Urinary exosomes: Potential diagnostic markers and application in bladder cancer.

Background: The exosome is a critical component of the intercellular communication., playing a vital role in regulating cell function. These small vesicles contain proteins, mRNAs, miRNAs, and lncRNAs, surrounded by lipid bilayer substances. Most cells in the human body can produce exosomes, released into various body fluids such as urine, blood, and cerebrospinal fluid. Bladder cancer is the most common tumor in the urinary system, with high recurrence and metastasis rates. Early diagnosis and treatment are crucial for improving patient outcomes. Methods: This study employed the PubMed search engine to retrieve publicly accessible data pertaining to urinary exosomes. Results: We summarize the origins and intricate biological characteristics of urinary exosomes, the introduction of research methodologies used in basic experiments to isolate and analyze these exosomes, the discussion of their applications and progress in the diagnosis and treatment of bladder cancer, and the exploration of the current limitations associated with using urinary exosomes as molecular biomarkers for diagnosing bladder cancer. Conclusion: Exosomes isolated from urine may be used as molecular biomarkers for early detection of bladder cancer.

Asymmetric Dearomatization of Indoles through Cobalt-Catalyzed Enantioselective C-H Functionalization Enabled by Photocatalysis.

Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition-metal-catalyzed asymmetric C-H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt-catalyzed enantioselective C-H activation reaction enabled by visible-light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96% to >99% ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.

The functions and mechanisms of RNA modification in prostate: Current status and future perspectives.

The increasing incidence and mortality of prostate cancer worldwide significantly impact the life span of male patients, emphasizing the urgency of understanding its pathogenic mechanism and associated molecular changes that regulate tumor progression for effective prevention and treatment. RNA modification, an important post-transcriptional regulatory process, profoundly influences tumor cell growth and metabolism, shaping cell fate. Over 170 RNA modification methods are known, with prominent research focusing on N6-methyladenosine, N7-methylguanosine, N1-methyladenosine, 5-methylcytidine, pseudouridine, and N4-acetylcytidine modifications. These alterations intricately regulate coding and non-coding RNA post-transcriptionally, affecting the stability of RNA and protein expression levels. This article delves into the latest advancements and challenges associated with various RNA modifications in prostate cancer tumor cells, tumor microenvironment, and core signaling molecule androgen receptors. It aims to provide new research targets and avenues for molecular diagnosis, treatment strategies, and improvement of the prognosis in prostate cancer.

circKDM1A suppresses bladder cancer progression by sponging miR-889-3p/CPEB3 and stabilizing p53 mRNA.

Circular RNAs (circRNAs) play crucial biological functions in various tumors, including bladder cancer (BCa). However, the roles and underlying molecular mechanisms of circRNAs in the malignant proliferation of BCa are yet unknown. CircKDM1A was observed to be downregulated in BCa tissues and cells. Knockdown of circKDM1A promoted the proliferation of BCa cells and bladder xenograft growth, while the overexpression of circKDM1A exerts the opposite effect. The dual-luciferase reporter assay revealed that circKDM1A was directly bound to miR-889-3p, acting as its molecular sponge to downregulate CPEB3. In turn, the CPEB3 was bound to the CPE signal in p53 mRNA 3'UTR to stabilize its expression. Thus, circKDM1A-mediated CPEB3 downregulation inhibits the stability of p53 mRNA and promotes BCa malignant progression. In conclusion, circKDM1A functions as a tumor suppressor in the malignant proliferation of BCa via the miR-889-3p/CPEB3/p53 axis. CircKDM1A may be a potential prognostic biomarker and therapeutic target of BCa.

