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Sonodynamic therapy (SDT), a novel noninvasive therapeutic modality, provides many noteworthy benefits by generating reactive oxygen species (ROS). However, water-insoluble sonosensitizer delivery strategies have continuously underperformed because of unavoidable toxicity and a short circulation time. In this study, l-cystine derivative-based biocompatible nanoparticles (NPs) that can be used in SDT and induce limited cytotoxicity are designed and synthesized. After ultrasonic (US) irradiation, these sonosensitizer-loaded NPs show highly efficient sonodynamic performance that leads to cytotoxic ROS production. The ability to stop and start ROS generation induced by US irradiation enables accurate temporal and spatial control. In vivo and in vitro experiments are systematically performed to investigate the effects of this system on tumors, and the results indicate remarkable tumor suppression via markedly high persistent oxidative stress that induces peroxidation and endoplasmic reticulum stress. Thus, this novel temporally and spatially controllable ROS generation platform offers a safe and effective theranostic strategy for prostate cancer treatment.

Graphical abstract, MicroRNA (miRNA) deregulation plays a critical role in the heterogeneous development of prostate cancer (PCa) by tuning mRNA levels. Herein, we aimed to characterize the molecular features of PCa by clustering the miRNA-regulated transcriptome with non-negative matrix factorization. Using 478 PCa samples from The Cancer Genome Atlas, four molecular subtypes (S-I, S-II, S-III, and S-IV) were identified and validated in two merged microarray and RNAseq datasets with 656 and 252 samples, respectively. Interestingly, the four subtypes showed distinct clinical and biological features after comprehensive analyses of clinical features, multiomic profiles, immune infiltration, and drug sensitivity. S-I is basal/stem/mesenchymal-like and immune-excluded with marked transforming growth factor β, epithelial-mesenchymal transition and hypoxia signals, increased sensitivity to olaparib, and intermediate prognosis. S-II is luminal/metabolism-active and responsive to androgen deprivation therapy with frequent TMPRSS2-ERG fusion and a good prognosis. S-III is characterized by moderate proliferative and metabolic activity, sensitivity to taxane-based chemotherapy, and intermediate prognosis. S-IV is highly proliferative with moderate EMT and stemness, frequent deletions of TP53, PTEN and RB, and the poorest prognosis; it is also immune-inflamed and sensitive to anti-PD-L1 therapy. Overall, based on miRNA-regulated gene profiles, this study identified four distinct PCa subtypes that could improve risk stratification at diagnosis and provide therapeutic guidance.

Transcriptional addiction plays a pivotal role in maintaining the hallmarks of cancer cells. Thus, targeting super-enhancers (SEs), which modulate the transcriptional activity of oncogenes, has become an attractive strategy for cancer therapy. As yet, however, the molecular mechanisms of this process in bladder cancer (BC) remain to be elucidated. Here, we aimed to provide detailed information regarding the SE landscape in BC and to investigate new potential pharmaceutical targets for BC therapy. We employed THZ1 as a potent and specific CDK7 inhibitor. In vitro and in vivo studies were carried out to investigate the anticancer and apoptosis-inducing effects of THZ1 on BC cells. Whole-transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to investigate the mechanism and function of SE-linked oncogenic transcription in BC cells. We found that THZ1 serves as an effective and potent inhibitor with suppressive activity against BC cells. An integrative analysis of THZ1-sensitive and SE-associated oncogenes yielded potential new pharmaceutical targets, including DDIT4, B4GALT5, PSRC1 and MED22. Combination treatment with THZ1 and the DDIT4 inhibitor rapamycin effectively suppressed BC cell growth. In addition, we found that THZ1 and rapamycin sensitized BC cells to conventional chemotherapy. Our data indicate that exploring BC gene regulatory mechanisms associated with SEs through integrating RNA-seq and ChIP-seq data improves our understanding of BC biology and provides a basis for innovative therapies.

