Predicting Clinically Significant Prostate Cancer Using Urine Metabolomics via Liquid Chromatography Mass Spectrometry.

PURPOSE: Biomarkers predicting clinically significant prostate cancer (sPC) before biopsy are currently lacking. This study aimed to develop a non-invasive urine test to predict sPC in at-risk men using urinary metabolomic profiles. MATERIALS AND METHODS: Urine samples from 934 at-risk subjects and 268 treatment-naïve PC patients were subjected to liquid chromatography/mass spectrophotometry (LC-MS)-based metabolomics profiling using both C18 and hydrophilic interaction liquid chromatography (HILIC) column analyses. Four models were constructed (training cohort [n=647]) and validated (validation cohort [n=344]) for different purposes. Model I differentiates PC from benign cases. Models II, III, and a Gleason score model (model GS) predict sPC that is defined as National Comprehensive Cancer Network (NCCN)-categorized favorable-intermediate risk group or higher (Model II), unfavorable-intermediate risk group or higher (Model III), and GS ≥7 PC (model GS), respectively. The metabolomic panels and predicting models were constructed using logistic regression and Akaike information criterion. RESULTS: The best metabolomic panels from the HILIC column include 25, 27, 28 and 26 metabolites in Models I, II, III, and GS, respectively, with area under the curve (AUC) values ranging between 0.82 and 0.91 in the training cohort and between 0.77 and 0.86 in the validation cohort. The combination of the metabolomic panels and five baseline clinical factors that include serum prostate-specific antigen, age, family history of PC, previously negative biopsy, and abnormal digital rectal examination results significantly increased AUCs (range 0.88-0.91). At 90% sensitivity (validation cohort), 33%, 34%, 41%, and 36% of unnecessary biopsies were avoided in Models I, II, III, and GS, respectively. The above results were successfully validated using LC-MS with the C18 column. CONCLUSIONS: Urinary metabolomic profiles with baseline clinical factors may accurately predict sPC in men with elevated risk before biopsy.

Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

Comparison of Pathological Outcome and Recurrence Rate between En Bloc Transurethral Resection of Bladder Tumor and Conventional Transurethral Resection: A Meta-Analysis.

Current treatment for non-muscle invasive bladder cancer (NMIBC) is the conventional transurethral resection of bladder tumor (CTURBT), but the en bloc transurethral resection of bladder tumor (ERBT) has been gaining more attraction in recent years considering better specimen integrity. Thus, we conducted this meta-analysis to compare the safety and efficacy of ERBT versus CTURBT. Trials were collected from an online database. The primary outcomes included identification of detrusor muscle in specimen, residual tumor, 3, 12, and 24-month recurrence rates and same-site recurrence rate. A total of 31 trials were included. The ERBT group had a higher rate of identification of detrusor muscle in specimens (p = 0.003) and lower residual tumor (p < 0.001). Other than that, lower rates of 3-month (p = 0.005) and 24-month recurrence rate (p < 0.001), same-site recurrence rate (p < 0.001) and complications were also observed. For perioperative outcomes, shorter hospitalization time (HT) (p < 0.001), and catheterization time (CT) (p < 0.001) were also revealed in the ERBT group. No significant difference was found in operative time (OT) (p = 0.93). The use of ERBT showed better pathological outcomes and fewer complications, so it could be considered a more effective treatment option for NMIBC.

NKG2A and circulating extracellular vesicles are key regulators of natural killer cell activity in prostate cancer after prostatectomy.

Extracellular vesicles (EVs) are an important regulatory factor for natural killer cell activity (NKA) in the tumor microenvironment. The relationship between circulating EVs in the peripheral blood and natural killer (NK) cells in prostate cancer (PCa) is unclear. This study aimed at investigating the key regulators in the interaction between circulating EVs and NK cells in PCa patients before and after tumor removal. NK-cell characteristics were prospectively assessed in 79 patients treated with robot-assisted laparoscopic radical prostatectomy preoperatively and postoperatively. Compared with healthy donors, the existence of prostate tumors increased the number of circulating EVs and altered ligand expression of EVs. Circulating EVs extracted from cancer patients significantly decreased NKA of NK cells compared with those extracted from healthy donors. Upon treatment with an inhibiting antibody or small interfering RNA, natural killer cell protein group 2A (NKG2A) was identified as the main NKA regulator in cancer patients for accepting the signal from circulating EVs. After surgery, NKA was increased and NKG2A expression on NK cells was significantly reduced. The expression of ligands for natural killer cell protein group 2D (NKG2D) on EVs and the level of circulation EVs both significantly increased. With the decrease in NKG2A levels on NK cells and the increase in total NKG2D ligands on circulating EVs, which was increased postoperatively, both NKG2A on NK cells and NKG2D ligands on circulating exosomes are main regulators of NKA restoration after prostatectomy.