The marine-derived compound TAG alleviates Parkinson's disease by restoring RUBCN-mediated lipid metabolism homeostasis.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and its prevalence is increasing. Currently, no effective therapies for PD exist. Marine-derived natural compounds are considered important resources for the discovery of new drugs due to their distinctive structures and diverse activities. In this study, tetrahydroauroglaucin (TAG), a polyketide isolated from a marine sponge, was found to have notable neuroprotective effects on MPTP/MPP+-induced neurotoxicity. RNA sequencing analysis and metabolomics revealed that TAG significantly improved lipid metabolism disorder in PD models. Further investigation indicated that TAG markedly decreased the accumulation of lipid droplets (LDs), downregulated the expression of RUBCN, and promoted autophagic flux. Moreover, conditional knockdown of Rubcn notably attenuated PD-like symptoms and the accumulation of LDs, accompanied by blockade of the neuroprotective effect of TAG. Collectively, our results first indicated that TAG, a promising PD therapeutic candidate, could suppress the accumulation of LDs through the RUBCN-autophagy pathway, which highlighted a novel and effective strategy for PD treatment.

Combined MRI-TRUS fusion targeted and systematic biopsy versus systematic biopsy alone for the detection of prostate cancer: protocol for a prospective single-centre trial.

INTRODUCTION: The classic way of diagnosing prostate cancer (PCa) is by conducting the 12-core systematic biopsy (SB). However, it has a low detection rate for clinically significant PCa (csPCa) and can lead to the detection of clinically insignificant PCa (cisPCa). Although MRI-transrectal ultrasound (MRI-TRUS) fusion targeted biopsy (TB) can effectively improve the detection rate of csPCa, it may still miss some cases. Therefore, we propose using a combination of TB and SB methods to enhance the detection rate of csPCa while minimising the detection rate of cisPCa. METHODS AND ANALYSIS: This study is a prospective, single-centre investigation that aims to assess and compare the detection rate of csPCa using MRI-TRUS fusion TB combined with SB versus TRUS 12-core SB alone. Biopsy-naïve men with suspected PCa will be subjected to multiparametric MRI. Patients with Prostate Imaging Reporting and Data System (V.2.1) score ≥3 will be enrolled in the TB-SB combination group. The sample size is established as 660 participants, considering a 10% drop-out rate. The primary outcome is the detection rate of csPCa in men without prior biopsy using MRI-TRUS fusion TB combined with the standard TRUS-guided 12-core SB method. CsPCa will be defined as International Society of Urological Pathology Grade ≥2. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee at the Shanghai Tenth People's Hospital, an affiliated hospital of Tongji University School of Medicine. The research results will be published in a peer-reviewed international journal. TRIAL REGISTRATION NUMBER: ChiCTR2000036089.

Can uric acid affect the immune microenvironment in bladder cancer? A single-center multi-omics study.

Metabolic abnormalities are one of the important factors in bladder cancer (BCa) progression and microenvironmental disturbance. As an important product of purine metabolism, uric acid's (UA) role in BCa metabolism and immunotherapy remains unclear. In this study, we conducted a retrospective analysis of a cohort comprising 39 BCa patients treated with PD-1 and 169 patients who underwent radical cystectomy at Shanghai Tenth People's Hospital. Kaplan-Meier curves and Cox regression analysis showed that the prognosis of patients with high UA is worse (p = 0.007), and high UA is an independent risk factor for cancer specific survival in patients with BCa (p = 0.025). We established a hyperuricemia mouse model with BCa subcutaneous xenografts in vivo. The results revealed that the subcutaneous tumors of hyperuricemia mice had a greater weight and volume in comparison with the control group. Through flow cytometric analysis, the proportion of CD8+ and CD4+ T cells in these subcutaneous tumors was seen to decline significantly. We also evaluated the relationship of UA and BCa by muti-omic analysis. UA related genes were significantly increased in the CD8+ T cell of non-responders to immunotherapy by single-cell sequencing. An 11-gene UA related signature was constructed and the risk score negatively correlated with various immune cells and immune checkpoints. Finally, a nomogram was established using a UA related signature to forecast the survival rate of patients with BCa. Collectively, this study demonstrated that UA was an independent prognostic biomarker for BCa and was associated with worse immunotherapy response.

Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage.

