Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling.

BACKGROUND: Although trimodality therapy resecting tumours followed by chemoradiotherapy is emerged for muscle-invasive bladder cancer (MIBC), chemotherapy produces toxicities. Histone deacetylase inhibitors have been identified as an effective strategy to enhance cancer radiotherapy (RT). METHODS: We examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study. RESULTS: HDAC6 knockdown or HDAC6 inhibitor (HDAC6i) tubacin exerted a radiosensitizing effect, including decreased clonogenic survival, increased H3K9ac and α-tubulin acetylation, and accumulated γH2AX, which are similar to the effect of panobinostat, a pan-HDACi, on irradiated BC cells. Transcriptomics of shHDAC6-transduced T24 under irradiation showed that shHDAC6 counteracted RT-induced mRNA expression of CXCL1, SERPINE1, SDC1 and SDC2, which are linked to cell migration, angiogenesis and metastasis. Moreover, tubacin significantly suppressed RT-induced CXCL1 and radiation-enhanced invasion/migration, whereas panobinostat elevated RT-induced CXCL1 expression and invasion/migration abilities. This phenotype was significantly abrogated by anti-CXCL1 antibody, indicating the key regulator of CXCL1 contributing to BC malignancy. Immunohistochemical evaluation of tumours from urothelial carcinoma patients supported the correlation between high CXCL1 expression and reduced survival. CONCLUSION: Unlike pan-HDACi, the selective HDAC6i can enhance BC radiosensitization and effectively inhibit RT-induced oncogenic CXCL1-Snail-signalling, thus further advancing its therapeutic potential with RT.

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.

Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer.

PURPOSE: To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival. METHODS: This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS. RESULTS: Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001). CONCLUSIONS: Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.

Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review.

PURPOSE: The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC. METHODS: This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included. RESULTS: A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC. CONCLUSION: AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC.

Outcomes of stratified transurethral resection of bladder tumor: A propensity score-matched analysis.

BACKGROUND/PURPOSE: Several strategies have been reported for improving the integrity of transurethral resection of bladder tumor (TURBT). However, no standard has been established. Stratified TURBT (SR) is one of protocols for TURBT, wherein exophytic tumors are first resected and retrieved, and tumor bases are then resected. In this study, we aimed to evaluate the outcomes of SR in patients with nonmuscle invasive bladder cancer (NMIBC). METHODS: From January 2012 to December 2017, patients newly diagnosed as having NMIBC with a follow-up period of more than 2 years were enrolled and categorized into SR and conventional TURBT (CR) groups. Propensity score matching at a 2:1 ratio was performed. Outcomes were the detrusor muscle sampling rate, recurrence-free survival (RFS), and progression-free survival (PFS). RESULTS: In total, 205 patients were included in our study. The detrusor muscle sampling rate was higher in the SR group (P = 0.043). After propensity score matching, 162 patients were selected for outcome analysis, with 108 and 54 patients undergoing SR and CR, respectively. Compared with the CR group, the SR group showed a lower recurrence rate (P = 0.015) and better RFS in univariate (P = 0.010) and multivariate (P = 0.006) Cox proportional hazards regression. Progression rate and PFS were not significantly different between the two groups. CONCLUSION: SR results in a higher detrusor muscle sampling rate and better disease outcomes. Our findings suggest that SR is a promising strategy for TURBT in patients with NMIBC.

Tumor location on MRI determines outcomes of patients with prostate cancer after total prostate cryoablation.

We investigated the association between tumor location on multiparametric magnetic resonance imaging (mpMRI) and outcomes of prostate cancer patients after primary total prostate cryoablation (PTPC). Between March 2010 and December 2012, consecutive 192 prostate cancer patients receiving PTPC were enrolled. Tumor locations were determined and classified as anterior apex (AA), anterior midgland (AM), anterior base (AB), posterior apex (PA), posterior midgland (PM) and posterior base (PB) using mpMRI. Midline location, central location, seminal vesicle invasion, extraprostatic extension, multiple tumors, and tumor volume were also identified. Prostate local recurrence and biochemical failure were considered as primary and secondary endpoints, respectively. Tumors on mpMRI were identified in 148 (77.1%) patients. Tumor locations were most frequently noted in PM (89, 46.4%), followed by AM (55, 28.6%), PB (53, 27.6%), PA (46, 24%), AA (35, 18.2%) and AB (31, 16.1%). Midline and central tumors were observed in 34 (17.7%) and 14 (7.3%) patients, respectively. During a median follow-up duration of 81 months (range, 2-114 months), 71 (37.0%) and 29 (40.8%) patients experienced biochemical failure and local recurrence, respectively. Multivariable analyses revealed only AA tumors increased the risk of local recurrences (HR = 2.98, 95% CI. 1.36-6.49). None of location-related parameters was associated with biochemical failure. Tumor location on mpMRI has a significant association with local tumor recurrence in patients receiving PTPC. Physicians should be cautious when conducting cryoablation for prostate tumors in AA location.