Background: The biomarkers have an important guiding role in prognosis and treatment of patients with bladder cancer(BC). The aim of the present study was to identify and evaluate a prognostic gene signature in BC patients.Methods: The gene expression profiles of BC samples and the corresponding clinicopathological data were downloaded from GEO and TCGA. The differentially expressed genes (DEGs) were identified by R software. Univariate Cox regression and the least absolute shrinkage and selection operator(LASSO) Cox regression were applied to construct the prognostic score model. A nomogram was established with the identified prognostic factors to predict the overall survival rates of BC patients. The discriminatory and predictive capacity of the nomogram was evaluated based on the concordance index (C-index), calibration curves and decision curve analysis (DCA).Results: A 7-gene signature(KLRB1, PLAC9, SETBP1, NR2F1, GRHL2, ANXA1 and APOL1) was identified from 285 DEGs by univariate and LASSO Cox regression analyses. Univariate and multivariate Cox regression analyses showed that age, lymphovascular invasion, lymphatic metastasis, metastasis and the 7-gene signature risk score was an independent predictor of BC patient prognosis. A nomogram that integrated these independent prognostic factors was constructed. The C-index (0.73, CI 95%, 0.693–0.767) and calibration curve demonstrated the good performance of the nomogram. DCA of the nomogram further showed that this model exhibited good net benefit.Conclusions: The combined 7-gene signature could serve as a biomarker for predicting BC prognosis. The nomogram built by risk score and other clinical factors could be an effective tool for predicting the prognosis of patients with BC.

Objective: To develop and validate a non-invasive MRI-based radiomics signature for distinguishing between indolent and aggressive prostate cancer (PCa) prior to therapy. Methods: In all, 139 qualified and pathology-confirmed PCa patients were divided into a training set (n = 93) and a validation set (n = 46). A total of 1576 radiomics features were extracted from the T2WI (n = 788) and diffusion-weighted imaging (n = 788) for each patient. The Select K Best and the least absolute shrinkage and selection operator regression algorithm were used to construct a radiomics signature in the training set. The predictive performance of the radiomics signature was assessed in the training set and then validated in the validation set by receiver operating characteristic curve analysis. We computed the calibration curve and the decision curve to evaluate the calibration and clinical usefulness of the signature. Results: Nine radiomics features were identified to form the radiomics signature. The radiomics score (Rad-score) was significantly different between indolent and aggressive PCa (p < 0.001). The radiomics signature exhibited favorable discrimination between the indolent and aggressive PCa groups in the training set (AUC: 0.853, 95% CI: 0.766 to 0.941) and validation set (AUC: 0.901, 95% CI: 0.793 to 1.000). The decision curve analysis showed that a greater net benefit would be obtained when the threshold probability ranged from 20 to 90%. Conclusion: The multiparametric MRI-based radiomics signature can potentially serve as a non-invasive tool for distinguishing between indolent and aggressive PCa prior to therapy. Advances in knowledge: The multiparametric MRI-based radiomics signature has the potential to non-invasively distinguish between the indolent and aggressive PCa, which might aid clinicians in making personalized therapeutic decisions.

Androgen receptor (AR) signaling inhibitors provide limited survival benefits to patients with prostate cancer (PCa), and worse, few feasible genomic lesions restrict targeted treatment to PCa. Thus, a better understanding of the critical dependencies of PCa may enable more feasible therapeutic approaches to the dilemma. We performed a kinome-scale CRISPR/Cas9 screen and identified cyclin-dependent kinase 12 (CDK12) as being conservatively required for PCa cell survival. Suppression of CDK12 by the covalent inhibitor THZ531 led to an obvious anti-PCa effect. Mechanistically, THZ531 downregulated AR signaling and preferentially repressed a distinct class of CDK12 inhibition-sensitive transcripts (CDK12-ISTs), including prostate lineage-specific genes, and contributed to cellular survival processes. Integration of the super-enhancer (SE) landscape and CDK12-ISTs indicated a group of potential PCa oncogenes, further conferring the sensitivity of PCa cells to CDK12 inhibition. Importantly, THZ531 strikingly synergized with multiple AR antagonists. The synergistic effect may be driven by attenuated H3K27ac signaling on AR targets and an intensive SE-associated apoptosis pathway. In conclusion, we highlight the validity of CDK12 as a druggable target in PCa. The synergy of THZ531 and AR antagonists suggests a potential combination therapy for PCa.

AURKA is a potential kinase target in various malignancies. The kinase-independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN-based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP-based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the "mitotic cell cycle" and "stem cell" processes, while dAurA450 inhibits the "MYC/E2F targets" and "stem cell" processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial-temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent cancer stem cell-mediated drug resistance.