It is generally thought that under basal conditions, neurons produce ATP mainly through mitochondrial oxidative phosphorylation (OXPHOS), and glycolytic activity only predominates when neurons are activated and need to meet higher energy demands. However, it remains unknown whether there are differences in glucose metabolism between neuronal somata and axon terminals. Here, we demonstrated that neuronal somata perform higher levels of aerobic glycolysis and lower levels of OXPHOS than terminals, both during basal and activated states. We found that the glycolytic enzyme pyruvate kinase 2 (PKM2) is localized predominantly in the somata rather than in the terminals. Deletion of Pkm2 in mice results in a switch from aerobic glycolysis to OXPHOS in neuronal somata, leading to oxidative damage and progressive loss of dopaminergic neurons. Our findings update the conventional view that neurons uniformly use OXPHOS under basal conditions and highlight the important role of somatic aerobic glycolysis in maintaining antioxidant capacity.

Effect of tumor CD276 expression on infiltrating immune cells and clinicopathological features of prostate cancer.

BACKGROUND: Advanced prostate cancer (PCa) is often resistant to immunotherapy. In this study, we examined the role of CD276 in mediating immunotherapeutic effects through changes in immune cell infiltration. METHODS: Using transcriptomic and proteomic analyses, CD276 was identified as a potential target for immunotherapy. Subsequent in vivo and in vitro experiments confirmed its role as a potential mediator of immunotherapeutic effects. RESULTS: Multi-omic analysis suggested that CD276 was identified as a key molecule regulating the immune microenvironment (IM). In vivo experiments revealed that CD276 knockdown was found to enhance CD8+ T cell infiltration into the IM. Immunohistochemical analysis of PCa samples further confirmed the same findings. CONCLUSION: CD276 was found to inhibit the enrichment of CD8+ T cells in PCa. Thus, CD276 inhibitors may be potential targets for immunotherapy.

Corrigendum: MicroRNA-153 decreases tryptophan catabolism and inhibits angiogenesis in bladder cancer by targeting indoleamine 2,3-dioxygenase 1.

[This corrects the article DOI: 10.3389/fonc.2019.00619.].

Perioperative change of circulating tumor cells in cytoreductive radical prostatectomy for oligometastatic hormone-sensitive prostate cancer: the preliminary safety evidence from long-term oncologic outcomes.

Surgical manipulation has a risk of triggering the shedding of circulating tumor cells (CTCs) in patients with malignancies, However, perioperative change of circulating tumor cells in cytoreductive radical prostatectomy (CRP) for patients with oligometastatic hormone-sensitive prostate cancer (omHSPC) has not yet been well documented. This study aimed to assess whether CRP is a safe procedure for patients with omHSPC by monitoring the perioperative change of CTCs and investigating its impact on long-term oncologic outcomes. We have observed a significant decrease between the median CTC counts before and after surgery (6 vs. 4, p = 0.026). Comparing preoperative and postoperative CTC levels, seven patients increased (CTC increase group), one did not change and nineteen decreased (CTC non-increase group). PSA response rates in CTC increase group were lower than those in CTC non-increase group (73.0% vs 99.8%, p = 0.162), and nadir PSA was higher in CTC increase group (0.043 vs 0.003, p = 0.072). The CTC increase was positively correlated with the nadir PSA (r = 0.386, p = 0.047). The median follow-up period was 71.6 months, we found that there was no significant difference in clinical-pathological, operative variables or long-term oncologic outcomes between perioperative CTC increase and non-increase groups. In the entire cohort, the CTC level significantly decreased after surgery. There was no significant differences in long-term oncologic outcomes between the CTC increase and non-increase groups, implying that CRP potentially represents a safe procedure for the treatment of patients with omHSPC. The results need to be confirmed in a prospective large-scale clinical trial.

Bladder cancer-associated microbiota: Recent advances and future perspectives.