United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia.

OBJECTIVES: To document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real-world practice in Asia using the United in Fight against prOstate cancer (UFO) registry. PATIENTS AND METHODS: We established a multi-national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high-risk localised prostate cancer (HRL), non-metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed-up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient-reported quality of life was prospectively assessed using the European Quality of Life-five Dimensions, five Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017. RESULTS: Of the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co-morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ-5D-5L visual analogue score was 74.6-79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen-deprivation therapy (either orchidectomy or luteinising hormone-releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy). CONCLUSION: In the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow-up period; prospective follow-up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia.

Effect of diabetes mellitus and glycemic control on the prognosis of non-muscle invasive bladder cancer: a retrospective study.

BACKGROUND: Hyperglycemia is associated with series of process leading to oncogenesis. Evidence has shown that diabetes mellitus (DM) seems to be associated with poor prognosis in patients with bladder cancer. However, evidence on the effect of glycemic control on the outcomes of bladder cancer is still limited. In the current study, we aimed to investigate the effect of DM and glycemic control on the prognosis of bladder cancer. METHODS: We conducted a retrospective chart review of a prospective database from January 2012 to December 2017. Patients with newly diagnosed non-muscle invasive bladder cancer (NMIBC) were included. They were classified into the DM and non-DM groups. Prognosis including recurrence rate, progression rate, recurrence-free survival (RFS), and progression-free survival was compared between the two groups. Subgroup analysis of the DM subgroup, in which patients were classified by HbA1C level, was conducted to investigate the effect of glycemic control. RESULTS: A total of 287 patients were included in our study, with 61 patients in the DM group and 226 patients in the non-DM group. No statistically significant difference was found in the prognosis between the DM and non-DM groups. Subgroup analysis revealed higher recurrence rate (P = 0.037) and worse RFS (log-rank P = 0.019) in patients with HbA1C ≥ 7. CONCLUSIONS: DM is not a risk factor for recurrence and progression in patients with NMIBC. However, poor glycemic control is associated with poor prognosis in patients with both DM and NMIBC. Further prospective studies are needed to confirm current results.

Management of patients with advanced prostate cancer in the Asia Pacific region: 'real-world' consideration of results from the Advanced Prostate Cancer Consensus Conference (APCCC) 2017.

OBJECTIVE: The Asia Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2018) brought together 20 experts from 15 APAC countries to discuss the real-world application of consensus statements from the second APCCC held in St Gallen in 2017 (APCCC 2017). FINDINGS: Differences in genetics, environment, lifestyle, diet and culture are all likely to influence the management of advanced prostate cancer in the APAC region when compared with the rest of the world. When considering the strong APCCC 2017 recommendation for the use of upfront docetaxel in metastatic castration-naïve prostate cancer, the panel noted possible increased toxicity in Asian men receiving docetaxel, which would affect this recommendation in the APAC region. Although androgen receptor-targeting agents appear to be well tolerated in Asian men with metastatic castration-resistant prostate cancer, access to these drugs is very limited for financial reasons across the region. The meeting highlighted that cost and access to contemporary treatments and technologies are key factors influencing therapeutic decision-making in the APAC region. Whilst lower cost/older treatments and technologies may be an option, issues of culture and patient or physician preference mean, these may not always be acceptable. Although generic products can reduce cost in some countries, costs may still be prohibitive for lower-income patients or communities. The panellists noted the opportunity for a coordinated approach across the APAC region to address issues of access and cost. Developments in technologies and treatments are presenting new opportunities for the diagnosis and treatment of advanced prostate cancer. Differences in genetics and epidemiology affect the side-effect profiles of some drugs and influence prescribing. CONCLUSIONS: As the field continues to evolve, collaboration across the APAC region will be important to facilitate relevant research and collection and appraisal of data relevant to APAC populations. In the meantime, the APAC APCCC 2018 meeting highlighted the critical importance of a multidisciplinary team-based approach to treatment planning and care, delivery of best-practice care by clinicians with appropriate expertise, and the importance of patient information and support for informed patient choice.

