Publications by authors named "Ronald Rodriguez"

92 Publications

Association of TERT gene polymorphisms with clinical benign prostatic hyperplasia in a Chinese Han population of the Northwest region.

Transl Androl Urol 2021 Feb;10(2):692-702

Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephron-Urological Clinical Center, Lanzhou, China.

Background: To investigate the association between single nucleotide polymorphisms (rs10078761, rs12696304, rs2853669, rs16847897, rs2736100, rs10069690) of telomerase gene (TERT) and the risk clinical benign prostatic hyperplasia (BPH) in a Chinese Han population of the Northwest region.

Methods: A total of 150 BPH patients and 150 healthy older males from the northwest Chinese Han population were included in this study. The sample size for this unmatched case-control study was estimated by the look-up table method. Meanwhile, the general information and disease data of patients were collected. Age was only collected in healthy control subjects for statistical correction. Genotypes were detected using a multiplex PCR + ligase detection reaction (LDR). Typing results and clinical data were statistically analyzed using multiple linear regression and logistic regression. Pearson correlation was used for Hardy-Weinberg equilibrium.

Results: The included population is in Hardy-Weinberg equilibrium. There was no significant association between SNP and the risk of BPH by correlation analysis. However, 4 haplotypes (TCTGGT, TCTGTC, TGCCTC, and TGTGTC) were identified as risk factors of BPH by haplotype analysis. The SNP rs2853669 is an independent risk factor for smooth muscle type of hyperplasia. Besides, rs2736100, rs10078761, and rs10069690 which are in linkage disequilibrium are associated with the severity of BPH.

Conclusions: Polymorphism of the TERT gene determines the different disease development and pathological manifestations of BPH in the Chinese Han population the Northwest region.
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http://dx.doi.org/10.21037/tau-20-1032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947465PMC
February 2021

Teratogenic Toxicity Evaluation of Bladder Cancer Specific Oncolytic Adenovirus on Mice.

Curr Gene Ther 2020 Dec 17. Epub 2020 Dec 17.

Gansu Nephro-Urological Clinical Center; Key Laboratory of Urological Diseases, Gansu Province (Lanzhou University); Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou. China.

Background: In our previous studies, we had demonstrated the efficiency and specificity of constructed bladder tissue specific adenovirus Ad-PSCAE-UPII-E1A-AR (APU-EIA-AR) on bladder cancer, we also investigated the virus biodistribution and body toxicity in nude mice. However, the safety of the bladder cancer specific oncolytic adenovirus on fetal mice and F1 mice should be under intense investigation.

Objectives: In order to evaluate the teratogenic toxicity of bladder cancer specific oncolytic adenovirus APU-EIA-AR on mice, in this study, we investigated the fetal mice weight, fetal body length and tail length, fetal skeleton development, as well as the F1 mice weight, growth curve, and major organ pathology. These teratogenic toxicity data of bladder tissue specific adenovirus AdPSCAE-UPII-E1A-AR (AD) would provide safe information prior to embarking on clinical trials.

Methods: At sixth day of being fertilized, the pregnant mice began to be intramuscular administrated with AD (1×107VP, 1×108VP, 1×109VP) every other day for ten days. Then ,the pregnants were devided into two groups. One group was euthanized at seventeenth day, took out the fetal mice ,observing the bone structure of the infants. The oth er group was observed until natural childbirth. The Filial Generation (F1) are feeded and growth for 30 days, the variation in the growth progress and developmen t were assessed. Then the mice were euthenazied, the organ tissue were performed pathological section and HE staining, observing the changes under microscope.

Results: In the process of teratogenic toxicity test , comparing with control group ,the Placenta weight ,fetal mice weight , body len gth and tail length of mice fetal in adenovirus treated group did not reveal any alteration. Comparing with PBS group, there is no obvious change in skeleton of fetal mice treated with adenovirus. During the development process of F1 mice treated with adenovirus, the changes of mice weight show statistical significance. Howerer, in the progress of growth curve, this difference is not very obvious. Furthermore, the pathological section showed no obvious alteration in major organs.

Conclusion: Our study demonstrated that bladder cancer specific adenovirus Ad-PSCAE-UPII-E1A-AR appear safe in the pregnant mice without any discernable effects on fetal mice and F1 development. Hence, It is a relatively safe for tumor gene therapy.
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http://dx.doi.org/10.2174/1566523220999201217161258DOI Listing
December 2020

Comparative Efficacy of Combined Radiotherapy, Systemic Therapy, and Androgen Deprivation Therapy for Metastatic Hormone-Sensitive Prostate Cancer: A Network Meta-Analysis and Systematic Review.

Front Oncol 2020 20;10:567616. Epub 2020 Oct 20.

Key Laboratory of Urological Diseases in Gansu Province, Department of Urology, Gansu Nephro-Urological Clinical Center, Lanzhou University Second Hospital, Lanzhou, China.

Recent randomized clinical trials have examined the efficacy of different combinations of systemic and local treatment approaches for metastatic hormone-sensitive prostate cancer (mHSPC). We compared the efficacy of these combined regimens in order to identify the optimal therapy for specific patient subgroups. The treatments were abiraterone (ABI), apalutamide (APA), docetaxel (DOC), enzalutamide (ENZ), and radiotherapy (RT) combined with androgen-deprivation therapy (ADT). Five electronic databases were searched up to May 7, 2020 for relevant trials. The risk of bias in the included trials was evaluated with the Cochrane tool. The hazard ratio (HR) with 95% confidence interval (CI) was determined for the included trials and indirect comparisons were performed using the R software. In total, 10 randomized, controlled trials with 11,194 patients were included in the meta-analysis. ADT + RT was superior to ADT monotherapy in terms of overall survival (HR = 0.96, 95% CI: 0.85-1.1) and conferred a survival benefit in a subgroup of low-volume patients (HR = 0.68, 95% CI: 0.54-0.87). Combined systemic treatments were significantly superior to ADT monotherapy in comparisons of survival and prostate-specific antigen response, including in the high-volume subgroup; meanwhile, in the low-volume subgroup only ADT + ENZ (HR = 0.38, 95% CI 0.21-0.69) showed a significant clinical benefit. In the Gleason score <8 subgroup, all combined systemic treatments were superior to ADT monotherapy, but the results were only significant for ADT + APA (HR = 0.56, 95% CI: 0.33-0.95) and ADT + DOC (HR = 0.71, 95% CI: 0.54-0.92). In the Gleason score ≥8 subgroup, ADT monotherapy was inferior (albeit not significantly) to combined treatments. In a ranking of performed comparisons, ADT + ENZ was the optimal regimen, although this was non-significant. Combined therapies also demonstrated superiority in quality-of-life indicators such as time to skeletal events and pain progression. ADT + radiotherapy led to superior outcomes in mHSPC patients with low-volume disease. While all combined systemic regimens confer a survival advantage over ADT monotherapy, the optimal treatment approach for certain mHSPC patient subgroups remains to be determined.
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http://dx.doi.org/10.3389/fonc.2020.567616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606969PMC
October 2020

Reevaluation of metanephric stromal tumor two decades after it was named: A narrative review.