Antimicrobial Peptide LCN2 Inhibited Uropathogenic Escherichia coli Infection in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway.

JAK/STAT plays a key role in regulating uropathogenic Escherichia coli (UPEC) infection in urothelial cells, probably via antimicrobial peptide (AMP) production, in diabetic patients with urinary tract infections. Whether multiple pathways regulate AMPs, especially lipid-carrying protein-2 (LCN2), to achieve a vital effect is unknown. We investigated the effects of an LCN2 pretreatment on the regulation of the JAK/STAT pathway in a high-glucose environment using a bladder cell model with GFP-UPEC and phycoerythrin-labeled TLR-4, STAT1, and STAT3. Pretreatment with 5 or 25 µg/mL LCN2 for 24 h dose-dependently suppressed UPEC infections in bladder cells. TLR-4, STAT1, and STAT3 expression were dose-dependently downregulated after LCN2 pretreatment. The LCN2-mediated alleviation of UPEC infection in a high-glucose environment downregulated TLR-4 and the JAK/STAT transduction pathway and decreased the UPEC-induced secretion of exogenous inflammatory interleukin (IL)-6 and IL-8. Our study provides evidence that LCN2 can alleviate UPEC infection in bladder epithelial cells by decreasing JAK/STAT pathway activation in a high-glucose environment. LCN2 dose-dependently inhibits UPEC infection via TLR-4 expression and JAK/STAT pathway modulation. These findings may provide a rationale for targeting LCN2/TLR-4/JAK/STAT regulation in bacterial cystitis treatment. Further studies should explore specific mechanisms by which the LCN2, TLR-4, and JAK/STAT pathways participate in UPEC-induced inflammation to facilitate the development of effective therapies for cystitis.

Complete intraureteral stent placement reduces stent-related symptoms: Systemic review and meta-analysis.

PURPOSE: The distal coil of a double-J ureteral stent is considered the major cause of stent-related symptoms. We noticed that some recent studies investigated whether complete intraureteral stent placement (CIU-SP) reduced these symptoms. The current systemic review and meta-analysis aimed to evaluate the safety and the effectiveness of CIU-SP, as compared to conventional stent placement (C-SP). METHODS: We retrieved relevant trials published before December 2021 from three databases, including PubMED, Embase, and Web of Science. The following medical subject heading were used ((complete intraureteral stent) OR (suture stent)) AND (symptom OR pain) AND (randomized OR randomised). The above search was limited to English language publication. RESULTS: We identified six prospective randomized trials, all of which investigated a short-term (1-2 weeks) stent placement following uncomplicated ureteroscopic lithotripsy. The meta-analysis revealed that CIU-SP significantly reduced stent-related symptoms: CIU-SP had lower USSQ (Ureteral Stent Symptom Questionnaire) Urinary Symptom Index score (MD -5.13; 95%CI [-5.82,-4.44]; P < 0.00001), lower USSQ Pain Index score (MD -4.21; 95%CI [-5.25,-3.17]; P < 0.00001), and lower VAS pain scale (MD -1.93; 95%CI [-2.17,-1.69]; p < 0.00001). Besides, patients with CIU-SP were less likely to have pain (RR 0.78; 95%CI [0.67,0.91]; p = 0.001). There was no significant difference regarding the USSQ General Health and Work Performance. Both CIU-SP and C-SP had similarly few complications of Clavien-Dindo grade ≥2. CONCLUSION: This meta-analysis reveals that CIU-SP significantly decreases stent-related urinary symptoms and pain. Based on the current evidence, CIU-SP is ready to be applied in clinical practice, at least in those requiring short-term stent placement following uncomplicated ureteroscopic lithotripsy.