Transcriptional addiction plays a pivotal role in maintaining the hallmarks of cancer cells. Thus, targeting super-enhancers (SEs), which modulate the transcriptional activity of oncogenes, has become an attractive strategy for cancer therapy. As yet, however, the molecular mechanisms of this process in bladder cancer (BC) remain to be elucidated. Here, we aimed to provide detailed information regarding the SE landscape in BC and to investigate new potential pharmaceutical targets for BC therapy.We employed THZ1 as a potent and specific CDK7 inhibitor. In vitro and in vivo studies were carried out to investigate the anticancer and apoptosis-inducing effects of THZ1 on BC cells. Whole-transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to investigate the mechanism and function of SE-linked oncogenic transcription in BC cells.We found that THZ1 serves as an effective and potent inhibitor with suppressive activity against BC cells. An integrative analysis of THZ1-sensitive and SE-associated oncogenes yielded potential new pharmaceutical targets, including DDIT4, B4GALT5, PSRC1 and MED22. Combination treatment with THZ1 and the DDIT4 inhibitor rapamycin effectively suppressed BC cell growth. In addition, we found that THZ1 and rapamycin sensitized BC cells to conventional chemotherapy.Our data indicate that exploring BC gene regulatory mechanisms associated with SEs through integrating RNA-seq and ChIP-seq data improves our understanding of BC biology and provides a basis for innovative therapies.

BACKGROUND Skeleton is a preferred site for prostate cancer metastasis, and once metastases occur, the disease becomes incurable. Increasing evidence indicated the prognostic value of skeletal related parameters, but remains controversy. OBJECTIVE To perform a systematic review of the existing literature on assessing the prognostic value of alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BSAP), urinary N-telopeptide (uNTx), bone scan index (BSI) and Brief Pain Inventory Short Form (BPI-SF) score in castration-resistant prostate cancer (CRPC) patients with skeleton metastasis. EVIDENCE ACQUISITION PubMed, Web of Science, Cochrane Library, Medline, OVID, and Embase between 2010 and 2019 were reviewed. Key terms included randomized trials, prostate cancer, alkaline phosphatase, bone-specific alkaline phosphatase, urinary N-telopeptide, bone scan index and Brief Pain Inventory Short Form. Data were collected, checked, and analyzed from December 2019 to March 2020. Hazard ratios (HRs), overall survival (OS) were extracted to estimate the relationship between the parameters above and OS in patients with metastatic prostate cancer (mPCa). EVIDENCE SYNTHESIS Totally 1055 studies were identified in initial screening, including 1032 from database searching and 23 from other sources. After removing the duplicates, 164 records were further excluded according to tittle and abstract. Remaining 36 potential articles were screened carefully and finally 15 eligible studies syntheses, which were published between 2010 and 2019, comprised data for a total of 11,378 patients, whose mean age ranged from 66 to 72 years old. The sample size ranged from 82 to 1901 patients. And the median follow-up time ranged from 24-55 months. Based on 15 randomized controlled trials published between 2010 and 2019, including 11378 patients. The higher ALP levels (HR=1.60, 95% CI: 1.38-1.87 P

OBJECTIVES To explore the risk factors for systemic inflammatory response syndrome (SIRS) after percutaneous nephrolithotomy (PCNL). METHODS A retrospective chart review was performed to identify 1030 patients who had undergone PCNL from January 2014 to July 2016 in the Minimally Invasive Surgery Center. Multiple data, including age, sex, body mass index (BMI), operation time, Staghorn calculi, diabetes, Serun creatinine, preoperative urine culture and the urinary sediment microscopy white blood cell (WBC) were collected. These factors and postoperative SIRS were retrospectively analyzed. RESULTS There were 108 cases (10.49%) of SIRS among 1030 patients. The results of univariate analysis showed that sex (P=0.015), Staghorn calculi (P