J Pediatr Urol 2020 Dec 22;16(6):822-829. Epub 2020 Aug 22.

Institute of Urology, Lanzhou University Second Hospital; Key Laboratory of Gansu Province for Urological Diseases; Gansu Nephro-Urological Clinical Center, PR China. Electronic address:

Objective: The aim of this narrative review is to provide an overview and update of metanephric stromal tumor (MST).

Materials And Methods: All English language studies published from January 1, 2000 to December 31, 2019 in PubMed, EBSCO, Elsevier ScienceDirect, Springer Link and Taylor & Francis databases were searched with the search terms "metanephric stromal tumor" for this review.

Results: Seventeen eligible case reports representing 47 patients according to inclusion and exclusion criteria were included in this study. The average age of the patients was under 4 years (range from 2 d to 56 y) and over half of the cases (52.1%, 25/47) are were diagnosed as MST by accident or during examinations for other diseases. Morphologically, tumor specimens of almost all cases presented concentric "onion-skin cuffing" or characteristic collarettes around renal tubules under low power. There were 79.2% (18/25) of patients exhibited BRAF V600E mutations. Immunohistochemistry (IHC) is characterized by CD34 (+), Vimentin (+), Desmin (-), S-100 (-), SMA (-). Most patients underwent surgeries, and no metastasis or recurrence was found except for one case.

Conclusion: MST is a rare benign pediatric renal tumor with surgical treatment as the first choice. CT examinations and ultrasonography are two widely accepted techniques for the diagnosis of MST. Percutaneous renal biopsy (PRB) is an effective and accurate way of preoperative diagnosis, however, it is not recommended for children under 10 years or with a cystic mass in CT images. The relationship between BRAF V600E mutations and mild clinical manifestations of MST is in need of further verification by biological experiments and clinical studies.
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http://dx.doi.org/10.1016/j.jpurol.2020.08.011DOI Listing
December 2020

Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51.

Biochem Biophys Rep 2020 Sep 16;23:100778. Epub 2020 Jul 16.

Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu, 730000, PR China.

Reactivation of the androgen receptor signaling pathway in the emasculated environment is the main reason for the occurrence of castration-resistant prostate cancer (CRPC). The immunophilin FKBP51, as a co-chaperone protein, together with Hsp90 help the correct folding of AR. Rapamycin is a known small-molecule inhibitor of FKBP51, but its effect on the FKBP51/AR signaling pathway is not clear. In this study, the interaction mechanism between FKBP51 and rapamycin was investigated using steady-state fluorescence quenching, X-ray crystallization, MTT assay, and qRT-PCR. Steady-state fluorescence quenching assay showed that rapamycin could interact with FKBP51. The crystal of the rapamycin-FKBP51 complex indicated that rapamycin occupies the hydrophobic binding pocket of FK1 domain which is vital for AR activity. The residues involving rapamycin binding are mainly hydrophobic and may overlap with the AR interaction site. Further assays showed that rapamycin could inhibit the androgen-dependent growth of human prostate cancer cells by down-regulating the expression levels of AR activated downstream genes. Taken together, our study demonstrates that rapamycin suppresses AR signaling pathway by interfering with the interaction between AR and FKBP51. The results of this study not only can provide useful information about the interaction mechanism between rapamycin and FKBP51, but also can provide new clues for the treatment of prostate cancer and castration-resistant prostate cancer.
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http://dx.doi.org/10.1016/j.bbrep.2020.100778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365970PMC
September 2020

Novel strategy to monitor fluid absorption and blood loss during urological endoscopic surgery.

Transl Androl Urol 2020 Jun;9(3):1192-1200

Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.

Background: There is paucity of an optimal method to detect fluid absorption and hemorrhage during urological endoscopic surgery. We designed an endoscopic surgical monitoring system (ESMS) and estimated its performance to establish a practical instrument that can monitor the blood loss and fluid absorption accurately and non-invasively during urological endoscopic surgery.

Methods: Our system employed the strain gauge transducers to detect the inflows and outflows of the irrigating solutions and the photoelectric sensor to determine the hemoglobin concentration of the collected irrigating fluid. The amount of blood lost and the volume of fluid absorbed during endoscopic surgery could be calculated by computer program. The accuracy and validity of this system were validated in simulated experiment and clinical study of 200 patients who underwent transurethral resection of the prostate (TURP).

Results: The relative errors for fluid absorption detection were between 0.07% and 1.00% and the coefficient of variation in serial analysis ranged from 0.78% to 3.86%. Furthermore, the relative errors for blood loss detection were between 0.06% and 1.33% and the coefficient of variation in serial analysis ranged from 0.86% to 3.94%. In clinical study for TURP, the mean fluid absorption was 644 mL and blood loss was 238 mL.

Conclusions: We provide the accuracy and validity of ESMS. It provides an early and real time detection and warning of irrigation fluid absorption and blood loss to make endoscopic surgical procedure safer for the patient.
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http://dx.doi.org/10.21037/tau-19-780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354347PMC
June 2020

Percutaneous Cryoablation for Stage 1 Renal Cell Carcinoma: Outcomes from a 10-year Prospective Study and Comparison with Matched Cohorts from the National Cancer Database.

Radiology 2020 Aug 9;296(2):452-459. Epub 2020 Jun 9.

From the Department of Radiology (J.M., K.A.P.R., A.Z., A.R.K.), Department of Biostatistics (C.F.), and Department of Vascular and Interventional Radiology (C.S.G.), Johns Hopkins University, 1800 Orleans St, Zayed 7203, Baltimore, MD 21231; and Department of Urology, University of Texas Health Sciences Center, San Antonio, TX (R.R.).