Trifecta outcome of ureteral reconstruction in iatrogenic injury and non-iatrogenic ureteral lesions: a 10-year experience at a tertiary referral center.

PURPOSE: To analyze the trifecta outcome (functional, anatomical, and surgical aspects) of surgical reconstruction for ureteral lesions and investigate the factors affecting the success rate of such reconstruction. METHODS: We retrospectively reviewed the data of patients who underwent ureteral reconstruction at our institute between March 2007 and November 2016. Patient profiles, surgical methods, complications, ureteral stenting, laboratory data, and image studies were collected. The trifecta outcome was defined as preserved renal function, no progression of hydronephrosis, and no long-term stenting. The primary endpoint was the percentage of patients who achieved the trifecta outcome. The secondary endpoint was risk factors for trifecta outcome failure. RESULTS: We retrospectively reviewed 178 adult patients who had undergone ureteral reconstruction. The median follow-up period was 37.4 months. In total, 70 (39.3%) patients had iatrogenic ureteral injuries and 108 (60.7%) patients had non-iatrogenic ureteral lesions. Overall, 70% of the patients achieved the trifecta outcome after ureteral reconstruction. A multivariate analysis revealed that risk factors for trifecta failure were malignant diseases [odds ratio (OR) 2.93, p = 0.005], a history of pelvic radiation (OR 3.08, p = 0.032), preoperative estimated glomerular filtration rate < 60 (OR 2.52, p = 0.039), and a type of reconstruction ureteroureterostomy (OR 2.99, p = 0.014). CONCLUSIONS: Trifecta outcome could be used to evaluate the ureteral reconstruction in iatrogenic injury and non-iatrogenic ureteral lesions. This study revealed several risk factors that affected the trifecta outcome.

Practice pattern of non-muscle invasive bladder cancer in Japan, Korea and Taiwan: A Web-based survey.

OBJECTIVES: To investigate the treatment pattern of non-muscle invasive bladder cancer patients among urologists in Japan, Korea and Taiwan, with emphasis on compliance with important treatment guidelines. METHODS: A Web-based questionnaire survey was conceived by representative members of each country's urological oncology society and was open from June 2016 to February 2017 to each society's members. Descriptive statistics and multinomial logistic regression analysis were used. RESULTS: A total of 2334 urologists were invited and 701 responded to the survey with a response rate of 30.0%. Instruments used during transurethral resection of bladder cancer varied significantly between countries and depended on their availability. The re-transurethral resection rate for pT1 or high-grade disease >50% of the time was significantly higher in Japan than in the other two countries, but the collective rate was just 49%. The frequency of intravesical therapy in intermediate- to high-risk disease was generally consistent across countries. However, the choice of agent between chemotherapy and bacillus Calmette-Guérin was significantly different between countries. Maintenance bacillus Calmette-Guérin was used <10% of the time by 45% of respondents, the most important reasons being fear of side-effects, followed by a lack of efficacy and shortage of drug supply. CONCLUSIONS: There are significant differences between Japan, Korea and Taiwan in the management of intermediate- to high-risk non-muscle invasive bladder cancer. The results of this survey can serve as the basis for joint efforts to develop common clinical guidelines.

The application of p2PSA% and prostate health index in prostate cancer detection: A prospective cohort in a Tertiary Medical Center.

BACKGROUND/PURPOSE: Prostate specific antigen (PSA) with low specificity that causes unnecessary prostate biopsies increases clinical morbidities, psychological stress, and medical expenses. We aimed to test the accuracy and cutoff value of Prostate Health Index (PHI) in men for prostate cancer detection. METHODS: We prospectively enrolled 213 men who underwent prostate biopsy with PSA≦10 ng/ml or abnormal findings on digital rectal examination. Total PSA (tPSA), free PSA (fPSA) and p2PSA levels were measured by serum samples before prostate biopsy. PHI was calculated as (p2PSA/fPSA) × âˆštPSA. Multivariable logistic regression analyses were used to predict the risk of cancer and detect clinically significant prostate cancer. RESULTS: 33 (27.0%) patients were confirmed with the diagnoses of prostate cancer by prostate biopsy. The levels of p2PSA, %p2PSA, and PHI showed statistically significant differences between prostate cancer patients and non-cancer patients. %p2PSA and PHI had the highest area under the receiver operating characteristic curve (AUC) of 0.723 and 0.772 (both p < 0.001), respectively, predicting cancer detection at biopsy than other predictors (tPSA, fPSA, %fPSA, and PSA density (AUC: 0.544, 0.538, 0.593, and 0.664, respectively). In multivariable logistic regression, %p2PSA had a statistical significant odds ratio 8.51 (p = 0.003) and PHI had an odds ratio with marginal significance 4.18 (p = 0.06). CONCLUSION: %p2PSA and PHI increased the diagnostic accuracy with significantly greater sensitivity and specificity than tPSA. We determined an optimal cut-off value of PHI among Taiwanese population. These findings support the usefulness in the decisional process of prostate biopsy.

