The function and mechanisms of action of circular RNAs in Urologic Cancer.

Kidney, bladder, and prostate cancer are the three major tumor types of the urologic system that seriously threaten human health. Circular RNAs (CircRNAs), special non-coding RNAs with a stabile structure and a unique back-splicing loop-forming ability, have received recent scientific attention. CircRNAs are widely distributed within the body, with important biologic functions such as sponges for microRNAs, as RNA binding proteins, and as templates for regulation of transcription and protein translation. The abnormal expression of circRNAs in vivo is significantly associated with the development of urologic tumors. CircRNAs have now emerged as potential biomarkers for the diagnosis and prognosis of urologic tumors, as well as targets for the development of new therapies. Although we have gained a better understanding of circRNA, there are still many questions to be answered. In this review, we summarize the properties of circRNAs and detail their function, focusing on the effects of circRNA on proliferation, metastasis, apoptosis, metabolism, and drug resistance in kidney, bladder, and prostate cancers.

Construction of a robust prognostic model for adult adrenocortical carcinoma: Results from bioinformatics and real-world data.

This study aims to construct a robust prognostic model for adult adrenocortical carcinoma (ACC) by large-scale multiomics analysis and real-world data. The RPPA data, gene expression profiles and clinical information of adult ACC patients were obtained from The Cancer Proteome Atlas (TCPA), Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Integrated prognosis-related proteins (IPRPs) model was constructed. Immunohistochemistry was used to validate the prognostic value of the IPRPs model in Fudan University Shanghai Cancer Center (FUSCC) cohort. 76 ACC cases from TCGA and 22 ACC cases from GSE10927 in NCBI's GEO database with full data for clinical information and gene expression were utilized to validate the effectiveness of the IPRPs model. Higher FASN (P = .039), FIBRONECTIN (P < .001), TFRC (P < .001), TSC1 (P < .001) expression indicated significantly worse overall survival for adult ACC patients. Risk assessment suggested significantly a strong predictive capacity of IPRPs model for poor overall survival (P < .05). IPRPs model showed a little stronger ability for predicting prognosis than Ki-67 protein in FUSCC cohort (P = .003, HR = 3.947; P = .005, HR = 3.787). In external validation of IPRPs model using gene expression data, IPRPs model showed strong ability for predicting prognosis in TCGA cohort (P = .005, HR = 3.061) and it exhibited best ability for predicting prognosis in GSE10927 cohort (P = .0898, HR = 2.318). This research constructed IPRPs model for predicting adult ACC patients' prognosis using proteomic data, gene expression data and real-world data and this prognostic model showed stronger predictive value than other biomarkers (Ki-67, Beta-catenin, etc) in multi-cohorts.

Large-scale transcriptome profiles reveal robust 20-signatures metabolic prediction models and novel role of G6PC in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common and highly malignant pathological type of kidney cancer. We sought to establish a metabolic signature to improve post-operative risk stratification and identify novel targets in the prediction models for ccRCC patients. A total of 58 metabolic differential expressed genes (MDEGs) were identified with significant prognostic value. LASSO regression analysis constructed 20-mRNA signatures models, metabolic prediction models (MPMs), in ccRCC patients from two cohorts. Risk score of MPMs significantly predicts prognosis for ccRCC patients in TCGA (P < 0.001, HR = 3.131, AUC = 0.768) and CPTAC cohorts (P = 0.046, HR = 2.893, AUC = 0.777). In addition, G6PC, a hub gene in PPI network of MPMs, shows significantly prognostic value in 718 ccRCC patients from multiply cohorts. Next, G6Pase was detected high expressed in normal kidney tissues than ccRCC tissues. It suggested that low G6Pase expression significantly correlated with poor prognosis (P < 0.0001, HR = 0.316) and aggressive progression (P < 0.0001, HR = 0.414) in 322 ccRCC patients from FUSCC cohort. Meanwhile, promoter methylation level of G6PC was significantly higher in ccRCC samples with aggressive progression status. G6PC significantly participates in abnormal immune infiltration of ccRCC microenvironment, showing significantly negative association with check-point immune signatures, dendritic cells, Th1 cells, etc. In conclusion, this study first provided the opportunity to comprehensively elucidate the prognostic MDEGs landscape, established novel prognostic model MPMs using large-scale ccRCC transcriptome data and identified G6PC as potential prognostic target in 1,040 ccRCC patients from multiply cohorts. These finding could assist in managing risk assessment and shed valuable insights into treatment strategies of ccRCC.

