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

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

Cell-Free DNA, MicroRNAs, Proteins, and Peptides as Liquid Biopsy Biomarkers in Prostate Cancer and Bladder Cancer.

Liquid biopsy, as a novel noninvasive tool for biomarker discovery, has gained a lot of attention and represents a significant innovation in precision medicine. Due to its minimally invasive nature, liquid biopsy has fewer complications and can be scheduled more frequently to provide individualized snapshots of the disease at successive time points. This is particularly valuable in providing simultaneous measurements of tumor burden during treatment and early detection of tumor recurrence or drug resistance. Blood-based liquid biopsy is an attractive, minimally invasive alternative, which has shown promise in diagnosis, risk stratification, disease monitoring, and more. Urine has gained popularity due to its less invasive sampling, the ability to easily repeat samples, and the ability to track tumor evolution in real time, making it a powerful tool for diagnosis and treatment monitoring, especially in urologic cancers. In this review, we provide a detailed discussion on the potential clinical applications of prostate cancer (PCa) and bladder cancer (BCa), with cell-free DNA (cfDNA), microRNAs (miRNAs), proteins, and peptides as liquid biopsy biomarkers.

5-Aminolevulinic acid combined with ferrous iron ameliorates scrotal heat stress-induced spermatogenic damage by enhancing HO-1 expression.

OBJECTIVE: To explore whether 5-Aminolevulinic acid combined with ferrous iron (5-ALA/Fe2+) could protect testicular tissues damage of mice subjected to heat stress (HS) and provide its underlying mechanisms. METHODS: 5-ALA/Fe2+ was administered intragastrically to mice for 10 days, then exposed to a scrotal heat stress at 43°C for 20 min on third day. Testes were harvested for morphologic and histopathological examination, oxidative stress, apoptosis, heme oxygenase-1 (HO-1) and inflammation detection. The mitogen-activated protein kinases (MAPK) signaling pathway in testis and CD4+FoxP3+regulatory T (Treg) cells in spleen were also investigated. RESULTS: Compared to control group, the testis weight decreased and histological damage severed in HS group. Besides, HS also increased the oxidative stress, apoptosis and inflammation in testis. However, these indicators were ameliorated after 5-ALA/Fe2+ treatment but deteriorated after receiving ZnPPIX. The expression of HO-1 was increased both in HS group and 5-ALA/Fe2+ group. The protein expression levels of MAPK proteins were activated by HS and inhibited by 5-ALA/Fe2+. The CD4+FoxP3+ Treg generation was reduced by HS and increased by 5-ALA/Fe2+. CONCLUSION: In this study, we have demonstrated that 5-ALA/Fe2+ ameliorated the spermatogenic damage induced by scrotal heat stress via up-regulating the expression of HO-1 and inhibiting MAPK mediated oxidative stress and apoptosis and inducing CD4+Foxp3+ Tregs to inhibit the inflammation induced by HS in mice.

Systematic evaluation of narrow-sense validity of polygenic risk score for prostate cancer in a Chinese prostate biopsy cohort.

The aim of this study was to assess the narrow-sense validity of polygenic risk score (PRS) for prostate cancer (PCa) in a Chinese prostate biopsy cohort. We performed an observational prospective study with 2640 men who underwent prostate biopsy. Germline DNA samples were genotyped and PRS was calculated for each subject using 17 PCa risk-associated genetic variants. Additional GWAS data of the ChinaPCa dataset was also used to compliment the evaluation process. The mean PRS was 1.02 in patients with negative biopsy results, which met the baseline benchmark. The mean PRS was significantly higher in the PCa cases (1.32 vs. 1.02, p = 5.56 × 10-17 ). Significant dose-response associations between PRS values and odds ratios for PCa were observed. However, the raw calibration slope was 0.524 and the average bias score between the observed risk and uncorrected PRS value was 0.307 in the entire biopsy cohort. After applying a correction factor derived from a training set, the corrected calibration slope improved to 1.002 in a testing set. Similar and satisfied results were also seen in the ChinaPCa dataset and two datasets combined, while the calibration results were inaccurate when the calibration process were performed mutually between two different study populations. In conclusion, assessing the narrow-sense validity of PRS is necessary prior to its clinical implementation for accurate individual risk assessment.

