGROUND: The aim of this study was to provide a randomized controlled trial comparing single B-mode ultrasound guidance and color doppler ultrasound guidance in minimally invasive percutaneous nephrolithotomy. METHODS: Three hundred patients with renal calculus were prospectively randomly assigned into 2 groups. In group 1 (150 patients), minimally invasive percutaneous nephrolithotomy (m-PCNL) were managed with single B-mode ultrasound guidance; In group 2 (150 patients), m-PCNL were managed with color Doppler ultrasound guidance and a needle bracket in order to guide placement at a target location beneath the skin. The characteristics of patients, operation, complications and prognosis, including body temperature, urine culture, and hematologic tests after the operation were recorded and compared. RESULTS: Our vessel-sparing technique showed a statistically significant decrease in hemoglobin drop, postoperative procalcitonin values, the frequency of postoperative fever, systemic inflammatory response syndrome, and urosepsis (P < .05). CONCLUSION: Using color Doppler ultrasound in real time and a needle bracket to detect and avoid main renal blood vessels decreased incidences of hemorrhagic complications and postoperative infection.

Carnosol protects against renal ischemia-reperfusion injury in rats.

Acute kidney injury, which is caused by renal ischemia-reperfusion injury (IRI), occurs in several clinical situations and causes severe renal damage. There is no effective therapeutic agent available for renal IRI at present. In this study, we performed an experiment based on an in vivo murine model of renal IRI to examine the effect of carnosol. Thirty Sprague-Dawley rats were randomized into three groups (10 rats in each group): the sham, IRI, and carnosol groups. Rats in the carnosol group were injected intravenously with 3 mg/kg of carnosol, and those in the sham and IRI groups were injected intravenously with 10% dimethyl sulfoxide 1 h before ischemia. Rats were sacrificed after 24 h of reperfusion. The blood and kidneys were harvested, renal function was assessed, and histologic evaluation was performed to analyze renal injury. A renal myeloperoxidase activity assay, in-situ apoptosis examination, enzyme-linked immunosorbent assay, immunohistochemical assay, and western blot were also performed. Carnosol pretreatment significantly reduced renal dysfunction and histologic damage induced by renal IRI. Carnosol pretreatment suppressed renal inflammatory cell infiltration and pro-inflammatory cytokine expression. In addition, carnosol markedly inhibited apoptotic tubular cell death, caspase-3 activation, and activation of the p38 pathway. Carnosol pretreatment protects rats against renal IRI by inhibiting inflammation and apoptosis. Although future investigation is needed, carnosol may be a potential therapeutic agent for preventing renal IRI.

Adjustable single-incision mini-slings (Ajust®) versus other slings in surgical management of female stress urinary incontinence: a meta-analysis of effectiveness and complications.

BACKGROUND: Adjustable single-incision mini-sling (SIMS) is a new category of SIMS for stress urinary incontinence (SUI). The aim of this study was to compare the efficacy and safety of adjustable single-incision mini-sling with other slings. METHODS: Literature search in databases such as Pubmed, and Conchrane Library was performed up to December, 2015. The outcomes including cure rate, operation time, postoperative pain score and complications were reanalyzed. The pooled relative risk (RR) and mean difference (MD) with their 95% confidence interval (95% CI) were calculated by RevMan v5.0. RESULTS: Eight studies with 1093 SUI female patients were included. There was no significant difference between adjustable SIMS and other slings (transobturator slings and MiniArc) in patients subjective cure rate and objective cure rate. In addition, adjustable SIMS was associated with a significantly shorter operative time and lower postoperative pain score when comparing adjustable SIMS with transobturator tape (MD = - 1.35; 95%CI: -2.24 to - 0.46, P = 0.003). For the complications, there was also no significant difference between adjustable SIMS and transobturator slings. CONCLUSIONS: Adjustable SIMS had equally efficacy for SUI compared with transobturator slings and MiniArc. However, the significantly shorter operative time and lower postoperative pain score than transobturator tape supported the clinical application of adjustable SIMS.

MicroRNA expression profiles in benign prostatic hyperplasia.

Although alterations in microRNA (miRNA) expression have been previously investigated prostate cancer, the expression of miRNAs specifically in benign prostate hyperplasia (BPH) of the prostatic stroma remains to be fully elucidated. In the present study, miRNAs and gene expression profiles were investigated using microarray analysis and reverse transcription quantitative­polymerase chain reaction (RT­qPCR) in BPH tissue to clarify the associations between miRNA expression and target genes. Prostate tissue samples from five patients with BPH and five healthy men were analyzed using human Affymetrix miRNA and mRNA microarrays and differentially expressed miRNAs were validated using RT­qPCR with 30 BPH and 5 healthy control samples. A total of 8 miRNAs, including miRNA (miR)­96­5p, miR­1271­5p, miR­21­3p, miR­96­5p, miR­181a­5p, miR­143­3p, miR­4428 and miR­106a­5p were upregulated and 8 miRNAs (miR­16­5p, miR­19b­5p, miR­940, miR­25, miR­486­3p, miR­30a­3p, let­7c and miR­191) were downregulated. Additionally, miR­96­5p was demonstrated to have an inhibitory effect on the mRNA expression levels of the following genes: Mechanistic target of rapamycin (MTOR), RPTOR independent companion of MTOR complex 2, syntaxin 10, autophagy­related protein 9A, zinc finger E­box binding homeobox 1, caspase 2 and protein kinase c ε. Additionally, 16 differentially expressed miRNAs were identified using RT­qPCR analysis. This preliminary study provides a solid basis for a further functional study to investigate the underlying regulatory mechanisms of BPH.