Background Percutaneous cryoablation (PCA) is an increasingly utilized treatment for stage I renal cell carcinoma (RCC), albeit without supportive level I evidence. Purpose Primary objective was to determine the 10-year oncologic outcomes of PCA for stage I RCC in a prospective manner. Secondary objectives were to compare outcomes after partial nephrectomy (PN) and radical nephrectomy (RN) from the National Cancer Database (NCDB), to determine long-term renal function, and to determine the risk of metachronous disease. Materials and Methods In this institutional review board-approved prospective observational study (2006-2013), study participants with single, sporadic, biopsy-proven RCC were included to calculate the 10-year overall survival, recurrence-free survival, and disease-specific survival after PCA. Results were compared with matched PN and RN NCDB cohorts. Overall and recurrence-free survival probabilities were estimated by using nonparametric maximum likelihood estimator. Disease-specific survival was estimated by using the redistribution-to-right method. Age at diagnosis was stratified as a risk for survival. The effect on estimated glomerular filtration rate, serum creatinine level, and the risk for hemodialysis and metachronous disease were calculated. Results One hundred thirty-four patients (46% men) with single, sporadic, biopsy-proven RCC (median size ± standard deviation, 2.8 cm ± 1.4) were included. Overall survival was 86% (95% confidence interval [CI]: 80%, 93%) and 72% (95% CI: 62%, 83%), recurrence-free survival was 85% (95% CI: 79%, 91%) and 69% (95% CI: 59%, 79%) (improved over surgery), and disease-specific survival was 94% (95% CI: 90%, 98%) at both 5 years and 10 years (similar to surgery), respectively. The 10-year risk of hemodialysis was 2.3%. Risk of metachronous RCC was 6%. Charlson/Deyo Combined Comorbidity score analysis showed decreasing overall survival with increasing comorbidity index. The PCA cohort outperformed both RN- and PN-matched subgroups in all Charlson/Deyo Combined Comorbidity score categories. Conclusion Percutaneous cryoablation yielded a 10-year disease-specific survival of 94%, equivalent to that reported after radical or partial nephrectomy. Overall survival probability after percutaneous cryoablation at 5 years and 10 years was longer than for radical or partial nephrectomy, especially for patients at higher risk (Charlson/Deyo Combined Comorbidity score ≥2). © RSNA, 2020.
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http://dx.doi.org/10.1148/radiol.2020192325DOI Listing
August 2020

Nuclear NADPH oxidase-4 associated with disease progression in renal cell carcinoma.

Transl Res 2020 09 31;223:1-14. Epub 2020 May 31.

Department of Urology, University of Texas Health, San Antonio, Texas.

Nuclear NADPH oxidase-4 (Nox4) is a key component of metabolic reprogramming and is often overexpressed in renal cell carcinoma (RCC). However, its prognostic role in RCC remains unclear. Here we examined the significance of nuclear Nox4 on disease progression and development of drug resistance in advanced RCC. We analyzed human RCC tissue from multiple regions in the primary index tumor, cancer-associated normal adjacent parenchyma, intravascular tumor in locally advanced cancer patients. We found that the higher nuclear Nox4 expression was significantly associated with progression and death. These findings were consistent after controlling for other competing clinical variables. In contrast, patients with lower nuclear Nox4, even in higher stage RCC had better prognosis. We identified a subset of patients with high nuclear Nox4 who had rapid disease progression or died within 6 months of surgery. In addition, higher nuclear Nox4 level correlated with resistance to targeted therapy and immunotherapy. Western blotting performed on fresh human RCC tissue as well as cell-lines revealed increased nuclear Nox4 expression. Our data support an important prognostic role of Nox4 mediated regulation of RCC independent of other competing variables. Nox4 localizes to the nucleus in high-grade, high-stage RCC. Higher nuclear Nox4 has prognostic significance for disease progression, poor survival, and development of drug resistance in RCC.
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http://dx.doi.org/10.1016/j.trsl.2020.05.009DOI Listing
September 2020

Analyzing National Incidences and Predictors of Open Conversion During Minimally Invasive Partial Nephrectomy for cT1 Renal Masses.

J Endourol 2021 Jan 22;35(1):30-38. Epub 2020 Jun 22.

Department of Urology and UT Health San Antonio, San Antonio, Texas, USA.

To analyze predictors of open conversion during minimally invasive partial nephrectomy (MIPN) for cT1 renal masses. The National Cancer Database (NCDB) was investigated for kidney cancer patients who underwent partial nephrectomy (PN) between 2010 and 2015. Patients who underwent MIPN were stratified into converted and nonconverted groups. Sociodemographics, facility characteristics, and surgical outcomes were compared between the two groups, and multivariate logistic regression model was fitted to identify independent predictors of open conversion. In total, 54,246 patients underwent PN for kidney cancer during the 6-year period. Of those, 18,994 (35%) were open partial nephrectomies (OPNs) and 35,252 (64%) were MIPN. Overall, 1010 (2.87%) of MIPNs were converted to OPN. There was an increasing utilization of MIPN from 50.35% in 2010 to 74.73% in 2015. Patients who had open conversion had more 30-day readmissions (5.95% 3.31%,  < 0.01). On multivariate analysis; high-volume facility (>30 MIPNs/year), year of surgery (2015 2010), and robotic approach predicted a lower likelihood of conversion (odds ratio [OR] 0.52, confidence interval [CI] 0.44-0.62; OR 0.59, CI 0.47-0.73; and OR 0.31, CI 0.27-0.35; respectively,  < 0.001 for all). Conversely, Medicaid ( private insurance; OR 1.75, CI 1.39-2.19,  < 0.001) and male sex (OR 1.26, CI 1.11-1.44,  < 0.001) were independent predictors of conversion. Open conversion in MIPN occurred in 2.87% of cases. There was an increasing utilization of MIPN associated with decreased conversion rates. Higher volume hospitals and progressing year of surgery were associated with less likelihood of conversion.
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http://dx.doi.org/10.1089/end.2020.0161DOI Listing
January 2021

Microbiome within Primary Tumor Tissue from Renal Cell Carcinoma May Be Associated with PD-L1 Expression of the Venous Tumor Thrombus.

Adv Urol 2020 18;2020:9068068. Epub 2020 Feb 18.

Department of Urology, University of Texas Health San Antonio, San Antonio, TX, USA.

Objective: To perform a proof of concept microbiome evaluation and PD-L1 expression profiling in clear-cell renal cell carcinoma (cc-RCC) with associated tumor thrombus (TT).

Methods: After IRB approval, six patients underwent radical nephrectomy (RN) with venous tumor thrombectomy (VTT). We collected fresh tissue specimens from normal adjacent, tumor, and thrombus tissues. We utilized RNA sequencing to obtain PD-L1 expression profiles and perform microbiome analysis. Statistical assessment was performed using Student's -test, chi-square, and spearman rank correlations using SPSS v25.

Results: We noted the tumor thrombus to be mostly devoid of diverse microbiota. A large proportion of was detected and unknown if this is a surgical or postsurgical contaminant; however, it was noted more in the thrombus than other tissues. Microbiome diversity profiles were most abundant in the primary tumor compared to the thrombus or normal adjacent tissue. Differential expression of PD-L1 was examined in the tumor thrombus to the normal background tissue and noted three of the six subjects had a threshold above 2-fold. These three similar subjects had foreign microbiota that are typical residents of the oral microbiome.