Recent evidence suggests that the human genitourinary microbiome plays a significant role in mediating the development and progression of urological tumors, including bladder cancer (BC). Clinicians widely recognize the role of Bacille Calmette Guérin (BCG), an attenuated Mycobacterium tuberculosis vaccine, in the management of intermediate- and high-risk NMIBC. However, compared to the large body of evidence on the gut microbiota and gastrointestinal tumors, limited information is available about the interaction between BC and the genitourinary microbiome. This is an expanding field that merits further investigation. Urologists will need to consider the potential impact of the microbiome in BC diagnosis, prevention of recurrence and progression, and treatment prospects in the future. This review highlights the approaches adopted for microbiome research and the findings and inadequacies of current research on BC.

Metabolic-associated signature and hub genes associated with immune microenvironment and prognosis in bladder cancer.

The relationship between metabolism and immune microenvironment remains to be studied in bladder cancer (BCa). We aimed to construct a metabolic-associated signature for prognostic prediction and investigate its relationship with the immune microenvironment in BCa. The RNA expression of metabolism associated genes was obtained from a combined data set including The Cancer Genome Atlas, GSE48075, and GSE13507 to divide BCa patients into different clusters. A metabolic-associated signature was constructed using the differentially expressed genes between clusters in the combined data set and validated in the IMvigor210 trial and our center. The composition of tumor-infiltrating immune cells (TIICs) was evaluated using the single-sample Gene Set Variation Analysis. BCa patients in Cluster A or high-risk level were associated with advanced clinicopathological features and poor survival outcomes. The percentage of high-risk patients was significantly lower in patients responding to anti-PD-L1 treatment. Compared with low-risk patients, the IC50 values of cisplatin and gemcitabine were significantly lower in high-risk patients. Thiosulfate transferase (TST) and S100A16 were significantly associated with clinicopathological features and prognosis. Downregulation of TST promoted BCa cell invasion, migration, and epithelial-to-mesenchymal transition, which are inhibited by downregulation of S100A16. CD8 + T cells, neutrophils, and dendritic cells had higher infiltration in the TST low-level and the S100A16 high-level. Furthermore, loss of function TST and S100A16 significantly affected the expression of PD-L1 and CD47. The metabolic-associated signature can stratify BCa patients into distinct risk levels with different immunotherapeutic susceptibility and survival outcomes. Metabolism disorder promoted the dysregulation of immune microenvironment, thus contributing to immunosuppression.

Urinary microbiota signatures associated with different types of urinary diversion: a comparative study.

Background: Radical cystectomy and urinary diversion (UD) are gold standards for non-metastatic muscle-invasive bladder cancer. Orthotopic neobladder (or Studer), ileal conduit (or Bricker) and cutaneous ureterostomy (CU) are mainstream UD types. Little is known about urinary microbiological changes after UD. Methods: In this study, urine samples were collected from healthy volunteers and patients with bladder cancer who had received aforementioned UD procedures. Microbiomes of samples were analyzed using 16S ribosomal RNA gene sequencing, and microbial diversities, distributions and functions were investigated and compared across groups. Results: Highest urine microbial richness and diversity were observed in healthy controls, followed by Studer patients, especially those without hydronephrosis or residual urine, α-diversity indices of whom were remarkably higher than those of Bricker and CU groups. Studer UD type was the only independent factor favoring urine microbial diversity. The urine microflora structure of the Studer group was most similar to that of the healthy individuals while that of the CU group was least similar. Studer patients and healthy volunteers shared many similar urine microbial functions, while Bricker and CU groups exhibited opposite characteristics. Conclusion: Our study first presented urinary microbial landscapes of UD patients and demonstrated the microbiological advantage of orthotopic neobladder. Microbiota might be a potential tool for optimization of UD management.

PHGDH Inhibits Ferroptosis and Promotes Malignant Progression by Upregulating SLC7A11 in Bladder Cancer.