Extracellular vesicles from human urine-derived stem cells merged in hyaluronic acid ameliorate erectile dysfunction in type 2 diabetic rats by glans administration.

BACKGROUND: The high prevalence of erectile dysfunction (ED) in patients with type 2 diabetes mellitus (DM2) is a challenging clinical problem. Researches on extracellular vesicles from urine-derived stem cells (USC-EVs) have shown that they have significant therapeutic effects in a variety of diseases by injection including ED. Hyaluronic acid (HA) is especially useful for delivering bioactive molecules. This study investigated the effects and related mechanisms of local administration of human USC-EVs combined with HA (USC-EVs-HA) on a rat model of DM2ED. METHODS: UCSs were extracted from human urine samples and identified for preparation of the corresponding USC-EVs. The effects of high glucose and USC-EVs on human umbilical vein endothelial cells (HUVECs) were assessed in vitro using a CCK-8 assay to determine cell proliferation and pick the most appropriate concentration for subsequent experiments. Scratch and tube formation assays were performed to assess the function of HUVECs. Quantitative real-time polymerase chain reaction (PCR) was used to detect the expression of genes such as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (BAX), and superoxide dismutase-2 (SOD2). HA, USC-EVs, and USC-EVs-HA were prepared at concentrations and then administered topically to DM2ED rats multiple times. Intracavernous pressure and mean arterial pressure were measured to assess erectile function in rats. Masson, Tunel, Immunohistochemistry, and Western blot analysis were performed to assess the fibrosis and endothelial function in corpus cavernosum, respectively. RESULTS: Compared with the control group, the proliferation, migration ability, and tube-forming ability of HUVECs decreased in high glucose environment, while USC-EVs could optimize the function of HUVECs, reverse the expression of apoptotic genes, and enhance the antioxidant capacity. USC-EVs-HA showed improvement in ED compared to the HA and USC-EVs groups, and the 10-dose group was better than the 5-dose group. Histologically, the USC-EVs-HA group significantly improved apoptosis, angiogenesis, and smooth muscle regeneration in the corpus cavernosum compared to the HA group. CONCLUSIONS: The topical application of USC-EVs-HA in the treatment of DM2ED rats has been proved effective. The potential mechanism might to promote the proliferation of endothelial cells and smooth muscle in the corpus cavernosum, which leads to the remodeling of erectile function. And multiple dosing at intervals may make the effect more pronounced.

Hengli® Chinese Botulinum Toxin Type A for Treatment of Patients With Overactive Bladder: A Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: To evaluate the efficacy and safety of Hengli® Chinese botulinum toxin type A (BTX-A; 100 U) in Chinese patients with overactive bladder. Methods: This study was a multicenter, randomized, double-blind, placebo-controlled trial in Chinese patients who were inadequately managed with anticholinergic medications. Eligible patients were randomized 2:1 to receive intradetrusor injections of Hengli® BTX-A (n = 144) or placebo (n = 72). The primary endpoint was the change in the number of daily micturition episodes at week 6 from baseline. The secondary efficacy endpoints included the average frequency of urgency and urinary incontinence (UI) episodes per day, urgency score, average micturition volume per day, OABSS, and QoL score. Results: In the Hengli® BTX-A group, there was a significantly greater reduction in the average number of micturition episodes per 24 h compared with the placebo group (3.28 vs. 1.43; p = 0.003). Moreover, there was a significantly greater improvement in the daily number of urgency episodes, micturition volume and OABSS score. An increased post-void residual urine volume, dysuria, and urinary tract infection represented adverse events (AEs) in the Hengli® BTX-A group. Most AEs were mild or moderate in severity. One patient in the BTX-A group initiated clean intermittent catheterization (CIC) during treatment. Conclusion: Hengli® BTX-A treatment was well-tolerated and resulted in significant improvements in OAB symptoms among Chinese patients inadequately managed by anticholinergics. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/clinicaltrials.prosearch.dhtml, Identifier: CTR20131190.

Prostate Health Index (phi) and its derivatives predict Gleason score upgrading after radical prostatectomy among patients with low-risk prostate cancer.