Conclusion: Renal tumors have more diverse microbiomes than normal adjacent tissue. Identification of resident oral microbiome profiles in clear-cell renal cancer with tumor thrombus provides a potential biomarker for thrombus response to PD-L1 inhibition.
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http://dx.doi.org/10.1155/2020/9068068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049446PMC
February 2020

The utilization status of neoadjuvant chemotherapy in muscle-invasive bladder cancer: a systematic review and meta-analysis.

Minerva Urol Nefrol 2020 Jan 7. Epub 2020 Jan 7.

Key Laboratory of Gansu Province for Urological Diseases, Gansu Nephro-Urological Clinical Center, Institute of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China -

Introduction: To give a comprehensive depiction of the utilization status of neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC) worldwide.

Evidence Acquisition: Potential relevant research papers of Pubmed, Embase, Web of Science, and the Cochrane Library were reviewed to identify eligible studies. Primary outcomes of this meta-analysis were utilization rate of NAC and its utility distribution in different genders, races, ages, countries and temporal trends. The utilization rates of NAC were calculated as 'Proportion (s)' with 95% confidence intervals (CIs) and pooled estimates were calculated by using a random-effect model.

Evidence Synthesis: A total of thirteen studies and 35,738 patients were included. The total proportion of NAC applied in MIBC populations prior to radical cystectomy (RC) was 17.2% (95% CI: 12.5%-21.9%, I2=99.7%). The comparative analyses showed there were no significant differences existing in different genders or races on NAC utilization rates. In terms of age distribution, <60 age group conferred higher utilization rate of NAC than the older (OR=1.919, 95% CI: 1.671-2.202, P=0.0001). As for regional distribution, our meta-analysis showed that Japan (Proportion: 44.0%, 95% CI: 6.5%-81.5%, I2=99.6%) and Sweden (37.9%, 95% CI: 34.9%-40.8%) were the top two leading countries which contributed to the most frequent application of NAC. In respect of pathologic responses after NAC, complete, partial and down-staged pathologic responses were achieved in 16.6% (95% CI: 7.4%-25.9%, I2=89.7%), 14.6% (95% CI: 0.8%-28.5%, I2=89.7%) and 45.0% (95% CI: 17.8%-72.2%, I2=98.8%) patients, respectively.

Conclusions: The present study shows the low utilization rate of NAC in MIBC patients. Standardization of the treatment modality of MIBC and promotion of guidelines might be necessary to expedite the adoption of NAC in near future.
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http://dx.doi.org/10.23736/S0393-2249.19.03648-8DOI Listing
January 2020

Carotenoid Intake and Circulating Carotenoids Are Inversely Associated with the Risk of Bladder Cancer: A Dose-Response Meta-analysis.

Adv Nutr 2020 05;11(3):630-643

Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX, USA.

Some evidence indicates that carotenoids may reduce the risk of bladder cancer (BC), but the association is unclear. We conducted a systematic review and meta-analysis of case-control and cohort studies investigating the relation between carotenoid intake or circulating carotenoid concentrations and BC risk in men and women. All relevant epidemiologic studies were identified by a search of PubMed and Scopus databases, and the Cochrane Library from inception to April 2019 with no restrictions. A random-effects model was used to calculate pooled RRs and their 95% CIs across studies for high compared with low categories of intake or circulating concentrations. We also performed a dose-response meta-analysis using the Greenland and Longnecker method and random-effects models. A total of 22 studies involving 516,740 adults were included in the meta-analysis. The pooled RRs of BC for the highest compared with the lowest category of carotenoid intake and circulating carotenoid concentrations were 0.88 (95% CI: 0.76, 1.03) and 0.36 (95% CI: 0.12, 1.07), respectively. The pooled RR of BC for the highest compared with lowest circulating lutein and zeaxanthin concentrations was 0.53 (95% CI: 0.33, 0.84). Dose-response analysis showed that BC risk decreased by 42% for every 1 mg increase in daily dietary β-cryptoxanthin intake (RR: 0.58; 95% CI: 0.36, 0.94); by 76% for every 1 μmol/L increase in circulating concentration of α-carotene (RR: 0.24; 95% CI: 0.08, 0.67); by 27% for every 1 μmol/L increase in circulating concentration of β-carotene (RR: 0.73; 95% CI: 0.57, 0.94); and by 56% for every 1 μmol/L increase in circulating concentrations of lutein and zeaxanthin (RR: 0.44; 95% CI: 0.28, 0.67). Dietary β-cryptoxanthin intake and circulating concentrations of α-carotene, β-carotene, and lutein and zeaxanthin were inversely associated with BC risk. The protocol was registered at PROSPERO as CRD42019133240.
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http://dx.doi.org/10.1093/advances/nmz120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231589PMC
May 2020

Health Care Disparities in Urologic Oncology: A Systematic Review.

Urology 2020 02 23;136:9-18. Epub 2019 Nov 23.

University of Texas Health Science Center San Antonio, Department of Urology, San Antonio, TX 78229.

For prostate cancer, we review racial differences in incidence, androgen pathways, growth factors, tumor location, rate of definitive treatment, and outcomes. We review the effect of race on risk-stratification and discuss studies of active surveillance in the African American population. For bladder cancer, race- and gender- associated differences in incidence, sex hormone pathways. For renal cell carcinoma, disparities in incidence, genetic factors, tumor pathology, time to presentation, and disease specific survival have been observed. We evaluate the impact of race and ethnicity on tumor pathology and discuss gaps in our current understanding of renal cell carcinoma pathogenesis.
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http://dx.doi.org/10.1016/j.urology.2019.09.058DOI Listing
February 2020

Increased expression of TRIP13 drives the tumorigenesis of bladder cancer in association with the EGFR signaling pathway.

Int J Biol Sci 2019 2;15(7):1488-1499. Epub 2019 Jun 2.

Department of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou 730000, China.

Thyroid hormone receptor interactor 13 (TRIP13) is a crucial regulator of the spindle apparatus checkpoint and double-stranded break repair. The abnormal expression of TRIP13 was recently found in several human cancers, whereas the role of TRIP13 in the development of bladder cancer (BCa) has not been fully elucidated. Here, we reported that TRIP13 expression was elevated in BCa tissues compared with normal bladder tissues. Notably, the increased expression of TRIP13 was correlated with advanced tumor stage, lymph node metastasis, distant metastasis and reduced survival in BCa patients. Knockdown of TRIP13 in bladder cancer cells suppressed proliferation, induced cell cycle arrest, promoted apoptosis, and impaired cell motility, ultimately inhibiting tumor xenograft growth. Mechanistic investigations revealed that TRIP13 directly bound to epidermal growth factor receptor (EGFR), modulating the EGFR signaling pathway. Furthermore, TRIP13 expression was positively correlated with EGFR expression in BCa specimens, and the high expression of both TRIP13 and EGFR predicted poor survival. Overall, our results underscore the crucial role of TRIP13 in the tumorigenesis of BCa and provide a novel biomarker and therapeutic target for BCa treatment.
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http://dx.doi.org/10.7150/ijbs.32718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643140PMC
April 2020

Pan-cancer analysis of iron metabolic landscape across the Cancer Genome Atlas.