Background: Bladder cancer (BCa) is a prevalent urologic malignancy that shows a poor prognosis. Abnormal metabolism and its key genes play a critical role in BCa progression. In this study, the role played by PhosphoGlycerol Dehydrogenase (PHGDH), an important molecule of serine metabolism, was investigated with regard to the regulation of ferroptosis in BCa. Methods: The BCa tissues of 90 patients were analyzed by RNA-sequencing for differential pathways and genes. Western blot, qPCR, and IHC were used to determine PHGDH expression in the cell lines (in vitro) and patient tissues (in vivo). R software was used to analyze PHGDH expression, prognosis, and PHGDH+SLC7A11 score. The biological functions of PHGDH were examined through organoids, and in vitro and in vivo experiments. C11 probes, electron microscopy, and ferroptosis inhibitors/ inducers were used to detect cellular ferroptosis levels. Protein profiling, co-IP, and RIP assays were used to screen proteins that might bind to PHGDH. PHGDH-targeted inhibitor NCT-502 was used to evaluate its effect on BCa cells. Results: PHGDH was highly expressed in patients with BCa. Knock-down of PHGDH promoted ferroptosis, while the decreased proliferation of BCa cells. Additionally, PHGDH knock-down downregulated the expression of SLC7A11. Co-IP and mass spectrometry experiments indicate that PHGDH binds to PCBP2, an RNA-binding protein, and inhibits its ubiquitination degradation. PCBP2 in turn stabilizes SLC7A11 mRNA and increases its expression. NCT-502, a PHGDH inhibitor, promotes ferroptosis and inhibits tumor progression in BCa. The PHGDH+ SLC7A11 score was significantly correlated with patient prognosis. Conclusions: To conclude, the PHGDH, via interaction with PCBP2, upregulates SLC7A11 expression. This inhibits ferroptosis and promotes the malignant progression of BCA. The results of this study indicated that NCT-502 could serve as a therapeutic strategy for BCa.

Erratum: Depletion of CDC5L inhibits bladder cancer tumorigenesis: Erratum.

[This corrects the article DOI: 10.7150/jca.32850.].

Urological cancer organoids, patients' avatars for precision medicine: past, present and future.

Urological cancers are common malignant cancers worldwide, with annually increasing morbidity and mortality rates. For decades, two-dimensional cell cultures and animal models have been widely used to study the development and underlying molecular mechanisms of urological cancers. However, they either fail to reflect cancer heterogeneity or are time-consuming and labour-intensive. The recent emergence of a three-dimensional culture model called organoid has the potential to overcome the shortcomings of traditional models. For example, organoids can recapitulate the histopathological and molecular diversity of original cancer and reflect the interaction between cancer and surrounding cells or stroma by simulating tumour microenvironments. Emerging evidence suggests that urine-derived organoids can be generated, which could be a novel non-invasive liquid biopsy method that provides new ideas for clinical precision therapy. However, the current research on organoids has encountered some bottlenecks, such as the lack of a standard culture process, the need to optimize the culture medium and the inability to completely simulate the immune system in vivo. Nonetheless, cell co-culture and organoid-on-a-chip have significant potential to solve these problems. In this review, the latest applications of organoids in drug screening, cancer origin investigation and combined single-cell sequencing are illustrated. Furthermore, the development and application of organoids in urological cancers and their challenges are summarised.

DJ-1 inhibits glutathione degradation by downregulating CHAC1 expression in astrocytes.

The PARK7 gene, which encodes DJ-1 protein, is the causative gene of autosomal recessive early-onset Parkinson's disease. DJ-1 has many biological functions, including regulating glutathione (GSH) levels. However, the molecular mechanism by which DJ-1 regulates GSH levels in astrocytes remains unclear. With high throughput sequencing, we discovered that DJ-1 knockout could significantly upregulate the expression of ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1). We demonstrate that DJ-1 can bind with the basic leucine zipper domain of activating transcription factor 3 (ATF3) through bimolecular fluorescence complementation. Besides, DJ-1 inhibits ATF3 binding to the CHAC1 promoter and downregulates the expression of CHAC1 to reduce GSH degradation. Our research suggests that the loss of DJ-1 in astrocytes promotes the degradation of GSH, leading neurons more vulnerable to oxidative damage. It provides a theoretical basis for developing drugs targeting DJ-1 and GSH in the brain.