Adiponectin gene polymorphisms and obesity increase the susceptibility to arsenic-related renal cell carcinoma.

Our recent study found that high urinary total arsenic levels were associated with renal cell carcinoma (RCC). Recent studies demonstrated that low circulating adiponectin was related to RCC. The aim of the present study was to explore the relationship between adiponectin gene (ADIPOQ) polymorphisms and RCC and investigate whether individuals with an ADIPOQ risk genotype, obesity, and high urinary total arsenic levels have a modified odds ratio (OR) of RCC. A total of 389 RCC patients and 389 age- and sex-matched controls were recruited between November 2006 and December 2012 in Taiwan. Image-guided biopsy or surgical resection of renal tumors was performed to pathologically verify RCC. Genomic DNA was used to examine the genotypes of the ADIPOQ rs182052, ADIPOQ rs2241766, ADIPOQ rs1501299, and ADIPOQ rs1063539 SNPs by PCR-RFLP. HPLC-HG-AAS was used to measure the concentrations of urinary arsenic species. Participants with the ADIPOQ rs182052 G/A+A/A genotype had a significantly higher OR of RCC compared with those with the ADIPOQ rs182052 G/G genotype. The OR (95% confidence interval [CI]) was 1.70 (1.23-2.36). The OR of RCC for the combined effect of high urinary total arsenic levels and obesity, which was dose-dependent, in individuals with the ADIPOQ rs182052 G/A+A/A genotype was 9.33 (3.85-22.62). The present study found significant combined effects of obesity and the ADIPOQ rs182052 G/A+A/A genotype on the arsenic-related risk of RCC in a population with low arsenic exposure. Arsenic exposure, obesity, and the ADIPOQ rs182052 polymorphism could be predictors of a higher OR of RCC.

Adjuvant androgen-deprivation therapy following prostate total cryoablation in high-risk localized prostate cancer patients - Open-labeled randomized clinical trial.

PURPOSE: To investigate the efficacy and safety profile of 12-month adjuvant androgen-deprivation therapy (ADT) following total-gland cryoablation (TGC) in patients with high-risk localized prostate cancer (HRLPC). MATERIALS AND METHODS: This open-label randomized trial included 38 HRLPC patients who received TGC between July 2011 and March 2013. Within 4 weeks after TGC, subjects were randomly assigned (1:1) to either the 12-month adjuvant ADT or non-adjuvant ADT group. The primary outcome was biochemical failure measured by the Phoenix definition. Adverse events were measured at month 1, 2, 3, 6, 9 and 12. In addition, a cohort of 145 HRLPC patients was selected retrospectively for outcome validation. RESULTS: The adjuvant ADT and non-adjuvant ADT groups did't differ in peri-operative characters, such as age, preoperative PSA, tumor stages, Gleason score, prostate size and cryoprobe number. Four patients with adjuvant ADT withdrew from this trial for personal reasons (N = 2), elevated liver function (N = 1) and poorly controlled hyperglycemia (N = 1). In contrast, none in non-adjuvant ADT group experienced adverse events. Biochemical failures were identified in 5 (26%) patients in each group during a median follow-up duration of 45 months. The median times to biochemical failure were 25 and 5.5 months for adjuvant ADT and non-adjuvant ADT groups, respectively. Biochemical-failure survival curves converged 24 months after TGC. Univariable and multivariable analyses revealed adjuvant ADT was not associated with biochemical recurrences in the validation cohort. CONCLUSIONS: Adjuvant ADT does not reduce biochemical failure for HRPLC patients undergoing TGC. It should be further confirmed by a larger cohort.

MiR-193b Mediates CEBPD-Induced Cisplatin Sensitization Through Targeting ETS1 and Cyclin D1 in Human Urothelial Carcinoma Cells.

Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) plays multiple roles in tumor progression. Studies have demonstrated that cisplatin (CDDP) induced CEBPD expression and had led to chemotherapeutic drug resistance. However, the underlying molecular mechanisms of CDDP-regulated CEBPD expression and its relevant roles in CDDP responses remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression in a sequence-specific manner. Abnormal miRNAs expression is associated with tumor progression. In current study, a large-scale PCR-based miRNA screening was performed to identify CEBPD-associated miRNAs in urothelial carcinoma cell line NTUB1. Eleven miRNAs were selected with more than twofold changes. MiR-193b-3p, a known tumor suppressor, down-regulated proto-oncogenes Cyclin D1, and ETS1 expression and led to cell cycle arrest, cell invasion, and migration inhibition. The expression of miR-193b-3p was associated with the DNA binding ability of CEBPD in CDDP response. CEBPD knocking-down approach provided a strong evidence of the positive correlation between CEBPD and miR-193b-3p. CDDP-induced CEBPD trans-activated miR-193b-3p expression and it directly targeted the 3'-UTR of Cyclin D1 and ETS1 mRNA, and silenced the protein expression. In addition, miR-193b-3p also inhibited cell migration activity, arrested cell at G1 phase, and sensitized NTUB1 to CDDP treatment. In conclusion, this study indicates that CEBPD exhibits an anti-tumorigenic function through transcriptionally activating miR-193b-3p expression upon CDDP treatment. This study provides a new direction for managing human urothelial carcinoma. J. Cell. Biochem. 118: 1563-1573, 2017. © 2016 Wiley Periodicals, Inc.

The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased susceptibility to arsenic-related renal cell carcinoma.

This study was designed to explore the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms and renal cell carcinoma (RCC) and to investigate whether individuals with an XRCC1 risk genotype, a high level of 8-OHdG or a high urinary total arsenic concentration have a modified odds ratio (OR) of RCC. We recruited 180 RCC patients and 360 age- and sex-matched controls from a hospital-based pool. Image-guided biopsy or surgical resection of renal tumors was performed on RCC patients for pathological verification. Genomic DNA was used to examine the genotype of XRCC1(Arg399Gln), XRCC1(Arg194Trp), XRCC3(Thr241Met) and XPD(Lys751Gln) by PCR-RFLP. Liquid chromatography with tandem mass spectrometry was used to determine urinary 8-OHdG levels. A HPLC-HG-AAS was used to determine the concentrations of urinary arsenic species. Participants with the genotype XRCC1(Arg194Trp) Arg/Trp+Trp/Trp had a significantly higher OR of RCC than those with the Arg/Arg genotype; the OR and 95% confidence interval was 0.66 (0.45-0.97) after multivariate adjustment. The OR of RCC for the combined effect of high urinary 8-OHdG levels and high urinary total arsenic concentration in individuals with a XRCC1(Arg194Trp) Arg/Trp+Trp/Trp genotype was higher than in patients with an Arg/Arg genotype, which was evident in a dose response manner. In conclusion, this is the first study to show that the XRCC1 Arg194 allele is a predicting factor for RCC. The more risk factors (high urinary 8-OHdG levels, high urinary total arsenic concentrations, and XRCC1 Arg194 allele) that were present, the higher the OR of RCC.

Antagonistic effect of N-ethylmaleimide on arsenic-mediated oxidative stress-induced poly(ADP-ribosyl)ation and cytotoxicity.

Long-term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As2 O3 ) in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H2 O2 )-induced PARylation was suppressed by As2 O3 exposure in different human cancer cells. Moreover, As2 O3 treatment promoted H2 O2 -induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide (NEM), an organic compound derived from maleic acid, could reverse As2 O3 -mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione with l-buthionine-sulfoximine blocked the antagonistic effect of NEM on As2 O3 , thereby continuing As2 O3 -mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against As2 O3 -mediated DNA damage in a glutathione-dependent manner. Copyright © 2016 John Wiley & Sons, Ltd.

A role of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer plus hydronephrosis with or without pelvic nodal involvement.