RNase 7 Inhibits Uropathogenic Escherichia coli-Induced Inflammation in Bladder Cells under a High-Glucose Environment by Regulating the JAK/STAT Signaling Pathway.

Antimicrobial peptides (AMPs), which are natural antibiotics, protect against pathogens invading the urinary tract. RNase 7 with antimicrobial properties has rapid and powerful suppressive effects against Gram-positive and Gram-negative bacterial infections. However, its detailed antibacterial mechanisms have not been fully determined. Here, we investigate whether RNase 7 had an impact on bladder cells under uropathogenic Escherichia coli (UPEC) infection in a high-glucose environment using in vitro GFP-UPEC-infected bladder cell and PE-labeled TLR4, STAT1, and STAT3 models. We provide evidence of the suppressive effects of RNase 7 on UPEC infection and UPEC-induced inflammatory responses by regulating the JAK/STAT signaling pathway using JAK inhibitor and STAT inhibitor blocking experiments. Pretreatment with different concentrations of RNase 7 for 24 h concentration-dependently suppressed UPEC invasion in bladder cells (5 µg/mL reducing 45%; 25 µg/mL reducing 60%). The expressions of TLR4, STAT1, and STAT3 were also downregulated in a concentration-dependent manner after RNase 7 pretreatment (5 µg/mL reducing 35%, 54% and 35%; 25 µg/mL reducing 60%, 75% and 64%, respectively). RNase 7-induced decrease in UPEC infection in a high-glucose environment not only downregulated the expression of TLR4 protein and the JAK/STAT signaling pathway but also decreased UPEC-induced secretion of exogenous inflammatory IL-6 and IL-8 cytokines, although IL-8 levels increased in the 25 µg/mL RNase 7-treated group. Thus, inhibition of STAT affected pSTAT1, pSTAT3, and TLR4 expression, as well as proinflammatory IL-6 and IFN-γ expression. Notably, blocking JAK resulted in the rebound expression of related proteins, especially pSTAT1, TLR4, and IL-6. The present study showed the suppressive effects of RNase 7 on UPEC infection and induced inflammation in bladder epithelial cells in a high-glucose environment. RNase 7 may be an anti-inflammatory and anti-infective mediator in bladder cells by downregulating the JAK/STAT signaling pathway and may be beneficial in treating cystitis in DM patients. These results will help clarify the correlation between AMP production and UTI, identify the relationship between urinary tract infection and diabetes in UTI patients, and develop novel diagnostics or possible treatments targeting RNase 7.

Switched phenotypes of macrophages during the different stages of Schistosoma japonicum infection influenced the subsequent trends of immune responses.

BACKGROUND: Macrophages play crucial roles in immune responses during the course of schistosomal infections. METHODS: We currently investigated influence of immunocompetent changes in macrophages via microarray-based analysis, mRNA expression analysis, detection of serum cytokines, and subsequent evaluation of the immune phenotypes following the differentiation of infection-induced lymphocytes in a unique T1/T2 double-transgenic mouse model. RESULTS: The gradual upregulation of genes encoding YM1, YM2, and interleukin (IL)-4/IL-13 receptors in infected mice indicated the role of type 2 alternatively activated macrophages (M2, AAMφs) in immune responses after Schistosoma japonicum egg production. FACS analysis showed that surface markers MHC class II (IA/IE) and CD8α+ of the macrophages also exhibited a dramatic change at the various time points before and after egg-production. The transgenic mouse experiments further demonstrated that the shifting of macrophage phenotypes influenced the percentage of helper T (Th)-2 cells, which was observed to be higher than that of Th1 cells, which increased only at 3 and 5 weeks post-infection. The differentiation of effector B cells showed a similar but more significant trend toward type-2 immunity. CONCLUSION: These results suggest that the infection of mice with S. japonicum resulted in a final Th2- and Be2-skewed immune response. This may be due to phenotypic changes in the macrophages. The influence of alternatively activated macrophages was also activated by S. japonicum egg production. This study elucidated the existence of variations in immune mechanisms at the schistosome infection stages.