Prognostic implication and functional annotations of Rad50 expression in patients with prostate cancer.

Increasing evidence has shown that Rad50, a protein involved in the DNA damage repair process, significantly correlated with tumor prognosis. This study focused on Rad50 expression in tumor samples and its prognostic value for patients with prostate cancer (PCa). In this study, significantly elevated Rad50 expression in PCa tissues compared to normal tissues (P < .01). Five independent Oncomine databases validated significant differential expression of Rad50 (P < .001). Hence, 80 patients with PCa from Fudan University Shanghai Cancer Center (FUSCC) and 351 patients with PCa with available protein expression data from The Cancer Genome Atlas (TCGA) were included to investigate the survival benefit. Univariate and multivariate Cox regression analyses were performed to investigate the significance of clinicopathological factors on disease-free survival (DFS) and overall survival (OS). Kaplan-Meier analysis indicated that elevated Rad50 protein expression levels significantly correlated with unfavorable DFS (P = .005) in the FUSCC cohort and poorer OS (P = .04) in TCGA cohort. Furthermore, coregulation analysis of proteins indicated that 76 coregulated proteins were associated with Rad50, while 11 most highly involved hub proteins, including Rad50, MRE11A, DUT, POLR3A, MCM3AP, RECQL, PNPT1, RANBP3, DDX1, SNRPB, and UGN, were significantly coregulated in the protein-protein interaction network. Functional enrichment analysis consecutively indicated significant functions and signaling pathways including DNA replication, spliceosome, DNA geometric change, homologous recombination, and G2M checkpoint. This study first reveals that elevated Rad50 expression is significantly associated with aggressive progression and poor survival for patients with PCa. Together, these data suggest that Rad50 may act as an oncoprotein, guide the molecular diagnosis, and may shed light on novel individual therapeutic strategies for progressive PCa patients.

Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma.

BACKGROUND: Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients. METHODS: A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes. RESULTS: Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK-STAT3, inflammatory response and TNF-alpha signaling pathways. CONCLUSION: Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.

C-Reactive Protein Levels and Survival Following Cytoreductive Nephrectomy in 118 Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Study.

BACKGROUND This study aimed to evaluate the factors associated with a survival benefit for patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib, with and without cytoreductive nephrectomy (CN). MATERIAL AND METHODS This retrospective clinical study included 118 patients with mRCC who were treated with CN and sunitinib (CN-sunitinib) (N=70) and with sunitinib-alone (N=48). Categorical clinicopathological variables were compared with hypothesis tests using contingency tables and a chi-squared test. Independent indicators for progression-free survival (PFS) and overall survival (OS) were analyzed with univariate and multivariate Cox regression models. The Kaplan-Meier method and log-rank test were used to evaluate patient survival. RESULTS The median PFS and OS for the 118 patients were 8.38 and 15.48 months, respectively. There were no significant differences between the CN-sunitinib group and the sunitinib-alone group for either PFS (7.2 months vs. 11.6 months; P=0.525) or OS (16.7 months vs. 15.2 months; P=0.839). Stratification of patients based on clinicopathological characteristics showed that CN was significantly associated with reduced PFS and OS for patients with lymph node metastasis (PFS, P<0.001; OS, P<0.001) and high International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores (PFS, P=0.003; OS, P=0.011). However, CN was associated with a significant survival benefit for patients with low levels of serum C-reactive protein (CRP<10 mg/L) (PFS, P=0.026; OS, P=0.007). CONCLUSIONS Sunitinib-alone without CN improved the survival of patients with mRCC who had high IMDC risk scores or lymph node metastasis. CN and sunitinib resulted in significantly improved survival in patients with low serum CRP.