To analyze the performance of the Prostate Health Index (phi) and its derivatives for predicting Gleason score (GS) upgrading between prostate biopsy and radical prostatectomy (RP) in the Chinese population, an observational, prospective RP cohort consisting of 351 patients from two medical centers was established from January 2017 to September 2020. Pathological reclassification was determined by the Gleason Grade Group (GG). The area under the receiver operating characteristic curve (AUC) and logistic regression (LR) models were used to evaluate the predictive performance of predictors. In clinically low-risk patients with biopsy GG ≤2, phi (odds ratio [OR] = 1.80, 95% confidence interval [95% CI]: 1.14-2.82, P = 0.01) and its derivative phi density (PHID; OR = 2.34, 95% CI: 1.30-4.20, P = 0.005) were significantly associated with upgrading to GG ≥3 after RP, and the results were confirmed by multivariable analysis. Similar results were observed in patients with biopsy GG of 1 for the prediction of upgrading to RP GG≥2. Compared to the base model (AUC = 0.59), addition of the phi or PHID could provide additional predictive value for GS upgrading in low-risk patients (AUC = 0.69 and 0.71, respectively, both P < 0.05). In conclusion, phi and PHID could predict GS upgrading after RP in clinically low-risk patients.

A Germline Variant at 8q24 Contributes to the Serum p2PSA Level in a Chinese Prostate Biopsy Cohort.

INTRODUCTION: The clinical performance of [-2]proPSA (p2PSA) and its derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) has been well evaluated in prostate biopsy patients. However, no study has been performed to evaluate the common genetic determinants that affect serum level of p2PSA. MATERIALS AND METHODS: Here, we performed a two-stage genome-wide association study (GWAS) on the p2PSA level in Chinese men who underwent a transperineal ultrasound-guided prostate biopsy at Huashan Hospital, Shanghai Cancer Center, and Ruijin Hospital in Shanghai, China. Germline variants significantly associated with the p2PSA level in the first stage (n = 886) were replicated in the second stage (n = 1,128). Multivariate linear regression was used to assess the independent contribution of confirmed single nucleotide polymorphisms (SNPs) and known covariates, such as age, to the level of p2PSA. RESULTS: A novel non-synonymous SNP, rs72725879, in region 8q24.21 of the PRNCR1 gene was significantly associated with the serum level of p2PSA in this two-stage GWAS (p = 2.28 × 10-9). Participants with homozygous "T" alleles at rs72725879 had higher p2PSA levels compared to allele "C" carriers. This variant was also nominally associated with PCa risk (p-combined = 3.44 × 10-18). The association with serum level of p2PSA was still significant after adjusting for PCa risk and age (p = 0.017). CONCLUSIONS: Our study shows that the genetic variants in the 8q24.21 region are associated with the serum level of p2PSA in a large-scale Chinese population. By taking inherited variations between individuals into account, the findings of these genetic variants may help improve the performance of p2PSA in predicting prostate cancer.

Genetic risk scores based on risk-associated single nucleotide polymorphisms can reveal inherited risk of bladder cancer in Chinese population.

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with bladder cancer (BCa) risk in Caucasian and East Asian population. The objective of this study was to validate these SNPs in Chinese population and evaluate whether these SNPs could differentiate the individual inherited risk for BCa.A case-control study including 581 BCa cases and 1561 healthy controls was performed. Germline DNA samples from all individuals were genotyped for eight SNPs. Genetic risk score (GRS) was calculated for each individual based on the odds ratios and risk allele frequencies of five risk-associated SNPs.Among eight SNPs evaluated in this study, rs798766 at 4p16.3 [OR = 1.39 (1.15-1.67), P < .001], rs9642880 [OR = 1.17 (1.06-1.30), P < .001] and rs4813953 at 20p12.2 [OR = 1.09 (1.02-1.17), P = .016] were found associated with BCa risk in Chinese population. A genetic risk score was established based on five SNPs (including the above three SNPs and two other SNPs which have the consistent direction with previous reported genome-wide association study). The mean GRS was significantly higher in BCa cases than controls (1.22 vs. 1.01, P < .001). When subjects were categorized into low- (<0.8), average- (0.8-1.2), and high-risk (>1.2) groups, the likelihoods of BCa were 25.2%, 33.7% and 55.0%, respectively (P-trend < 2.2 × 10). In subgroup analyses, no significant difference was observed in mean GRS among BCa patients with different stages or grades.In conclusion, two SNPs derived from East Asian and one SNP from Caucasian were associated with BCa risk in Chinese population. These results provided additional information of genetic risks for BCa in Chinese population. Genetic risk score based on these SNPs can reveal inherited risk of BCa, and may have potential for modifying personalized cancer screening strategy.

Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation.

Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In-silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin-3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin-3a inhibited cellular proliferation in ACC cell line NCI-H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin-3a induced cell apoptosis and G1 cell-cycle arrest in NCI-H295R cells. Nutlin-3a also decreased cellular migration and inhibited epithelial-to-mesenchymal transition (EMT) process in terms of EMT index. Nutlin-3a resulted in decreased ß-catenin level independent of p53 level in NCI-H295R but not SW13 cells. We also evaluated the effect of Nutlin-3a on hormonal secretion of NCI-H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin-3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin-3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta-Catenin signaling in ACC warrants further study.

The preclinical assessment of XL388, a mTOR kinase inhibitor, as a promising anti-renal cell carcinoma agent.

XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation. Notably, XL388 was more efficient than mTORC1 inhibitors (rapamycin, everolimus and temsirolimus) in killing RCC cells. Further studies showed that activation of MEK-ERK might be a key resistance factor of XL388. Pharmacological or shRNA-mediated inhibition of MEK-ERK pathway sensitized XL388-induced cytotoxicity in RCC cells. In vivo, oral administration of XL388 inhibited in nude mice 786-0 RCC tumor growth, and its anti-tumor activity was sensitized with co-administration of the MEK-ERK inhibitor MEK162. Together, these results suggest that concurrent inhibition of mTORC1/2 by XL388 may represent a fine strategy to inhibit RCC cells.

Results of a randomized, double-blind, active-controlled clinical trial with propiverine extended release 30 mg in patients with overactive bladder.

OBJECTIVE: To compare the efficacy and safety of the 30 mg extended release (ER) formulation of propiverine hydrochloride with the 4 mg ER formulation of tolterodine tartrate in patients with overactive bladder (OAB) in a non-inferiority trial. PATIENTS AND METHODS: Eligible patients, aged 18-75 years and with symptoms of OAB, were enrolled in this multicentre, randomized, double-blind, parallel-group, active-controlled study. After a 2-week screening period, patients were randomized at a 1:1 ratio to receive either propiverine ER 30 mg or tolterodine ER 4 mg daily during the 8-week treatment period. Efficacy was assessed using a 3-day voiding diary and patient's self-reported assessment of treatment effect. Safety assessment included recording of adverse events, laboratory test results, measurement of post-void residual urine and electrocardiograms. RESULTS: A total of 324 patients (244 female and 80 male) were included in the study. Both active treatments improved the variables included in the voiding diary and in the patient's self-reported assessment. The change from baseline in the number of voidings per 24 h was significantly greater in the propiverine ER 30 mg group compared with the tolterodine ER 4 mg group after 8 weeks of treatment (full analysis set [FAS] -4.6 ± 4.1 vs -3.8 ± 5.1; P = 0.005). Significant improvements were also observed for the change of urgency incontinence episodes after 2 weeks (P = 0.026) and 8 weeks (P = 0.028) of treatment when comparing propiverine ER 30 mg with tolterodine ER 4 mg. Both treatments were well tolerated, with a similar frequency of adverse drug reactions in both the propiverine ER 30 mg and tolterodine ER 4 mg groups (FAS 40.7 vs 39.5%; P = 0.8). More patients treated with tolterodine ER 4 mg discontinued the treatment because of adverse drug reactions compared with propiverine ER 30 mg (7.4 vs 3.1%). CONCLUSIONS: Propiverine ER 30 mg was confirmed to be an effective and well-tolerated treatment option for patients with OAB symptoms. This first head-to-head study showed non-inferiority of propiverine ER 30 mg compared with tolterodine ER 4 mg.