Concomitant High Apoptosis Inhibitor of Macrophage (AIM) and Low Prostate-Specific Antigen (PSA) Indicates Activated T Cell-Mediated Anticancer Immunity, Enhance Sensitivity to Pembrolizumab, and Elicit Good Prognosis in Prostate Cancer.

BACKGROUND: Despite its widespread use, the use of prostate-specific antigen (PSA) alone as a screening biomarker for prostate cancer (PCa) leads often to unwarranted prostate biopsy, over-diagnosis, and consequently, over-treatment, because of its limited specificity. There are reports that the apoptosis inhibitor of macrophage (AIM), secreted mainly by macrophages and epithelial cells, is upregulated during inflammation and facilitates immune recognition of cancerous cells by blocking human regulator of complement activation. OBJECTIVE: These controversies around the PSA utility necessitate a reexamination of its use as a screening tool. More so, despite the suggested implication of AIM in anticancer immunosurveillance, there is a dearth of information on its role in therapy response, disease progression, and clinical outcomes of patients with PCa. These inform the present study to probe the nature and role of AIM/PSA signaling in anticancer immunity and prognosis in PCa. METHODS: A combination of bioinformatics-aided statistical analyses, gene function annotation, and immune infiltrate analyses, coupled with tissue staining, and function assays, namely migration, invasion, and clonogenicity assays, we employed. RESULTS: We demonstrated that AIM and PSA expression levels are inversely correlated in PCa clinical samples and cell lines, with AIMlowPSAhigh defining PCa, compared to AIMhighPSAlow in normal samples. Concomitant aberrant PSA and significantly suppressed AIM expression levels positively correlated with high-grade disease and characterized by advanced stage prostate cancer, regardless of mutation status. We found that a high PSA/AIM ratio is associated with disease recurrence in patients with prostate cancer but is equivocal for overall survival. In addition, PSA-associated AIM suppression is implicated in the enhanced 'metastability' of PCa and a high AIM/PSA ratio is associated with strong castration-induced regression. CRISPR-mediated AIM knockout was associated with higher PSA expression while ectopic expression of AIM significantly attenuated the migration and invasive capability of PC3 and DU145 cells. Interestingly, compared to normal samples, we observed that AIM, biomarkers of T-cell activation and M1 phenotype markers are co-suppressed in PCa samples. CONCLUSION: Herein, we demonstrate that AIM/CD5L binds to PSA and that a high PSA/AIM ratio defines advanced stage PCa (regardless of mutation status), is implicated in enhanced metastability, and associated with disease recurrence, while a high AIM/PSA ratio is associated with strong castration-induced regression. More so, the ectopic expression of AIM significantly enhances the anticancer effect of Pembrolizumab and elicits an increased CD8+ T-cell count in AIMhiPSAloPDL1+ PCa cases that are respondent to Pembrolizumab treatment.

Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2).

BACKGROUND: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. OBJECTIVE: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. METHODS: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. RESULTS: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1-TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. CONCLUSION: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1-TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Enhanced uropathogenic Escherichia coli-induced infection in uroepithelial cells by sugar through TLR-4 and JAK/STAT1 signaling pathways.

BACKGROUND: Patients with diabetes mellitus (DM) have higher incidence and more severe urinary tract infections (UTIs) for longer duration than those of the patients without DM. It causes more complicated etiologies during uropathogenic Escherichia coli (UPEC) infection. However, studies regarding the molecular mechanism are scarce. METHODS: The present study (1) aimed to verify if sugar influences the process of UPEC-induced cystitis and invasion into the uroepithelial cells and (2) illustrated the mechanism of effects for sugar enhanced the UPEC infection into uroepithelial cells is related to TLR-4-mediated and JAK/STAT1-dependent pathway. RESULTS: The results of the present study indicated that sugar can enhance UPEC infection in uroepithelial cells by up-regulating the transduced circuit between TLR-4-mediated UPEC interaction and JAK/STAT-1 signal pathways. The results of the inhibitor-co-incubating experiments demonstrated that the mechanism involved in the synergistic amplification of TLR-4-mediated UPEC interaction and JAK/STAT1 signaling pathways is responsible for the increased UPEC infection in uroepithelial cells. CONCLUSION: The results also proved that STAT-1 plays a critical role in the regulation of UPEC invasion and infection in the uroepithelial cells, especially those pretreated with glucose. The present study suggests a possible therapeutic approach to preferentially suppress UPEC infection during UTIs in the patients with diabetes.

Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3.

BACKGROUND: UPEC can internalize clonally in prostate to form biofilm-like intracellular bacterial communities (IBCs) for recurrent or chronic infection. We previously indicated that the exposure of prostate cells to testosterone could suppress UPEC invasion and their persistent survival within cells by effectively inhibiting the JAK/STAT1 signaling pathway. However, the regulatory mechanism by which testosterone affects UPEC-induced prostatitis via STAT3, another latent transcription factor signaling pathway is still unclear. The present study aimed to clarify the role of STAT3 in the process of UPEC-induced inflammation and colonization in prostate epithelial cells. METHODS: The effects of testosterone-mediated inhibition were compared between the prostatitis by different UPEC strains (CFT073 and J96) through the specific GFP-UPEC-infected prostate cell model. Fluorescence microscopy was used for UPEC IBCs detection and quantifying, and Flow cytometry, RT-PCR and western blotting were used for analyzing related gene and protein expressions. Pretreatment of JAK and STAT3 inhibitors were also applied to verify the regulation of transduction pathway in testosterone-mediated anti-UPEC infection. RESULTS: This study revealed that testosterone effectively suppresses UPEC infection and IBC formation in prostate cells through the JAK/STAT3 pathway. The results show that CFT073 and J96 UPEC infection rates and colony numbers were dose-dependently reduced in RWPE-1 cells pretreated with 5 and 20 µg/mL testosterone at 0 and 24 h post-infection. Further, testosterone reduced the amounts of UPEC infecting and surviving within the prostate cells, as well as suppressed the size of IBCs formed. We demonstrated that pretreating testosterone effectively inhibited UPEC infection along with dose-dependent suppression of STAT3 and the phosphorylated-STAT3 expression in prostate cells, especially in 24 h J96 UPEC infected groups. The STAT inhibitor, SOCS3 also up-regulated at the same time. In addition, we pretreated the JAK1 or STAT3 inhibitor with testosterone to block the signaling transduction before CFT073 and J96 UPEC infection, and found the significant restoring in both the sizes of IBCs and bacterial numbers in RWPE-1 cells. Therefore, our results suggest that the suppression of STAT3 by testosterone treatment attenuate UPEC growing within IBCs and interfere with their infection to prostate cells. CONCLUSIONS: Overall, our study demonstrates that testosterone suppresses the initial infection of prostate epithelial cells by UPEC and reduces the survival of UPEC within IBCs after infection. These results indicate a critical role for STAT3 in facilitating UPEC infection and persistence, and its participation in driving testosterone-suppressive responses in prostate epithelial cells. In conclusion, this study suggests that testosterone may be beneficial in treating clinically recurrent UPEC infections and, thus, the persistent recurrence of prostatic inflammation.

Phosphodiesterase Type 5 Inhibitors Synergize Vincristine in Killing Castration-Resistant Prostate Cancer Through Amplifying Mitotic Arrest Signaling.