The purpose of the present study was to identify key genes and investigate the related molecular mechanisms of bladder cancer (BC) progression. From the Gene Expression Omnibus database, the gene expression dataset GSE7476 was downloaded, which contained 43 BC samples and 12 normal bladder tissues. GSE7476 was analyzed to screen the differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for the DEGs using the DAVID database, and a protein‑protein interaction (PPI) network was then constructed using Cytoscape software. The results of the GO analysis showed that the upregulated DEGs were significantly enriched in cell division, nucleoplasm and protein binding, while the downregulated DEGs were significantly enriched in 'extracellular matrix organization', 'proteinaceous extracellular matrix' and 'heparin binding'. The results of the KEGG pathway analysis showed that the upregulated DEGs were significantly enriched in the 'cell cycle', whereas the downregulated DEGs were significantly enriched in 'complement and coagulation cascades'. JUN, cyclin‑dependent kinase 1, FOS, PCNA, TOP2A, CCND1 and CDH1 were found to be hub genes in the PPI network. Sub‑networks revealed that these gene were enriched in significant pathways, including the 'cell cycle' signaling pathway and 'PI3K‑Akt signaling pathway'. In summary, the present study identified DEGs and key target genes in the progression of BC, providing potential molecular targets and diagnostic biomarkers for the treatment of BC.

The present study aimed to investigate the gene expression changes in prostate cancer (PC) and screen the hub genes and associated pathways of PC progression. The authors employed integrated analysis of GSE46602 downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases to identify 484 consensual differentially expressed genes (DEGs) in PC, when compared with adjacent normal tissue samples. Functional annotation and pathway analysis were performed. The protein-protein interaction (PPI) networks and module were constructed. RT-qPCR was used to validate the results in clinical PC samples. Survival analysis of hub genes was performed to explore their clinical value. GO analysis results revealed that DEGs were significantly enriched in negative regulation of nitrobenzene metabolic process, extracellular space and protein homodimerization activity. KEGG pathway analysis results revealed that DEGs were most significantly enriched in focal adhesion. The top 10 hub genes were identified to be hub genes from the PPI network, and the model revealed that these genes were enriched in various pathways, including neuroactive ligand-receptor interaction, p53 and glutathione metabolism signaling pathways. RT-qPCR results validated that expression levels of eight genes (PIK3R1, BIRC5, ITGB4, RRM2, TOP2A, ANXA1, LPAR1 and ITGB8) were consistent with the bioinformatics analysis. ITGB4 and RRM2 with genetic alterations exhibited association with a poorer survival rate, compared with those without alterations. These results revealed that PC-related genes and pathways have an important role in tumor expansion, metastasis and prognosis. In summary, these hub genes and related pathways may act as biomarkers or therapeutic targets for PC.

The purpose of the study was to present our experience of retaining encrusted ureteral stents (EUS) and discuss the effectiveness of 4.5/6.5F ureteroscope (URS) in the procedure. The data of patients with EUS in our center from January 2012 to December 2016 were retrospectively analyzed. The inclusion criterion was ureteral stents that required intervention above the ureteral orifice to retain and was proved to be encrusted. Impacted stents would be removed by ureteroscope lithotripsy (URL) via 8/9.8F or 4.5/6.5F URS. Percutaneous nephrolithotomy (PCNL) then be the further step if URL failed. 46 cases of EUS were treated in 36 patients from January 2012 to December 2016 in our institution. All subjects consisted of 18 males and 18 females; the average age was 49.81 ± 16.40 years (range 5–86). The mean time from stent insertion to encrustation was 9.28 ± 17.15 months (range 1–120). URL was performed in 44 cases (95.7%), including 19 cases (41.3%) by 8/9.8F URS and 25 cases (54.4%) by 4.5/6.5F URS due to the conventional URS’s failure to get into ureteral orifice or further part of ureter. Two patients (4.3%) underwent PCNL due to the inseparable circle developed by the intra-renal segment of encrusted stents. None of the patients underwent extracorporeal shock wave lithotripsy (ESWL) and open surgery. All stents were eventually removed without blood transfusion or ureteral injury, except three cases with post-operative fever. All procedures were performed under one-session anesthesia. URL by 4.5/6.5F ureteroscope might increase the success rate of retaining encrusted ureteral stents remarkably, and then reduce the possibility of PCNL effectively.

According to the literature and our experimental results, it was found that (1) the suitability of the energy gap between the excited triplet energy level of the ligands and the lowest excited energy level of Ln3+ is a critical factor for sensitized luminescence of the central Ln3+; (2) the high intensity of the sensitized luminescence of Ln3+ should be caused by a rigid planar molecular structure of the complex; (3) the existence of both a suitable conjugated system and ideal coordinating groups should be considered for ligand-design.