J Cell Physiol 2020 02 25;235(2):1013-1024. Epub 2019 Jun 25.

Department of Urology, Lanzhou University Second Hospital, Lanzhou, China.

Iron is an essential metal ion in the human body and usually dysregulated in cancers. However, a comprehensive overview of the iron-related genes and their clinical relevance in cancer is lacking. In this study, we utilized the expression profiling, proteomics, and epigenetics from the Cancer Genome Atlas database to systematically characterized the alterations of iron-related genes. There were multiple iron-related genes with dysregulation across 14 cancers and some of these ectopic changes may be associated with aberrant DNA methylation. Meanwhile, a variety of genes were significantly associated with patient survival, especially in kidney renal clear cell carcinoma. Then differentially expressed genes were validated in clinical samples. Finally, we found deferoxamine and erastin could inhibit proliferation in various tumor cells and influence the expression of several iron-related genes. Overall, our study provides a comprehensive analysis of iron metabolism across cancers and highlights the potential treatment of iron targeted therapies for cancers.
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http://dx.doi.org/10.1002/jcp.29017DOI Listing
February 2020

Association of CCL2, CCR2 and CCL5 genetic polymorphisms with the development and progression of benign prostatic hyperplasia.

Oncol Rep 2019 Apr 6;41(4):2491-2501. Epub 2019 Feb 6.

Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu 730030, P.R. China.

Benign prostatic hyperplasia (BPH) is a common chronic disease in older males. The pathogenesis of BPH remains elusive but may be associated with chronic inflammation. Chemokines and chemokine receptors have been implicated as critical mediators in the immune response and inflammatory processes. In the present study, the aim was to evaluate the association of three polymorphisms in chemokine genes, namely C‑C motif chemokine ligand (CCL)2 rs1024611, CC chemokine receptor 2 (CCR2) rs1799864 and CCL5 rs2107538, with BPH risk. These polymorphisms were genotyped in 109 patients with BPH and 160 control subjects, using the polymerase chain reaction and multiple ligase detection reaction method. The CCL5 rs2107538 polymorphism was identified to be associated with a significantly lower risk of BPH [A/G vs. G/G: odds ratio (OR)=0.37, 95% confidence interval (CI)=0.17‑0.78; A/A + A/G vs. G/G: OR=0.39, 95% CI=0.19‑0.79; A vs. G: OR=0.58, 95% CI=0.35‑0.96). However, this polymorphism was also associated with the development of larger prostate volumes in patients with BPH (A/G vs. G/G: OR=3.02, 95% CI=1.28‑7.11; AA + AG vs. GG: OR=2.83, 95% CI=1.28‑6.26; A vs. G: OR=1.94, 95% CI=1.08‑3.49). The CCR2 rs1799864 polymorphism was associated with lower International Prostate Symptom Score values (A/A + A/G vs. G/G: OR=0.39, 95% CI=0.17‑0.91; A vs. G: OR=0.43, 95% CI=0.20‑0.90) and low Qmax (A/G vs. G/G: OR=0.38, 95% CI=0.16‑0.92; AA + AG vs. GG: OR=0.39, 95% CI=0.17‑0.91) in the patients. No association was observed between the CCL2 rs1024611 polymorphism and BPH. These results suggest that the CCR2 and CCL5 genes may contribute to the occurrence and progression of BPH.
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http://dx.doi.org/10.3892/or.2019.7002DOI Listing
April 2019

Immunogenic Heterogeneity of Renal Cell Carcinoma With Venous Tumor Thrombus.

Urology 2019 02 29;124:168-173. Epub 2018 Oct 29.

Department of Urology, University of Texas Health San Antonio, San Antonio, TX; Department of Cell and Molecular Biology, University of Texas Health San Antonio, San Antonio, TX; Department of Epidemiology and Biostatistics, University of Texas Health San Antonio, San Antonio, TX; GreeheyChildren's Cancer Research Institute, University of Texas Health San Antonio, SanAntonio, TX.

Objective: To perform immune-cell enumeration and programmed death-ligand 1 (PD-L1) expression in clear cell renal cell carcinoma (cc-RCC) with tumor thrombus (TT) to guide therapeutic decisions.

Methods: After obtaining IRB approval and surgical consent, 6 patients underwent radical nephrectomy with venous tumor thrombectomy. We utilized RNA Sequencing to obtain RNAseq expression profiles. Computational calculation and enumeration of immune cells were performed using CIBERSORT, xCell, and ingenuity pathway analysis software. Statistical assessment was conducted using a t test, chi-square, ANOVA and Spearman rank correlations using SPSS v21.

Results: We observed a higher proportion of M1 macrophages in the primary tumor and tumor thrombus, while we noted no difference in M2 macrophages despite M2 representing a high number in thrombus samples. (ANOVA, P = .032, and P = .89, respectively). Validation with xCell and ingenuity pathway analysis analysis showed a high involvement of macrophages. We observed a higher number of M1 macrophages (CIBERSORT mean 0.11 vs 0.03, P < 0.01) and (nonactivated) resting Natural Killer (NK) cells (0.077 vs 0.017, P = .02) associated PD-L1 high expression of the primary tumor. PDL1 expression was variable without differences in tumor stage, level, or immune cell detection. We observed an inverse correlation of mean platelet volume with PD-L1 expression within the primary tumor (Spearman, -0.89, P = 02) and the TT (Spearman, -0.77, P = 0.07).

Conclusion: Renal tumor thrombus has higher levels of M1 macrophages that could be utilized as additional targets for future drug development. The PD-L1 expression on clear cell RCC biopsy may not represent its corresponding TT. Future studies are needed to confirm mean platelet volume as a potential blood-based biomarker for PD-L1 expression in RCC.
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http://dx.doi.org/10.1016/j.urology.2018.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382529PMC
February 2019

Loss of Cyclin-Dependent Kinase Inhibitor Alters Oncolytic Adenovirus Replication and Promotes More Efficient Virus Production.

Cancers (Basel) 2018 Jun 15;10(6). Epub 2018 Jun 15.

Department of Urology, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.