Genetic Analysis of Mismatch Repair Genes Alterations in Extramammary Paget Disease.

Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm. The familial occurrence of EMPD and the high risk of concomitant secondary tumors in EMPD patients have gained much attention. These findings highlight the importance of genetic alterations in the tumorigenesis of this skin cancer. Genetic tests and functional analysis of mismatch repair (MMR) genes were performed in EMPD. The results showed that 8 of 20 cases with germline MMR genes mutations and 5 of them exhibited microsatellite instability (MSI). Immunohistochemical staining showed that the tumor tissues from 20 patients had the normal expression of MLH1 but 5 cases had the reduced expression of MSH2. There is a nearly significant correlation between MSI and germline mutations. In 172 cases, rates of germline and somatic mutations were 34.3% and 13.4%, respectively. The mutations of MLH1 V384D (15.7%), R217C (4.1%), and I219V (5.2%) were common in this cancer. In addition, the yeast 2-hybrid and immunoprecipitation assays exhibited reduced interaction between MLH1 and PMS2 in MLH1 V384D and R217C but not I219V. Moreover, MLH1 V384D and R217C had impaired MMR activity compared with the wild-type and I219V mutation by an in vitro MMR assay. The germline mutations in MMR genes are involved in the pathogenesis of EMPD and partially explain the genetic abnormalities for this disease.

Genetic alteration in notch pathway is associated with better prognosis in renal cell carcinoma.

Notch signaling was associated with a variety of cancers but was not comprehensively studied in clear-cell renal cell carcinoma (ccRCC). We have in this study studied the genetic alteration (mutation and copy number variance) of Notch gene set in the Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) database. We found that Notch pathway was frequently altered in ccRCC. The Notch gene set was genetically altered in 182 (44%) of the 415 ccRCC patients. CNV was the predominant type of alteration in most genes. Alterations in KAT2B and MAML1 occurred in 13% and 19% of patients, respectively, both of which were functionally active in ccRCC. Deletion of VHL was exclusively found in cases with Notch alteration. Overall survival was longer in ccRCC patients with altered-Notch pathway. The median survival was 90.41 months in Notch-altered cases and 69.15 in Notch-unaltered cases (P = 0.0404). The median disease free time was 89.82 months in Notch-altered cases and 77.27 months in in Notch-unaltered cases (P = 0.935). Conclusively, Notch signaling was altered in almost half of the ccRCC patients and copy number variances in MAML1 and KAT2B were predominant changes. These findings broadened our understanding of the role of Notch in ccRCC.

EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression.

Metastasis is the primary cause of prostate cancer (CaP)-related death. We investigate the molecular, pathologic and clinical outcome associations of EphA6 expression and CaP metastasis. The expression profiling of Eph receptors (Ephs) and their ephrin ligands was performed in parental and metastatic CaP cell lines. Among Ephs and ephrins, only EphA6 is consistently overexpressed in metastatic CaP cells. Metastatic potential of EphA6 is assessed by RNAi in a CaP spontaneous metastasis mouse model. EphA6 knock-down in human PC-3M cells causes decreased invasion in vitro and reduced lung and lymph node metastasis in vivo. In addition, knock-down of EphA6 decreases tube formation in vitro and angiogenesis in vivo. EphA6 mRNA expression is higher in 112 CaP tumor samples compared with benign tissues from 58 benign prostate hyperplasia patients. Positive correlation was identified between EphA6 expression and vascular invasion, neural invasion, PSA level, and TNM staging in CaP cases. Further, genome-wide gene expression analysis in EphA6 knock-down cells identified a panel of differentially regulated genes including PIK3IPA, AKT1, and EIF5A2, which could contribute to EphA6-regulated cancer progression. These findings identify EphA6 as a potentially novel metastasis gene which positively correlates with CaP progression. EphA6 may be a therapeutic target in metastatic CaP.

Renal hemangiopericytoma secondary to refractory hypertension in a child: A case report.