Gender dimorphism in survival of patients with lymph node metastasis of bladder cancer.

Background: The effect of gender on the prognosis of bladder cancer (BCa) in different metastatic sites is insufficiently understood. We aimed to assess the impact and potential mechanisms of a combination of gender dimorphism and BCa metastasis sites on the risk of death. Methods: Independent predictors of overall survival and cancer-specific survival were analyzed after stratification by gender and metastasis sites from the Surveillance, Epidemiology, and End Results database. Furthermore, gender-differentially expressed genes (DEGs) and function-enriched annotations for patients with lymph node metastasis (LNM) were identified from The Cancer Genome Atlas (TCGA) database. A gender-associated signature was constructed in TCGA and validated in the IMvigor210 trial, and the magnetic resonance imaging-based radiomics signature was developed in our center to predict the gender-associated signature. Results: In patients with metastatic BCa, the most common site of metastasis is bone in men and lung in women. Moreover, stratified by sex, LNM had a better prognosis in men than visceral metastasis, which was not observed in female. Similarly, stratified by the metastasis site, the prognosis of men in patients with LNM is better than that of women, which was not observed in visceral metastasis patients. Enrichment of DEGs between sexes in patients with LNM may be related to metastasis and tumor immunity, especially the role of neutrophils. Moreover, the gender-associated signature is related to the clinicopathological characteristics of patients, and patients in the high-risk group had worse survival outcomes, and higher susceptibility to cisplatin, docetaxel, camptothecin, and paclitaxel. A nomogram combined with the signature and clinical staging showed significant predictive power in survival prediction. Furthermore, patients with high radiomics scores had a strong tendency for high-risk group. Conclusion: These results may improve the understanding of the differences in tumor biology between sexes and thus provide additional evidence for individualized treatment in BCa.

Causes of Death after Prostate Cancer Diagnosis: A Population-Based Study.

Background: Mortality from noncancer causes in patients with prostate cancer (PCa) is unclear. This study assesses the causes and risks of noncancer death with each follow-up time period after PCa diagnosis. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) program were analyzed for noncancer causes of death in PCa patients from 2000 to 2016. The standard mortality ratio (SMR) was calculated for noncancer mortality. Results: Altogether, 752,352 patients with PCa were identified, and 180,862 (24.0%) died during follow-up. The largest proportion of deaths from noncancer causes (36%) occurred within 5 to 10 years after diagnosis. The most common causes of noncancer death are cardiovascular and cerebrovascular diseases and chronic obstructive pulmonary disease (COPD). Compared with the general age-matched male population, patients with PCa had a higher risk of death from any noncancer cause within 5 years, in particular other infectious diseases and suicide and self-inflicted injury. However, the risk of death from noncancer causes of PCa for more than 5 years is lower, except for Alzheimer's disease and hypertension from 5 to 10 years after diagnosis. In addition, the risk of death from noncancer causes was influenced by treatment, ethnicity, and staging differences. In particular, compared with the general population, many noncancer causes of death have higher risk of death in patients with or without treatment within 1 to 5 years after diagnosis, whereas patients undergoing radical prostatectomy (RP) with or without radiotherapy (RT) or chemotherapy (CTx) are not at high risk of death from COPD, pneumonia and influenza, nephritis, nephrotic syndrome and nephrosis, septicemia, and atherosclerosis. Conclusion: The risk of death from noncancer causes gradually decreased in all patients with PCa during each follow-up period after diagnosis In addition, the risk of dying from noncancer causes are influenced by differences in stage, ethnicity, and treatment. In particular, patients undergoing RP±RT/CTx and RT/CTx have a lower risk of death compared to the general population. These findings provide important implications for the healthcare management of patients with PCa.