Tumor growth velocity: A modified tumor growth rate defining tumor progression during sorafenib treatment in patients with metastatic renal cell carcinoma.

OBJECTIVES: To investigate the role of tumor growth velocity in defining tumor progression in metastatic renal cell carcinoma patients treated with the vascular endothelial growth factor tyrosine kinase inhibitor, sorafenib. METHODS: A modified calculation for tumor growth velocity was introduced to evaluate the tumor growth velocity, before and after sorafenib withdrawal. Known prognostic factors together with tumor growth velocity before drug withdrawal and tumor growth velocity after drug withdrawal were compared using a χ2 -test from a contingency table, and partial likelihood test from a Cox regression model for overall survival. RESULTS: A total of 114 patients who reached progressive disease and withdrew from sorafenib were enrolled after a median follow-up period of 107.8 months. Tumor growth velocity before drug withdrawal was 7.347 ± 4.040, and tumor growth velocity after drug withdrawal was 11.647 ± 5.937 (P < 0.001). Higher tumor growth velocity before drug withdrawal was correlated with a higher risk Memorial Sloan Kettering Cancer Center score (P = 0.022), Karnofsky Performance Status <80 (P = 0.028), non-clear cell carcinoma (P = 0.037), higher tumor nucleus grade (P < 0.001) and best treatment response (P < 0.001). Patients with tumor growth velocity before drug withdrawal >5.0 had shorter overall survival (P < 0.001). On multivariate analysis, factors associated with overall survival were high/intermediate Memorial Sloan Kettering Cancer Center risk score (hazard ratio 2.119, P = 0.006), non-clear histological subtype (hazard ratio 1.900, P = 0.031), tumor growth velocity before drug withdrawal ≥5.0 (hazard ratio 2.758, P < 0.001) and progressive disease as best response (hazard ratio 2.069, P = 0.001). CONCLUSIONS: Significantly faster tumor growth can be observed if sorafenib is discontinued in the case of disease progression. Thus, we suggest not to withdraw targeted agents until tumor growth velocity is >5.0.

Pretreatment neutrophil-to-lymphocyte ratio predicts prognosis in patients with metastatic renal cell carcinoma receiving targeted therapy.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcomes of various cancers. This study aimed to evaluate whether pretreatment NLR can be used as a prognostic factor in patients with metastatic renal cell carcinoma (mRCC) receiving targeted therapy. METHODS: In this single-center retrospective study, the Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) of 373 mRCC patients receiving targeted therapy. The survival outcomes of patients with high (≥ 2.2) and low (< 2.2) pretreatment NLRs were compared by log-rank test, and Cox proportional hazard regression model was used to compare OS and PFS between groups. RESULTS: The overall median PFS and OS times for all 373 patients were 18.4 and 34.3 months, respectively. Patients with high NLRs had significantly shorter median OS (28.8 vs 410 months, P = 0.005) and PFS (15.4 vs 23.9 months, P = 0.001) than those with low NLRs. After adjusting for confounding variables, each unit increase of NLR was associated with a 40 % increase in mortality (hazard ratio [HR] 1.391; 95 % confidence interval [CI] 1.022-1.894; P = 0.036). High NLR was also an independent predictor of poor PFS (HR 1.544; 95 % CI 1.166-2.045; P = 0.002). CONCLUSION: Pretreatment NLR may be an independent prognostic factor for mRCC patients who are receiving targeted therapy.

Nephrometry score-guided off-clamp laparoscopic partial nephrectomy: patient selection and short-time functional results.