We elucidate the role of p21/Waf-1, a cyclin-dependent kinase inhibitor, on the oncolytic infection and replication cycle of adenovirus by studying both mRNA and adenoviral proteins expression. We found that infection in the absence of p21 causes a significant increase in adenoviral genomes and late gene expression. Similarly, the oncolytic adenoviral infected p21 cells have earlier formation of replication foci and robust replication kinetics that were not observed in the wild type p21/Waf-1 intact cells. These findings suggest a culmination that the presence of intact p21 in host cells causes defects in the oncolytic viral life cycle which results in the production of immature and noninfectious particles.
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http://dx.doi.org/10.3390/cancers10060202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025342PMC
June 2018

Contemporary surgical outcomes of venous tumour thrombectomy managed with intraoperative Doppler ultrasound for kidney cancer.

Can Urol Assoc J 2018 May 14. Epub 2018 May 14.

Department of Urology.

Introduction: Radical nephrectomy (RN) with venous tumour thrombectomy (VTT) carries a significant morbidity and mortality risk. Examination of a contemporary single-institution series permits the development of a management algorithm and an audit its results. We report outcomes following the use of intraoperative colour Doppler ultrasound and our surgical pathway.

Methods: We retrospectively reviewed the records of all patients who underwent RN with VTT for kidney cancer between January 1, 2013 and October 1, 2016. Surgical complications, postoperative complications (Clavien-Dindo classification ≥3), 90-day readmission rates, and outcomes are reported. Multivariate linear regression, logistic regression, and Cox proportional hazard modelling were used to identify associations.

Results: Fifty-eight patients underwent RN with VTT. Of these, 26 (45%) patients had Mayo Clinic level III or IV thrombus and nineteen required venovenous/cardiopulmonary bypass. Three patients required patch grafting. The median length of hospital stay was eight days and there were 20 major complications. The 30-day readmission rate was 21% and the 90-day mortality rate was 8.9%. In multivariate analysis, low serum albumin and age-adjusted Charlson comorbidity score predicted length of stay. Increased intraoperative blood loss was significantly associated with increasing body mass index, serum creatinine, tumour thrombus level, and a history of significant weight loss >9.1kg. Low serum hematocrit predicted 90-day mortality.

Conclusions: Intraoperative colour Doppler ultrasound is a useful tool and can facilitate caval preservation. Caval grafting can be avoided in most cases. Venovenous bypass can be avoided in many level III cases. Early therapeutic anticoagulation should be instituted with caution.
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http://dx.doi.org/10.5489/cuaj.5013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143503PMC
May 2018

Conserved residues are critical for Haloferax volcanii archaeosortase catalytic activity: Implications for convergent evolution of the catalytic mechanisms of non-homologous sortases from archaea and bacteria.

Mol Microbiol 2018 05 23;108(3):276-287. Epub 2018 Mar 23.

Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.

Proper protein anchoring is key to the biogenesis of prokaryotic cell surfaces, dynamic, resilient structures that play crucial roles in various cell processes. A novel surface protein anchoring mechanism in Haloferax volcanii depends upon the peptidase archaeosortase A (ArtA) processing C-termini of substrates containing C-terminal tripartite structures and anchoring mature substrates to the cell membrane via intercalation of lipid-modified C-terminal amino acid residues. While this membrane protein lacks clear homology to soluble sortase transpeptidases of Gram-positive bacteria, which also process C-termini of substrates whose C-terminal tripartite structures resemble those of ArtA substrates, archaeosortases do contain conserved cysteine, arginine and arginine/histidine/asparagine residues, reminiscent of His-Cys-Arg residues of sortase catalytic sites. The study presented here shows that ArtA -GFP expressed in trans complements ΔartA growth and motility phenotypes, while alanine substitution mutants, Cys (C173A), Arg (R214A) or Arg (R253A), and the serine substitution mutant for Cys (C173S), fail to complement these phenotypes. Consistent with sortase active site replacement mutants, ArtA -GFP, ArtA -GFP and ArtA -GFP cannot process substrates, while replacement of the third residue, ArtA -GFP retains some processing activity. These findings support the view that similarities between certain aspects of the structures and functions of the sortases and archaeosortases are the result of convergent evolution.
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http://dx.doi.org/10.1111/mmi.13935DOI Listing
May 2018

The Candida albicans stress response gene Stomatin-Like Protein 3 is implicated in ROS-induced apoptotic-like death of yeast phase cells.

PLoS One 2018 1;13(2):e0192250. Epub 2018 Feb 1.

Department of Sciences, John Jay College of the City University of New York, New York, New York, United States of America.

The ubiquitous presence of SPFH (Stomatin, Prohibitin, Flotillin, HflK/HflC) proteins in all domains of life suggests that their function would be conserved. However, SPFH functions are diverse with organism-specific attributes. SPFH proteins play critical roles in physiological processes such as mechanosensation and respiration. Here, we characterize the stomatin ORF19.7296/SLP3 in the opportunistic human pathogen Candida albicans. Consistent with the localization of stomatin proteins, a Slp3p-Yfp fusion protein formed visible puncta along the plasma membrane. We also visualized Slp3p within the vacuolar lumen. Slp3p primary sequence analyses identified four putative S-palmitoylation sites, which may facilitate membrane localization and are conserved features of stomatins. Plasma membrane insertion sequences are present in mammalian and nematode SPFH proteins, but are absent in Slp3p. Strikingly, Slp3p was present in yeast cells, but was absent in hyphal cells, thus categorizing it as a yeast-phase specific protein. Slp3p membrane fluorescence significantly increased in response to cellular stress caused by plasma membrane, cell wall, oxidative, or osmotic perturbants, implicating SLP3 as a general stress-response gene. A slp3Δ/Δ homozygous null mutant had no detected phenotype when slp3Δ/Δ mutants were grown in the presence of a variety of stress agents. Also, we did not observe a defect in ion accumulation, filamentation, endocytosis, vacuolar structure and function, cell wall structure, or cytoskeletal structure. However, SLP3 over-expression triggered apoptotic-like death following prolonged exposure to oxidative stress or when cells were induced to form hyphae. Our findings reveal the cellular localization of Slp3p, and for the first time associate Slp3p function with the oxidative stress response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192250PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794166PMC
April 2018

Partial Nephrectomy versus Thermal Ablation for Clinical Stage T1 Renal Masses: Systematic Review and Meta-Analysis of More than 3,900 Patients.

J Vasc Interv Radiol 2018 Jan;29(1):18-29

Department of Urology, University of Texas Health, San Antonio, Texas; Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Electronic address:

Purpose: A systematic review and meta-analysis of clinical trials was undertaken to compare percutaneous thermal ablation versus partial nephrectomy (PN) for stage T1 renal tumors.

Materials And Methods: A comprehensive search of major databases was conducted from October 2000 to July 2016. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. Incidences of all-cause mortality (ACM), cancer-specific mortality (CSM), local recurrence (LR), and metastases, as well as complication rates and changes in estimated glomerular filtration rate (eGFR), were evaluated.