Combination therapies that display cancer-killing activities through either coexistent targeting of several cellular factors or more efficient suppression of a specific pathway are generally used in cancer treatment. Sildenafil, a specific phosphodiesterase type 5 (PDE5) inhibitor, has been suggested to display both cardioprotective and neuroprotective activities that provide a rationale for the combination with vincristine on the treatment against castration-resistant prostate cancer (CRPC). In the present work, vincristine arrested cells in the metaphase stage of mitosis. Vincristine-induced mitotic arrest was identified by Cdk1 activation (i.e., increased Cdk1Thr161 phosphorylation and decreased Cdk1Tyr15 phosphorylation), cyclin B1 upregulation, and increased phosphorylation of multiple mitotic proteins and stathmin. Sildenafil synergistically potentiated vincristine-induced mitotic arrest and a dramatic increase of mitotic index. Furthermore, sildenafil potentiated vincristine-induced mitochondrial damage, including Mcl-1 downregulation, Bcl-2 phosphorylation and downregulation, Bak upregulation and loss of mitochondrial membrane potential, and sensitized caspase-dependent apoptotic cell death. Sildenafil-mediated synergistic effects were mimicked by other PDE5 inhibitors including vardenafil and tadalafil, and also by PDE5A knockdown in cells, suggesting PDE5-involved mechanism. Notably, sildenafil amplified vincristine-induced phosphorylation and cleavage of BUBR1, a protein kinase in spindle assembly checkpoint (SAC) function and chromosome segregation. Sildenafil also significantly decreased kinetochore tension during SAC activation. Moreover, sildenafil synergized with vincristine on suppressing tumor growth in an in vivo model. In conclusion, the data suggest that sildenafil, in a PDE5-dependent manner, potentiates vincristine-induced mitotic arrest signaling, and sensitizes mitochondria damage-involved apoptosis in CRPC. Both in vitro and in vivo data suggest the combination potential of PDE5 inhibitors and vincristine on CRPC treatment.

Surgical outcome of anatomical endoscopic enucleation of the prostate: A systemic review and meta-analysis.

An increasing number of evidences demonstrate the safety and efficacy of endoscopic enucleation of the prostate (EEP) using various energy devices. We performed a systemic literature search for all relevant randomised controlled trials (RCTs) comparing any EEP technique with TURP or open prostatectomy (OP). A total of 21 RCTs with 2,957 patients were included; the majority were studies of holmium laser or bipolar diathermy. Compared to TURP, EEP resulted in greater improvement in IPSS (MD: -0.56, 95% CI: -0.90 to -0.23), PVR (MD: -2.24, 95% CI: -4.45 to -0.03) and Qmax (MD: -1.07, 95% CI: -1.53 to -0.61). EEP was associated with more prostate tissue removed (MD: -9.73, 95% CI: -15.71 to -3.75), less haemoglobin loss (MD: -0.47, 95% CI: -0.70 to -0.23), shorter catheterisation time (MD: -22.82, 95% CI: -30.11 to -15.52) and shorter length of hospitalisation (MD: -1.05, 95% CI: -1.33 to -0.78). Compared to OP, EEP resulted in equivalent functional outcomes. However, EEP was associated with less haemoglobin loss (MD: -1.17, 95% CI: -1.98 to -0.37), shorter catheterisation time (MD: -89.74, 95% CI: -112.60 to -66.88) and shorter length of hospitalisation (MD: -3.91, 95% CI: -4.63 to -3.60). The current evidence supports that EEP can be considered as a new standard of the surgical management for BPH.

Association between VEGF gene promoter polymorphisms and bladder cancer: An updated meta-analysis.

BACKGROUND: Vascular endothelial growth factor (VEGF) is the key regulator of angiogenesis in the development of various cancers. Previous studies have examined the relationship between VEGF gene promoter polymorphisms such as -2578C/A and -460C/T and bladder cancer risk; however, these results are inconclusive. Therefore, we performed this meta-analysis to investigate the association between VEGF gene promoter polymorphisms and bladder cancer risk. METHODS: PubMed, Embase, Cochrane Library and Web of Science databases were searched for studies published before September 2018. The methodological quality assessment of included studies was performed based on the Newcastle-Ottawa Quality Scale (NOS). We conducted a systematic review and meta-analysis using both fixed- and random-effect model. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the relationship. In addition, the stability of our analysis was evaluated by heterogeneity, sensitivity, subgroup of ethnicity, and publication bias analysis. RESULTS: We finally included 7 case-control studies with a total of 2412 bladder cancer patients and 3157 cancer-free controls. In Asian population with the VEGF -2578C/A polymorphism, significantly higher bladder cancer risks of 1.55 (95% CI = 1.25-1.93) and 1.53 (95% CI = 1.11-2.10) were found in the heterozygous model (AC vs CC) and the dominant model (AA + AC vs CC), respectively. Though there was no statistical association between VEGF -460C/T polymorphism and bladder cancer, a tendency to higher bladder cancer risk was observed in various genetic models (T vs C; TT vs CC; TC vs CC and TT + TC vs CC). CONCLUSIONS: Our findings suggest that VEGF -2578C/A polymorphism might be a risk factor with a modest significance for bladder cancer only in Asian population. Further studies with a larger sample size and other functional polymorphisms are needed to explore the effects of VEGF gene on the risk of bladder cancer.