BACKGROUND: Laparoscopic partial nephrectomy (LPN) is not a novel but a relatively technically challenging surgical procedure. Off-clamp LPN with zero ischemia can completely eliminate ischemic reperfusion injury to the kidney. The purpose of this study was to evaluate the safety and functional outcome of nephrometry score-guided off-clamp technique in LPN. METHODS: A total of 44 patients underwent LPN between January 2015 and July 2015 for renal mass with radius, exophytic/endophytic, nearness to sinus, anterior/posterior location (RENAL) score 4 were enrolled. Twenty-two of them underwent off-clamp LPN with zero ischemia, and the other 22 received standard LPN with common renal artery clamp. Estimate blood loss (EBL), total operation time, resection time, renorrhaphy time, preoperative estimated glomerular filtration rate (eGFR), postoperative eGFR, eGFR change, and drainage after surgery were compared between these two groups using t test. RESULTS: Patients' characteristics including gender, age, BMI, tumor size, and RENAL score were balanced between the two groups. Average EBL was more in the off-clamp group than in the on-clamp group (134.32 versus 70.23 ml, p = 0.001). Average eGFR change was less in the off-clamp group than in the on-clamp group (-1.56 versus -6.45, p < 0.001). Average drainage after surgery was 203.41 ml for the off-clamp group and 145.46 ml for the on-clamp group, p = 0.062. No urinary leakage and hematuria occurred in both groups. There were no statistical difference in total operation time, resection time, renorrhaphy time, preoperative eGFR, and postoperative eGFR between the two groups. CONCLUSIONS: Off-clamp LPN is a safe and feasible approach to excise certain kidney tumors with RENAL score 4. This technique can better preserve kidney function without ischemic reperfusion injury.

Impact of preoperative 5α-reductase inhibitors on perioperative blood loss in patients with benign prostatic hyperplasia: a meta-analysis of randomized controlled trials.

BACKGROUND: The ability of 5α-reductase inhibitors (5ARIs) to decrease blood loss during transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) remains controversial. We aimed to conduct a meta-analysis of all randomized controlled trials (RCTs) to establish the role of 5ARI use prior to TURP. METHODS: We searched studies from the electronic databases PubMed, Embase, Scopus, and Cochrane Library from inception to March 25, 2014. Meta-analysis was performed using the statistical software Review Manager version 5.1. RESULTS: Seventeen RCTs including 1489 patients were examined. We observed that preoperative treatment with finasteride can decrease total blood loss, blood loss per gram of resected prostate tissue, hemoglobin level alteration, microvessel density (MVD), and vascular endothelial growth factor level. Neither finasteride nor dutasteride reduced operative time, prostate volume, or the weight of gland resected. In contrast, pretreatment with dutasteride before TURP did not decrease the total blood loss or MVD. CONCLUSIONS: Pretreatment with finasteride does seem to reduce perioperative blood loss related to TURP for BPH patients. However, the effect of preoperative dutasteride was inconclusive. Further studies are required to strengthen future recommendations regarding the use of 5ARI as a standard pre-TURP treatment and its optimal regimen.

Visceral fat accumulation is associated with different pathological subtypes of renal cell carcinoma (RCC): a multicentre study in China.

OBJECTIVE: To investigate whether visceral obesity is associated with certain histological subtypes of renal cell carcinoma (RCC) ina multicentre Chinese cohort. PATIENTS AND METHODS: A kidney tumour database was created using three tertiary centres in China; 487 patients were enrolled presenting with localised RCC and complete computer tomography(CT)/magnetic resonance imaging (MRI) information. A single-slice CT image was used to measure the area of visceral and subcutaneous adipose tissues in each patient. Statistical methods were used to analyse clear-cell RCC (ccRCC) and non-clear-cell RCC (non-ccRCC) as they relate to visceral fat area (VFA) and other risk factors, such as age, gender, tumour size, diabetes, hypertension, total fat area (TFA) and body mass index (BMI). RESULTS: In all, 418 patients had a ccRCC subtype and 69 had a non-ccRCC subtype. For all the patients with RCC, the mean VFA was 102 cm2, while mean BMI was 24 kg/m2. The mean VFA was greater in ccRCC than non-ccRCC patients by 25 cm2. There were significant differences in the mean VFA and TFA between patients with ccRCC and those with non-ccRCC.Multivariate analysis showed that the presence ofVFA was more important than the effects of BMI and Type 2 diabetes on pathology prediction. In patients with a normal BMI, those with a higher quartile of VFA were more likely to develop ccRCC than those with a low VFA. CONCLUSIONS: Increased visceral fat was found to be associated with ccRCC and the significance of VFA outweighed the effects of BMI and Type 2 diabetes for the prediction of RCC pathology in multivariate analyses. As a result, VFA could constitute a primary explanation for the link between obesity and ccRCC.