Hemangiopericytoma is a rare perivascular tumor that often involves the extremities, pelvis, head and neck, and meninges, but rarely occurs in the kidney. The differentiation from renal cancer prior to surgery is extremely challenging; therefore, almost all cases of renal hemangiopericytoma are diagnosed by pathological examination. The majority of cases are identified in patients between the ages of 20 and 50 years of age, and a considerable proportion of patients exhibit hypertension, hypoglycaemia or additional paraneoplastic syndromes. The current study reports a rare case of renal hemangiopericytoma with drug refractory hypertension in a 14-year-old female. Following the complete resection of the tumor, the patient's blood pressure returned to normal. No evidence of recurrence or metastasis was observed during a follow-up of 12 months following surgery. The present case indicated that surgery provides satisfactory outcomes and appears to be the most effective modality of treatment for renal hemangiopericytoma. Furthermore, this case also demonstrated that secondary hypertension may also recover following tumor excision.

RNA sequencing reveals upregulation of RUNX1-RUNX1T1 gene signatures in clear cell renal cell carcinoma.

In the past few years, therapies targeted at the von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC). However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq) was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA). We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC.

Effect of amitriptyline in treatment interstitial cystitis or bladder pain syndrome according to two criteria: does ESSIC criteria change the response rate?

AIMS: The European Society for the Study of Interstitial Cystitis (ESSIC) recommended that interstitial cystitis (IC) should be replaced by bladder pain syndrome (BPS), which focused more attention on the painful or discomfort feeling related to bladder and weakened the importance of cystoscopy in diagnosis process. Our study aimed to explore whether this alteration changed the treatment outcomes of amitriptyline and whether cystoscopy was meaningful for the treatment of this disease. METHODS: We conducted a retrospective study including 25 IC patients fulfilled the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) criteria and 42 BPS patients diagnosed according to ESSIC criteria. All the patients received amitriptyline with a self-uptitration protocol. We compared the response rates of two groups by a patient reported global response assessment after 3 months and reclassified all the 67 patients according to ESSIC criteria, the response rates of different BPS types were also assessed. RESULTS: There was no significant difference of response rate between IC patients (12/25, 48%) and BPS patients (19/42, 45.2%) according to different criteria (P = 0.337). The response rate of BPS type 1 (13/30, 43.3%) was similar to that of type 2 or 3 (18/37, 48.6%) (P = 0.664). CONCLUSIONS: ESSIC criteria did not decrease the response rate of amitriptyline treatment for BPS patients compared to IC patients with complaint of bladder pain or discomfort. Cystoscopy showed no predictive effect for the treatment outcome of amitriptyline.

Genetic score of multiple risk-associated single nucleotide polymorphisms is a marker for genetic susceptibility to bladder cancer.

Genome-wide association studies have identified 13 single nucleotide polymorphisms (SNPs) that are associated with bladder cancer; three of these SNPs were validated in the Chinese population. This study assessed the performance of these three SNPs, in combination, to predict genetic susceptibility to bladder cancer in Chinese. Three previously established bladder cancer risk-associated SNPs (rs798766 in TACC3, rs9642880 in MYC, and rs2294008 in PSCA) were genotyped in 1,210 bladder cancer patients and 1,008 control subjects in Shanghai, China. A genetic score was calculated for each subject based on these three SNPs. Each of these three SNPs was significantly associated with bladder cancer risk in this independent study population, P < 0.05. The genetic score based on these three SNPs was significantly higher in cases than controls, with a mean of 1.05 and 0.99, respectively, P = 1.03E-05. Compared with subjects with a genetic score <= 1.00, subjects with an elevated genetic score (>1.00) had a significantly increased risk for bladder cancer after adjusting for age, gender, and smoking status, OR = 1.58, 95% Confidence Interval (CI) = 1.21 - 2.06, P = 0.0007. When tested separately for lower (Ta) or higher (Tis, T1-T4) tumor stage, the association was significantly stronger for lower (OR = 2.24, 95% CI = 1.66 - 3.01, P = 1.02E-07) than higher tumor stage (OR = 1.33, 95% CI = 1.00 - 1.78, P = 0.05), P = 0.001. In conclusion, A combination of three previously implicated bladder cancer risk-associated SNPs is a significant predictor of genetic susceptibility to bladder cancer in Chinese.