Association between interleukin-8 rs4073 polymorphism and prostate cancer: A meta-analysis.

BACKGROUND/PURPOSE: Interleukin-8 (IL-8) is an inflammatory cytokine and plays important role in development of cancers. We conducted a meta-analysis to explore the association between IL-8 rs4073 polymorphism and risk of prostate cancer. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were searched for only case-control studies published before February 2019. The methodological quality assessment of included studies was performed based on Newcastle-Ottawa Quality Scale (NOS). Based on the heterogeneity, we conducted a meta-analysis using random-effect models. Pooled odds ratios (ORs) with a 95% confidence interval (CI) were calculated using the allele (T vs. A), homozygous (TT vs. AA), heterozygous (TA vs. AA), dominant (TT + TA vs. AA), and recessive (TT vs. TA + AA) genetic models to assess the strength of the relationship between IL-8 rs4073 polymorphism and prostate cancer risk. In addition, the stability of our analysis was evaluated by heterogeneity, sensitivity, subgroup of ethnicity and study design, and publication bias analysis. RESULTS: We included 6 case-control studies with a total of 1752 cases and 1982 controls. Significantly higher prostate cancer risk of 1.12 (95% CI = 1.01-1.25), 1.26 (95% CI = 1.03-1.55), and 1.20 (95% CI = 1.02-1.41) were found for the allele, homogeneous, and recessive model, respectively. Though there was no statistical association with other genetic models in our meta-analyses, a tendency of higher prostate cancer risk was observed in all five genetic models. CONCLUSION: The major findings of this meta-analysis suggested that IL-8 rs4073 polymorphism is significantly associated with risk of prostate cancer.

Modified U-Shaped ileal neobladder designed for facilitating neobladder-urethral anastomosis in extracorporeal reconstruction after robotic-assisted radical cystectomy.

BACKGROUND/OBJECTIVE: To report the initial experience and the early outcomes of a modified U-shaped ileal neobladder, which was developed to facilitate the neobladder-urethral anastomosis by minimizing the anastomotic tension. PATIENTS AND METHODS: Between June 2015 and December 2016, two male and two female patients (median age: 65.5 years, range: 43-72 years) underwent the modified U-shaped ileal neobladder after robotic-assisted radical cystectomy (RARC). The most mobile and dependent ileal segment was first selected intracorporeally as the site for later neobladder-urethral anastomosis. The neobladder was formed extracorporeally, and the previously selected ileal segment formed the most dependent portion of the neobladder. The neobladder-urethral anastomosis was completed after robotic redocking. RESULTS: The median follow-up was 8 months (3-21 months). The median operative time, console time, and extracorporeal reconstruction time were 620 min (534-674 min), 372 min (314-420 min), and 151 min (128-215 min), respectively. In all patients, the neobladder-urethral anastomosis was completed intracorporeally with minimal tension. The median hospital time after the surgery was 14.5 days (14-19 days). Postoperatively, the median peak flow rate and void volume were 10 ml/s (4-35 ml/s) and 258 ml (88-775 ml). The median postvoid residual was 20 ml (10-53 ml). At daytime, two were completely continent; the other two reported mild (1-2 pads) and moderate (>2 pads) incontinence at the postoperative 3 and 4 months, respectively. Three reported nocturnal enuresis. CONCLUSIONS: Our initial experience demonstrated that the modified U-shaped neobladder designed for minimizing the anastomotic tension is safe and feasible with its satisfactory functional outcomes.

Laparoscopic total extraperitoneal inguinal hernia repair is safe and feasible in patients with continuation of antithrombotics.