A Phase II trial of dosage escalation of sorafenib in Asian patients with metastatic renal cell carcinoma.

AIM: To investigate the role of sorafenib dosage escalation in Asian patients with metastatic renal cell carcinoma that had progressed after routine dosages. PATIENTS & METHODS: Sorafenib dosage escalation to 600 or 800 mg twice a day was offered to 41 patients with metastatic renal cell carcinoma who had progressed on normal dosages. Clinical outcome, toxicity and favorable clinical covariables for progression-free survival (PFS) were evaluated. RESULTS: The median PFS with dosage-escalated therapy was 7 months. Drug-related adverse events were tolerable. The pre-escalation Karnofsky performance status, serum calcium concentration, neutrophil/lymphocyte ratio, PFS and the highest toxicity grade at the routine dosage were associated with a longer PFS in the dosage-escalation period. CONCLUSION: Sorafenib dosage escalation was efficacious and tolerable in Asian patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (no. ChiCTR-ONRC-12002088).

[Exploratory analysis of the effect of toxicity of sunitinib on the clinical outcome of patients with advanced renal cell carcinoma].

OBJECTIVE: To explore the effect of toxicity of sunitinib on the clinical outcome of patients with advanced renal cell carcinoma (RCC) . METHODS: A total of 136 patients with advanced RCC were treated with sunitinib from 2008 to 2011. There were 91 males and 45 females with an average age of 56 years. Their 6-week therapy cycle was 4 weeks of sunitinib 50 mg daily followed by 2-week off-treatment (schedule 4/2). The median follow-up time was 15 months. Correlation between toxicities and overall survival (OS) was evaluated in a Cox model using log-transformed levels after adjusting for MSKCC model.Log-rank test and Cox proportional hazard model were used to assess the value of drug toxicity as the prognostic factors. RESULTS: The increased hemoglobin on cycle 1 day 14 (HR:0.950, 95%CI:0.923-0.978) and the increased lymphocytes on cycle 1 days 28 and 42 (HR:0.405, 95%CI:0.203-0.809, HR:0.394, 95%CI:0.179-0.867) were significantly associated with OS (P adj = 0.001, 0.014 and 0.022 respectively). Hypertension class III/IV (HR:0.066, 95%CI:0.008-0.582), and the number of neutrophils screening and lymphocyte count ratio (HR:2.537, 95%CI:1.182-5.404) were the survival prognosis independent predictors. CONCLUSION: Early hematopoietic toxicities may potentially predict the outcomes of advanced RCC after a therapy of sunitinib.

Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor.

The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic-area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.

Narrow-band imaging flexible cystoscopy in the detection of clinically unconfirmed positive urine cytology.

INTRODUCTION: The objective of this study was to investigate the value of narrow-band imaging (NBI) cystoscopy in the detection of patients with positive voided urine cytology (VUC) who have no evidence of disease after standard initial investigations. PATIENTS AND METHODS: Between February 2009 and December 2010, 12 patients with positive or suspicious VUC but no regular endoscopic evidence of cancer were investigated with NBI flexible cystoscopy. All the specimens were biopsied both under NBI and white light imaging (WLI). Random biopsies of bladder and prostatic urethra were performed in cases without suspect lesions. RESULTS: Fourteen NBI cystoscopies were carried out in 12 patients. Non-muscle-invasive bladder cancer was diagnosed in 5 of 12 (42%) patients on the first NBI. One patient had carcinoma in situ diagnosed on repeat NBI 3 months later. The sensitivity and specificity in diagnosing unconfirmed positive VUC was 78 and 91% for NBI vs. 50 and 80% for WLI. CONCLUSIONS: NBI cystoscopy significantly improves detection of unconfirmed positive VUC over WLI. It should be carried out early in the investigation of such patients before random biopsies and ureteroscopy.

[Efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer].

OBJECTIVE: To assess the efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer (CRPC) and explore possible prognosis factors. METHODS: From August 2006 to August 2011, 71 patients with CRPC were analyzed retrospectively, who received oral ketoconazole 200 mg, three times a day with prednisone 5 mg, twice a day. Prostate specific antigen (PSA) response rate was defined as the percentage of patients with PSA decline ≥ 50% compared to baseline PSA level during low dose ketoconazole therapy. Multivariate Logistic regression analysis and receiver operating characteristic curve were used to assess the prognostic factors and their accuracy. RESULTS: The mean initial serum PSA level was (205 ± 38) ng/ml for these patients with mean age (69 ± 1) years old. After first androgen deprivation therapy failure, the prostate cancer progressed into castration resistant stage. The baseline PSA was (93 ± 24) ng/ml and the baseline serum testosterone was (0.13 ± 0.02) ng/ml. During the low dose ketoconazole therapy, 31 patients (43.7%) had PSA decrease and 22 cases (31.0%) were effective with PSA decline more than 50%. PSA doubling time and baseline serum testosterone were positive correlation with PSA response rate by multivariate Logistic regression analysis. Patients with PSA doubling time of ≥ 3.0 months had a PSA response rate of 64.3% and the PSA response rate in those with < 3.0 months decreased to 22.8%, hazard rate (HR) = 0.149 (95% confidence interval [CI] 0.029 - 0.766), P = 0.023, area under the curve (AUC) = 0.707. The PSA response rate for patients with baseline serum testosterone ≥ 0.1 and < 0.1 µg/L were 55.6% and 5.7%, respectively, HR = 0.068 (95%CI 0.012 - 0.380), P = 0.002, AUC = 0.749. The common adverse reactions included liver dysfunction (17.9%), renal dysfunction (16.4%), fatigue (11.9%), nausea (6.0%) and anorexia (4.5%) and so on. CONCLUSIONS: Low dose ketoconazole therapy was a moderate, low toxicity hormonal therapy option for patients with CRPC. PSA doubling time ≥ 3 months and baseline serum testosterone ≥ 0.1 µg/L were predictors of desired effect for low dose ketoconazole therapy.

Large-Scale Proteomics Data Reveal Integrated Prognosis-Related Protein Signatures and Role of SMAD4 and RAD50 in Prognosis and Immune Infiltrations of Prostate Cancer Microenvironment.

As prostate cancer (PCa) is one of the most commonly diagnosed cancer worldwide, identifying potential prognostic biomarkers is crucial. In this study, the survival information, gene expression, and protein expression data of 344 PCa cases were collected from the Cancer Proteome Atlas (TCPA) and the Cancer Genome Atlas (TCGA) to investigate the potential prognostic biomarkers. The integrated prognosis-related proteins (IPRPs) model was constructed based on the risk score of each patients using machine-learning algorithm. IPRPs model suggested that Elevated RAD50 expression (p = 0.016) and down-regulated SMAD4 expression (p = 0.017) were significantly correlated with unfavorable outcomes for PCa patients. Immunohistochemical (IHC) staining and western blot (WB) analysis revealed significant differential expression of SMAD4 and RAD50 protein between tumor and normal tissues in validation cohort. According to the overall IHC score, patients with low SMAD4 (p < 0.0001) expression and high RAD50 expression (p = 0.0001) were significantly correlated with poor outcomes. Besides, expression of SMAD4 showed significantly negative correlation with most immune checkpoint molecules, and the low SMAD4 expression group exhibited significantly high levels of LAG3 (p < 0.05), TGFß (p < 0.001), and PD-L1 (p < 0.05) compared with the high SMAD4 expression group in the validation cohort. Patients with low SMAD4 expression had significantly higher infiltration of memory B cells (p = 0.002), CD8 + T cells (p < 0.001), regulatory T cells (p = 0.006), M2-type macrophages (p < 0.001), and significantly lower infiltration of naïve B cells (p = 0.002), plasma cells (p < 0.001), resting memory CD4 + T cells (p < 0.001) and eosinophils (p = 0.045). Candidate proteins were mainly involved in antigen processing and presentation, stem cell differentiation, and type I interferon pathways. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00070-1.