Genome Evolution Analysis of Recurrent Testicular Malignant Mesothelioma by Whole-Genome Sequencing.

BACKGROUND/AIMS: Malignant mesothelioma of the tunica vaginalis testis is a rare and lethal disease. The genomic characteristics and genetic changes of tumor cells during the progression of this disease are unknown. METHODS: we performed whole-genome sequencing of four successive tumor samples derived from surgery and a blood sample in a single patient. RESULTS: All tumors were found to have significant C-to-T and T-to-C mutations, and amplification of copy number in chromosomes 1 and 12 were notified in all tumor samples. Subclone analysis revealed a parallel evolution of the tumor in this patient. We also identified some mutations in mesothelioma-associated genes such as KIF25, AHNAK, and PRDM2. CONCLUSIONS: The results showed a comprehensive genomic change in malignant mesothelioma of the tunica vaginalis testis and provide a better understanding of the clonal evolution during tumor recurrence and metastasis.

Effects of microRNA-135a on the epithelial-mesenchymal transition, migration and invasion of bladder cancer cells by targeting GSK3ß through the Wnt/ß-catenin signaling pathway.

This study investigated the effects of microRNA-135a (miR-135a) targeting of glycogen synthase kinase 3ß (GSK3ß) on the epithelial-mesenchymal transition (EMT), migration and invasion of bladder cancer (BC) cells by mediating the Wnt/ß-catenin signaling pathway. BC and adjacent normal tissues were collected from 165 BC patients. Western blotting and quantitative real-time PCR were used to detect the expression of GSK3ß, ß-catenin, cyclinD1, E-cadherin, vimentin and miR-135a in BC tissues and cells. Cells were assigned to blank, negative control (NC), miR-135a mimics, miR-135a inhibitors, small interfering RNA (siRNA)-GSK3ß or miR-135a inhibitors+siRNA-GSK3ß groups. miR-135a, ß-catenin, cyclinD1 and vimentin expression increased, while GSK3ß and E-cadherin expression decreased in BC tissues compared with adjacent normal tissues. Compared with the blank and NC groups, the expression of miR-135a, ß-catenin, cyclinD1 and vimentin was higher, and cell proliferation, migration, invasion and tumor growth were increased in the miR-135a mimics and siRNA-GSK3ß groups. These groups showed an opposite trend in GSK3ß and E-cadherin expression and cell apoptosis. The miR-135a inhibitors group was inversely correlated with the blank and NC groups. It was concluded that miR-135a accelerates the EMT, invasion and migration of BC cells by activating the Wnt/ß-catenin signaling pathway through the downregulation of GSK3ß expression.

Enzalutamide as an androgen receptor inhibitor prevents urothelial tumorigenesis.

Emerging preclinical evidence suggests the critical role of androgen-mediated androgen receptor (AR) signals in the development of bladder cancer. However, little is known about the efficacy of enzalutamide, an AR signaling inhibitor, in androgen-induced urothelial tumorigenesis. We therefore aimed to assess the effects of enzalutamide on neoplastic transformation of urothelial cells. An immortalized normal urothelial cell line SVHUC stably expressing wild-type AR (SVHUC-AR) was exposed to a chemical carcinogen 3-methylcholanthrene (MCA) to induce neoplastic transformation, and subsequently cultured for 6 weeks in the presence of anti-androgens, including enzalutamide, hydroxyflutamide, and bicalutamide. Tumorigenesis was then monitored, using plate and soft agar colony formation assays as well as mouse xenograft models. In SVHUC-AR cells exposed to MCA, each anti-androgen inhibited AR-mediated transcriptional activity, but only enzalutamide prevented AR nuclear translocation. In vitro transformation showed that treatment with each anti-androgen during the process of neoplastic transformation reduced the efficiency of colony formation in vitro. Compared with mock treatment, culture with enzalutamide (P = 0.028), hydroxyflutamide (P = 0.033), or bicalutamide (P = 0.038) also resulted in prevention/retardation of tumor formation in male NOD-SCID mice. In addition, anti-androgens up-regulated the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and PTEN, and down-regulated that of several oncogenic genes, such as c-myc, cyclin D1, and cyclin E, in MCA-exposed SVHUC-AR cells. Thus, enzalutamide, flutamide, and bicalutamide were found to similarly prevent neoplastic transformation of urothelial cells. These findings offer a potential chemopreventive approach for urothelial tumors using AR antagonists.