AIMS: We aimed to evaluate the safety and feasibility of laparoscopic total extraperitoneal (TEP) inguinal hernia repair in patients with the continuation of their antithrombotic agents. SETTINGS AND DESIGN: This was prospective cohort study. MATERIALS AND METHODS: A total of 115 patients who underwent TEP inguinal hernia repair between January 2015 and September 2016 were included in the analysis. Seventeen patients continued their antithrombotics (antithrombotic group); the other 98 had not been on antithrombotics (control group). STATISTICAL ANALYSIS USED: The analysis was performed by using Mann-Whitney U-test, Chi-square or Fisher's exact test. RESULTS: The antithrombotic group had a greater mean age (65.9 ± 8.0 vs. 57.7 ± 13.6,P= 0.002) and higher prevalence of hypertension (64.7% vs. 33.7%,P= 0.015), cardiovascular diseases (64.7% vs. 7.1%,P < 0.001), atrial fibrillation (23.5% vs. 0,P < 0.001), ischaemic heart disease (35.3% vs. 0,P < 0.001) and the American Society of Anaesthesiologists ≥2 (94.1% vs. 81.6%,P= 0.005). The operation time for the antithrombotic group was longer than that of the control group (92.06 ± 32.81 min vs. 72.33 ± 20.99 min,P= 0.015). None experienced conversion to open surgery in either group. There was no difference in the post-operative complications (29.4% vs. 28.6%) and sero-haematoma formation (23.5% vs. 11.1%). The analgesic requirement, hospital stays (23.72 ± 7.74 vs. 22.35 ± 10.33 h) and the time for return to normal daily activity (3.56 ± 1.74 vs. 3.63 ± 1.90) were not statistically different between the two groups. None in either group experienced major cardiovascular events within 30 days. CONCLUSIONS: Laparoscopic TEP inguinal hernia repair can be safely performed in patients with the continuation of their antithrombotic agents in experienced hands.

Primary large cell neuroendocrine carcinoma of the prostate in a hormone naive patient: A case report from Taiwan.

Large cell neuroendocrine carcinoma (LCNEC) of the prostate is extremely rare. Previously reported cases in the literature were almost exclusively developed in men receiving androgen deprivation therapy for prostate adenocarcinoma. We herein present a case of de novo LCNEC: A 66-year-old male was incidentally diagnosed as LCNEC after he underwent transurethral resection of prostate. The stage was T4N1M1. Therefore, the patient was treated with 6 cycles of cisplatin and etoposide in the following 6 months, which achieved a partial remission. He gave up the chance to eradicate the residual mass. Three months later, the tumor progressed rapidly. In conclusion, LCNEC is a rare prostate cancer. Our experience shows that chemotherapy with etoposide and cisplatin is effective to achieve a significant remission. However, LCNEC is highly malignant in nature, postchemotherapy surgery for the residual mass should be considered.

Association between the rs1800795G>C polymorphism in the promoter of interleukin-6 gene and bladder cancer.

Interleukin-6 (IL-6) is an inflammatory cytokines that plays a role in the development of cancer. Several studies have examined the relationship between the IL-6 -174G>C polymorphism and bladder cancer, but these results are inconclusive. Therefore, we conducted a meta-analysis to explore the association between IL-6 -174G>C polymorphism and bladder cancer risk. A comprehensive literature search was performed to identify eligible studies regarding the IL-6 -174G>C polymorphism and bladder cancer. Effect sizes under fixed- and random-effects models were calculated using odds ratios (ORs) with 95% confidence intervals (CIs). Finally, five case-control studies were included in the subsequent analyses. In the fixed-effect analysis, significantly higher bladder cancer risks of 1.20 (95% CI = 1.07-1.36) and 1.30 (95% CI = 1.08-1.56) were found for the dominant model (C/C+G/C vs. G/G) and recessive model (C/C vs. G/C+G/G), respectively. Especially for the Asian population, significantly greater bladder cancer risks of 1.63 (95% CI = 1.32-2.00) and 1.54 (95% CI = 1.07-2.21) were observed for the dominant model (C/C+G/C vs. G/G) and the recessive model (C/C vs. G/C+G/G), respectively. Non-significantly increased risks of bladder cancer were observed for the dominant and recessive models under the random-effects analysis. The major findings of this meta-analysis suggest that IL-6 -174G>C polymorphism is significantly associated with bladder cancer risk in the Asian population. Further studies with a larger sample size are needed to validate the effects of IL-6 polymorphisms on bladder cancer risk.