BACKGROUND/PURPOSE: To retrospectively evaluate the failure patterns of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer. METHODS: Patients with muscle-invasive bladder cancer underwent maximal transurethral resection of bladder tumor and induction chemotherapy, followed by concurrent chemoradiotherapy (CCRT). Radiotherapy was given with 45 Gy to the pelvis, 50.4 Gy to the bladder, and 64.8 Gy to the tumor bed. Three protocols of trimodality treatment were used: Protocol A, three cycles of cisplatin and fluorouracil (CF), followed by CCRT with 6 weekly cisplatin; Protocol B, three cycles of weekly paclitaxel plus CF, followed by CCRT with 6 weekly paclitaxel and cisplatin; Protocol C, three cycles of gemcitabine and cisplatin, followed by CCRT with 6 weekly cisplatin. Interval cystoscopy confirmed complete response (CR) after induction chemotherapy and 40-50 Gy of radiotherapy. Patients without CR were referred for salvage cystectomy. RESULTS: A total of 60 patients were enrolled, including 11 patients with unfavorable factors defined as hydronephrosis and/or pelvic nodal involvement. After a median follow-up of 86.7 months, the 5-year overall, progression-free, and bladder preservation-specific survival rates were 76.3%, 62.9%, and 71.5%, respectively. Three patients underwent salvage cystectomy for invasive bladder recurrence. Of 45 surviving patients, 42 patients (93.3%) retained functioning bladders. Patients with unfavorable factors had significantly lower metastasis-free survival (p=0.002), but not bladder preservation-specific survival (p=0.25). CONCLUSION: With trimodality treatment involving visually complete transurethral resection of bladder tumor, cisplatin-based induction chemotherapy, and CCRT, patients with unfavorable factors maintained satisfactory bladder preservation but not systemic control.

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma.

Our previous study showed that high urinary total arsenic levels were associated with higher odds ratio (OR) for renal cell carcinoma (RCC). Single nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMTs) might influence DNMT enzyme activity associated with tumorigenesis. In this study, we investigated the association of five SNPs from DNMT1 (rs8101626 and rs2228611), DNMT3A (rs34048824 and rs1550117), and DNMT3B (rs1569686) with the risk of clear cell renal cell carcinoma (ccRCC). We also examined the combined effects of DNMT genotypes and urinary arsenic levels on ccRCC risk. We conducted a hospital-based case-control study, which included 293 subjects with ccRCC and 293 age- and gender-matched controls. The urinary arsenic species were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Genotypes were investigated using polymerase chain reaction and restriction fragment length polymorphism analyses. We observed that the DNMT1 rs8101626 G/G genotype was significantly associated with reduced odds ratio (OR) of ccRCC [OR=0.38, 95% confidence interval (CI) 0.14-0.99]. Subjects with concurrent DNMT1 rs8101626 A/A+A/G and DNMT3A rs34048824 T/T+T/C genotypes had significantly higher OR for ccRCC [OR=2.88, 95% CI 1.44-5.77]. Participants with the high-risk genotype of DNMT1 rs8101626 and DNMT3A rs34048824 with concurrently high urinary total arsenic levels had even higher OR of ccRCC in a dose-response manner. This is the first study to evaluate variant DNMT1 rs8101626 and DNMT3A rs34048824 genotypes that modify the arsenic-related ccRCC risk in a geographic area without significant arsenic exposure in Taiwan.

Polymorphisms of human 8-oxoguanine DNA glycosylase 1 and 8-hydroxydeoxyguanosine increase susceptibility to arsenic methylation capacity-related urothelial carcinoma.

Arsenic causes oxidative stress in cultured animal and human cells, and it is a well-documented human carcinogen. We conducted a hospital-based case-control study including 167 cases of urothelial carcinoma (UC) and 334 age- and gender-matched healthy controls to evaluate the relationships between urinary arsenic profiles, urinary 8-hydroxydeoxyguanosine (8-OHdG) levels, and human 8-oxoguanine DNA glycosylase (hOGG1) genotypes and UC. The urinary arsenic species were analyzed by high-performance liquid chromatography and hydride generator-atomic absorption spectrometry. Genotyping for hOGG1 (Ser326Cys) and hOGG1 (-15C>G) was performed using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Urinary 8-OHdG was measured with high-sensitivity enzyme-linked immunosorbent assay kits. The results indicated that the hOGG1 326 Cys/Cys genotype and the hOGG1 -15C>G G/G genotype were associated with an increased risk of UC (OR [95 % CI] 1.57 [1.04-2.35] and 1.57 [1.04-2.35], respectively). Participants with high urinary total arsenic, regardless of the haplotype of hOGG1 Ser326Cys and the -15C>G polymorphism, had significantly higher urinary 8-OHdG compared to participants with low urinary total arsenic. This is the first study to investigate the joint effects of high urinary total arsenic or inefficient arsenic methylation capacity indices, and the high-risk G-G haplotype of hOGG1 on the risk of UC. The findings are especially meaningful for participants with risk factors such as high urinary total arsenic, inefficient arsenic methylation indices, high urinary 8-OHdG, and the high-risk G-G haplotype of hOGG1 which are all associated with an increased UC risk.