Results: Inclusion criteria were met by 15 of 961 papers. These studies represented 3,974 patients who had undergone an ablative procedure (cryoablation or radiofrequency ablation; n = 1,455; 37%) or PN (n = 2,519; 63%). ACM and CSM rates were higher for ablation than for PN (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.54-2.87 [P < .05]; HR, 3.84; 95% CI, 1.66-8.88 [P < .05], respectively). No statistically significant difference in LR rate or risk of metastasis was seen between ablation and PN (HR, 1.32; 95% CI, 0.79-2.22 [P = .22]; HR, 1.83; 95% CI, 0.67-5.01 [P = 0.23], respectively). Complication rates were lower for ablation than for PN (13% vs 17.6%; odds ratio, 0.49; 95% CI, 0.25-0.94; P < .05). A significantly greater decrease in eGFR was observed after PN (13.09 mL/min/1.73 m) vs ablation therapy (4.47 mL/min/1.73 m).

Conclusions: Thermal ablation showed no significant difference in LR or metastases compared with PN. Thermal ablation was associated with a lower morbidity rate and a lesser reduction in eGFR compared with PN, but with higher ACM and CSM rates.
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http://dx.doi.org/10.1016/j.jvir.2017.08.013DOI Listing
January 2018

NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance.

Nat Commun 2017 10 19;8(1):997. Epub 2017 Oct 19.

Department of Medicine, UT Health, San Antonio, TX, 78229, USA.

The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear. Here we identify an ATP-binding motif within the NADPH oxidase isoform, NOX4, and show that ATP directly binds and negatively regulates NOX4 activity. We find that NOX4 localizes to the inner mitochondria membrane and that subcellular redistribution of ATP levels from the mitochondria act as an allosteric switch to activate NOX4. We provide evidence that NOX4-derived reactive oxygen species (ROS) inhibits P300/CBP-associated factor (PCAF)-dependent acetylation and lysosomal degradation of the pyruvate kinase-M2 isoform (PKM2). Finally, we show that NOX4 silencing, through PKM2, sensitizes cultured and ex vivo freshly isolated human-renal carcinoma cells to drug-induced cell death in xenograft models and ex vivo cultures. These findings highlight yet unidentified insights into the molecular events driving cancer evasive resistance and suggest modulation of ATP levels together with cytotoxic drugs could overcome drug-resistance in glycolytic cancers.
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http://dx.doi.org/10.1038/s41467-017-01106-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648812PMC
October 2017

XBSeq2: a fast and accurate quantification of differential expression and differential polyadenylation.

BMC Bioinformatics 2017 Oct 3;18(Suppl 11):384. Epub 2017 Oct 3.

Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Background: RNA sequencing (RNA-seq) is a high throughput technology that profiles gene expression in a genome-wide manner. RNA-seq has been mainly used for testing differential expression (DE) of transcripts between two conditions and has recently been used for testing differential alternative polyadenylation (APA). In the past, many algorithms have been developed for detecting differentially expressed genes (DEGs) from RNA-seq experiments, including the one we developed, XBSeq, which paid special attention to the context-specific background noise that is ignored in conventional gene expression quantification and DE analysis of RNA-seq data.

Results: We present several major updates in XBSeq2, including alternative statistical testing and parameter estimation method for detecting DEGs, capacity to directly process alignment files and methods for testing differential APA usage. We evaluated the performance of XBSeq2 against several other methods by using simulated datasets in terms of area under the receiver operating characteristic (ROC) curve (AUC), number of false discoveries and statistical power. We also benchmarked different methods concerning execution time and computational memory consumed. Finally, we demonstrated the functionality of XBSeq2 by using a set of in-house generated clear cell renal carcinoma (ccRCC) samples.

Conclusions: We present several major updates to XBSeq. By using simulated datasets, we demonstrated that, overall, XBSeq2 performs equally well as XBSeq in terms of several statistical metrics and both perform better than DESeq2 and edgeR. In addition, XBSeq2 is faster in speed and consumes much less computational memory compared to XBSeq, allowing users to evaluate differential expression and APA events in parallel. XBSeq2 is available from Bioconductor: http://bioconductor.org/packages/XBSeq/.
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http://dx.doi.org/10.1186/s12859-017-1803-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629564PMC
October 2017

Overexpression of Exportin-5 Overrides the Inhibitory Effect of miRNAs Regulation Control and Stabilize Proteins via Posttranslation Modifications in Prostate Cancer.

Neoplasia 2017 Oct 4;19(10):817-829. Epub 2017 Sep 4.

Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, TX.

Although XPO5 has been characterized to have tumor-suppressor features in the miRNA biogenesis pathway, the impact of altered expression of XPO5 in cancers is unexplored. Here we report a novel "oncogenic" role of XPO5 in advanced prostate cancer. Using prostate cancer models, we found that excess levels of XPO5 override the inhibitory effect of the canoncial miRNA-mRNA regulation, resulting in a global increase in proteins expression. Importantly, we found that decreased expression of XPO5 could promote an increase in proteasome degradation, whereas overexpression of XPO5 leads to altered protein posttranslational modification via hyperglycosylation, resulting in cellular protein stability. We evaluated the therapeutic advantage of targeting XPO5 in prostate cancer and found that knocking down XPO5 in prostate cancer cells suppressed cellular proliferation and tumor development without significantly impacting normal fibroblast cells survival. To our knowledge, this is the first report describing the oncogenic role of XPO5 in overriding the miRNAs regulation control. Furthermore, we believe that these findings will provide an explanation as to why, in some cancers that express higher abundance of mature miRNAs, fail to suppress their potential protein targets.
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http://dx.doi.org/10.1016/j.neo.2017.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587889PMC
October 2017

A novel bladder cancer - specific oncolytic adenovirus by CD46 and its effect combined with cisplatin against cancer cells of CAR negative expression.

Virol J 2017 08 8;14(1):149. Epub 2017 Aug 8.

Department of Urology, University of Texas Health Science Center San Antonio 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.

Background: Conditionally replicative oncolytic adenoviruses (CRAds) display significant anti-tumor effects. However, the traditional adenovirus of serotype 5 (Ad5) entering cancer cells via coxsackie virus and adenovirus receptor (CAR) can't be utilized for bladder cancer with low expression of CAR, which limits the application of Ad5.

Methods: We utilized Ad5/F11p containing the chimeric fiber gene encoding the Ad5 fiber tail domain and Ad11p fiber shaft and knob domains to construct bladder cancer-specific chimeric type viruses Ad5/F11p-PSCAE-UPII-E1A, which can infect bladder cancer cells mediated by CD46 molecule. We carried out series of experiments in vitro to research anti-tumor effect of Ad5/F11p-PSCAE-UPII-E1A and the interaction in combination with cisplatin.