The Inflammasomes Adaptor Protein PYCARD Is a Potential Pyroptosis Biomarker Related to Immune Response and Prognosis in Clear Cell Renal Cell Carcinoma.

PYCARD is a protein engaged in inflammation, pyroptosis, and apoptosis. However, the function of PYCARD in human cancers remains unclear. The objective of our study was to explore PYCARD expression and prognostic value in human cancers. Public databases were used to assess PYCARD expression and prognostic value. The TISIDB database was used to explore the associations between PYCARD expression and different immune subtypes. The correlations between PYCARD expression and ICP genes, MMR genes, MSI, and TMB were also investigated. The immunotherapy response was assessed using the TIDE database. Single-cell RNA databases evaluated the PYCARD expression of immune cells. External datasets and immunohistochemical staining were conducted to validate PYCARD expression and prognostic value. The results showed that PYCARD expression varied in several cancers and was associated with prognosis, immune-related genes, published biomarkers, and immunotherapy response. Of note, PYCARD expression was upregulated in renal cancers with high diagnostic ability. Upregulation of PYCARD was correlated with worse prognosis in KIRC and external validation cohorts. In conclusion, PYCARD demonstrated strong correlations with prognosis, immune response, and disease progression in pan-cancer analysis. In ccRCC, PYCARD might serve as a biomarker for diagnosis and therapeutic target-boosting immunotherapy response.

The expression and prognostic value of transporter 1, ATP binding cassette subfamily B member in clear cell renal cell cancer with experimental validation.

Transporter associated with antigen processing 1(TAP1) serves as a protein to transport antigenic peptides from the surface of the endoplasmic reticulum to the lumen of the endoplasmic reticulum when the antigens are presented by major histocompatibility complex type I (MHC-I), which has been identified to play a critical role in antigen presentation in innate immunity. In tumors, the role of TAP1 seems to remain controversial. On the one hand, given the role of TAP1 in antigen presentation, it is indicated that high TAP1 expression corresponds to the emergence of more neoantigens epitopes that facilitate the recognition for phagocytes, T cells and other cells. On the other hand, the genetic ablation of transporter associated with antigen processing (TAP) results in the presentation of new class I-restricted epitopes encoded in house-keeping products. Opposite result has been revealed by studies in other tumors suggest, which implies a more complex function of TAP1. Therefore, it's significant to clarify the role of TAP1 in clear cell renal cell carcinoma (ccRCC). In this study, we found the elevated expression levels in mRNA and protein of TAP1 in ccRCC tissues, which indicated a relatively worse prognosis. Transwell assay and Scratch assay in vitro demonstrated the promotive role of TAP1 in ccRCC migration as well as a significant role in metastasis. And the increased expression of TAP1 resulted in more immune cells infiltrated in cancer tissues. TAP1 was also demonstrated to be related to immune regulator genes, as gene set enrichment analysis (GSEA) indicated its significant role in immune regulation. The results of CancerSEA indicated the positive association of the high-level TAP1 expression with epithelial-mesenchymal transition (EMT) and the inverse association with Cell Cycle. The effective drugs were also predicted based on TAP1 expression, of which the high level was indeed associated with resistance to multiple drugs, but some effective drugs still identified based on high TAP1 expression. According to the analysis of various databases, the role of TAP1 in ccRCC was explored, especially in relationship of TAP1 with tumor microenvironment. These results indicate that TAP1 can serve as a potential target for treatment of ccRCC.