Results: The results demonstrated Ad5/F11p-PSCAE-UPII-E1A could infect bladder cancer cells (T24, EJ and 5637) in a CAR-independent way, and exert anti-tumor effect by blocking the cancer cells in G1 phase and inducing apoptosis. Ad5/F11p-PSCAE-UPII-E1A plus cisplatin enhanced the anti-proliferative effect and increased the number of apoptotic cells compared with viruses or cisplatin alone. Ad5/F11p-PSCAE-UPII-E1A plus cisplatin could upregulate the proteins expression of p53, Bax, and cleaved caspase-3, and downregulated Bcl-2 protein expression in T24, EJ and 5637 cells.

Conclusion: We constructed a bladder cancer-specific oncolytic adenovirus and provided new combination treatment strategies for bladder cancer.
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http://dx.doi.org/10.1186/s12985-017-0818-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549334PMC
August 2017

Synergistic effect of bladder cancer-specific oncolytic adenovirus in combination with chemotherapy.

Oncol Lett 2017 Aug 19;14(2):2081-2088. Epub 2017 Jun 19.

Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Gene therapy with adenoviral early region gene (E1A) may enhance the susceptibility of neoplastic cells to chemotherapy-induced cell death. Our previous study developed a urothelium-specific oncolytic serotype 5 adenovirus (Ad5) with the uroplakin II (UPII) promoter controlling E1A expression. The present study investigated whether this urothelium-specific recombinant adenovirus (Ad5-UPII-E1A) enhanced mitomycin (MMC) and hydroxycamptothecin (HCPT) sensitization and drug-induced apoptosis in bladder cancer cells. The results of the MTT assay revealed that combination therapy, using Ad5-UPII-E1A and MMC or HCPT, synergistically inhibited the viability of bladder cancer cells in a dose- and time-dependent manner when compared with either agent alone. When cells were treated with Ad5-UPII-E1A alone they arrested in the G1 phase, but cell cycle analysis by flow cytometry revealed S phase arrest when treated with combined therapy. Treatment with MMC or HCPT enhanced Ad5-UPII-E1A-induced apoptosis in 5,637 cells, observed by transmission electron microscopy. Western blot analysis revealed that MMC and HCPT enhanced the E1A expression of the Ad5-UPII-E1A vectorin a dose-dependent manner. The present study demonstrated that Ad5-UPII-E1A combined with MMC or HCPT resulted in synergistic cytotoxicity in a process which involved the promotion of apoptosis in bladder cancer cell lines. MMC and HCPT also promoted the oncolytic effect of Ad5-UPII-E1A. Thus, treatment using Ad5-UPII-E1A combined with MMC or HCPT may be an attractive strategy for the sensitization of bladder cancer to chemotherapy.
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http://dx.doi.org/10.3892/ol.2017.6416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530188PMC
August 2017

Clinical and Prognostic Effect of Plasma Fibrinogen in Renal Cell Carcinoma: A Meta-Analysis.

Biomed Res Int 2017 5;2017:9591506. Epub 2017 Jan 5.

Institute of Urology, Lanzhou University Second Hospital, Key Laboratory of Gansu Province for Urological Diseases, Gansu Nephro-Urological Clinical Center, Lanzhou 730030, China.

. Although numerous studies have shown that plasma fibrinogen is linked to renal cell carcinoma (RCC) risk, the consistency and magnitude of the effect of plasma fibrinogen are unclear. The aim of the study was to explore the association between plasma fibrinogen and RCC prognosis. . An electronic search of Embase, PubMed/MEDLINE, and the Cochrane databases was performed to identify relevant studies published prior to June 1, 2016. . A total of 3744 patients with RCC from 7 published studies were included in the meta-analysis. The prognostic and clinical relevance of plasma fibrinogen are evaluated in RCC patients. Statistical significance of the combined hazard ratio (HR) was detected for overall survival, cancer-specific survival, and disease-free survival. Our pooled results showed that elevated plasma fibrinogen was significantly associated with clinical stage and Fuhrman grading. The level of plasma fibrinogen was not found to be associated with tumor type and gender. . Elevated plasma fibrinogen is a strong indicator of poorer prognosis of patients with RCC, whereas the plasma fibrinogen is not significantly associated with tumor type. Therefore, plasma fibrinogen could be used in patients with RCC for risk stratification and decision providing a proper therapeutic strategy.
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http://dx.doi.org/10.1155/2017/9591506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244001PMC
February 2017

Lentivirus-mediated p21/Waf-1 short hairpin RNA enhances the cytotoxic effects and replicative potential of a bladder cancer-specific oncolytic adenovirus in vitro.

Anticancer Drugs 2017 01;28(1):88-96

aInstitute of Cell Biology, School of Life Sciences bDepartment of Pharmacology, School of Basic Medical Sciences, Lanzhou University cKey Laboratory of Urological Diseases in Gansu Province, Department of Urology, Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, China dDepartment of Urology, University of Texas Health Science Center, San Antonio, Texas, USA.

Our previous work confirmed that the bladder cancer-specific oncolytic adenovirus Ad/PSCAE/UPII/E1A could selectively replicate in bladder cancer cells, thus causing specific tumor cell lysis. The replicative potential is a crucial factor in determining the therapeutic efficacy of oncolytic adenoviruses. However, viral replication is attenuated by the low-activity promoter that we used, thus compromising viral cytotoxicity. In this study, we investigated the effect of the cell cycle-dependent kinase inhibitor p21/Waf-1 on an adenovirus. We used lentivirus-mediated short hairpin RNA to knock down p21/Waf-1 in two bladder cancer cell lines EJ and 5637. The p21/Waf-1 knockdown not only induced stronger cytopathic effects but also augmented apoptosis, which was closely associated with the enhancement of Fas and the subsequent significant activation of caspase-3. A replicative assay showed that p21/Waf-1 knockdown increased the viral particle production. Western blot analysis confirmed that p21/Waf-1 knockdown upregulated the expression of androgen receptor (AR) and two adenovirus replication indicators E1A and hexon. A luciferase activity assay indicated higher transcriptional activity of the uroplakin II (UPII) promoter in the p21/Waf-1 knockdown cells, and one possible mechanism could be that the increased expression of AR induced the UPII promoter through the AR-binding sites of the prostate stem cell antigen enhancer. These findings indicating that p21/Waf-1 knockdown could enhance cell killing and viral replication have significant implications for the development of bladder cancer-specific oncolytic adenovirus therapies.
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http://dx.doi.org/10.1097/CAD.0000000000000433DOI Listing
January 2017

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells.

Oncol Lett 2016 Sep 18;12(3):1826-1832. Epub 2016 Jul 18.

Department of Minimally Invasive Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.

Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis ; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.
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http://dx.doi.org/10.3892/ol.2016.4880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998110PMC
September 2016