Identification and validation of an E2F-related gene signature for predicting recurrence-free survival in human prostate cancer.

BACKGROUND: It is well-established that biochemical recurrence is detrimental to prostate cancer (PCa). In the present study, we explored the mechanisms underlying PCa progression. METHODS: Five cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were used to perform gene set variation analysis (GSVA) between nonrecurrent and recurrent PCa patients. We obtained the intersection of pathway enrichment results and extracted the corresponding gene list. LASSO Cox regression analysis was used to identify recurrence-free survival (RFS)-related significant genes and establish an RFS prediction gene signature and nomogram. MTT and colony formation assays were conducted to validate our findings. RESULTS: The E2F signaling pathway was activated in recurrent PCa patients compared to nonrecurrent patients. We established an E2F-related gene signature for RFS prediction based on the four identified E2F-related genes (CDKN2C, CDKN3, RACGAP1, and RRM2) using LASSO Cox regression in the Memorial Sloan Kettering Cancer Center (MSKCC) cohort. The risk score of each patient in MSKCC was calculated based on the expression levels of CDKN2C, CDKN3, RACGAP1, and RRM2. PCa patients with low-risk scores exhibited higher RFS than those with high-risk scores. Receiver operating characteristic (ROC) curve analysis validated the good performance and prognostic accuracy of the E2F-related gene signature, which was validated in the TCGA-prostate adenocarcinoma (TCGA-PRAD) cohort. Compared to patients with low Gleason scores and early T stages, PCa patients with high Gleason scores and advanced T stages had high-risk scores. Moreover, the E2F-related gene signature-based nomogram yielded good performance in RFS prediction. Functional experiments further confirmed these results. CONCLUSIONS: The E2F signaling pathway is associated with biochemical recurrence in PCa. Our established E2F-related gene signature and nomogram yielded good accuracy in predicting the biochemical recurrence in PCa.

Establishment of a five-enzalutamide-resistance-related-gene-based classifier for recurrence-free survival predicting of prostate cancer.

To identify prostate cancer (PCa) patients with a high risk of recurrence is critical before delivering adjuvant treatment. We developed a classifier based on the Enzalutamide treatment resistance-related genes to assist the currently available staging system in predicting the recurrence-free survival (RFS) prognosis of PCa patients. We overlapped the DEGs from two datasets to obtain a more convincing Enzalutamide-resistance-related-gene (ERRG) cluster. The five-ERRG-based classifier obtained good predictive values in both the training and validation cohorts. The classifier precisely predicted RFS of patients in four cohorts, independent of patient age, pathological tumour stage, Gleason score and PSA levels. The classifier and the clinicopathological factors were combined to construct a nomogram, which had an increased predictive accuracy than that of each variable alone. Besides, we also compared the differences between high- and low-risk subgroups and found their differences were enriched in cancer progression-related pathways. The five-ERRG-based classifier is a practical and reliable predictor, which adds value to the existing staging system for predicting the RFS prognosis of PCa after radical prostatectomy, enabling physicians to make more informed treatment decisions concerning adjuvant therapy.

CXCR3 antagonist AMG487 ameliorates experimental autoimmune prostatitis by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation.

BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease that is characterized by infiltrating inflammatory cells in the prostate and pelvic or by perineal pain. Receptor CXCR3modulates immune and inflammatory responses; however, the effects of CXCR3 antagonist AMG487 in the context of CP/CPPS are unknown. Therefore, we investigated the effect of AMG487 in experimental autoimmune prostatitis (EAP) mice and explored the potential functional mechanisms. METHODS: The EAP model was induced by intradermally injecting a mixture of prostate antigens and complete Freund's adjuvant on Days 0 and 28. To evaluate the effect of AMG487 on EAP mice, treatment with AMG487 and vehicle solution was conducted for the indicated period. Then, procedures were performed, including behavioral test, to evaluate the pain response to stimulation before the mice were killed and a histological assessment to evaluate the inflammation after the mice were killed. Immunofluorescence, flow cytometry, and Western blot assay were used to analyze the functional phenotype and regulation mechanism of AMG487 on T helper type 1 (Th1) cells and macrophages. RESULTS: We found high expression of CXCR3 in human benign prostate tissues with inflammation and EAP mice. The elevated CXCR3 in prostate tissues correlates with the severity of inflammation. CXCR3 antagonist AMG487 treatment ameliorated the inflammatory changes and the pelvic pain of EAP mice. AMG487 inhibits Th1 cell differentiation through the IL-12/STAT4pathway and inhibits pro-inflammatory M1 macrophages through the lipopolysaccharide/NF-κB p65signaling. AMG487 could inhibit the secretion of inflammatory mediators in EAP mice. CONCLUSION: CXCR3 antagonist AMG487 could ameliorate the inflammatory changes and the pelvic pain of EAP mice by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation. Thus, the results imply that AMG487 has the potential as an effective therapeutic agent in the prevention and treatment of EAP.

An automatic method for counting wheat tiller number in the field with terrestrial LiDAR.

BACKGROUND: The tiller number per unit area is one of the main agronomic components in determining yield. A real-time assessment of this trait could contribute to monitoring the growth of wheat populations or as a primary phenotyping indicator for the screening of cultivars for crop breeding. However, determining tiller number has been conventionally dependent on tedious and labor-intensive manual counting. In this study, an automatic tiller-counting algorithm was developed to estimate the tiller density under field conditions based on terrestrial laser scanning (TLS) data. The novel algorithm, which is named ALHC, involves two steps: (1) the use of an adaptive layering (AL) algorithm for cluster segmentation and (2) the use of a hierarchical clustering (HC) algorithm for tiller detection among the clusters. Three field trials during the 2016-2018 wheat seasons were conducted to validate the algorithm with twenty different wheat cultivars, three nitrogen levels, and two planting densities at two ecological sites (Rugao & Xuzhou) in Jiangsu Province, China. RESULT: The results demonstrated that the algorithm was promising across different cultivars, years, growth stages, planting densities, and ecological sites. The tests from Rugao and Xuzhou in 2016-2017 and Rugao in 2017-2018 showed that the algorithm estimated the tiller number of the wheat with regression coefficient (R2) values of 0.61, 0.56 and 0.65, respectively. In short, tiller counting with the ALHC generally underestimated the tiller number and performed better for the data with lower plant densities, compact plant types and the jointing stage, which were associated with overlap and noise between plants and inside the dense canopy. CONCLUSIONS: Differing from the previous methods, the ALHC proposed in this paper made full use of 3D crop information and developed an automatic tiller counting method that is suitable for the field environment.

Prognostic Role of Prothrombin Time Activity, Prothrombin Time, Albumin/Globulin Ratio, Platelets, Sex, and Fibrinogen in Predicting Recurrence-Free Survival Time of Renal Cancer.

BACKGROUND: To help with the clinical practice of renal cancer patients, prognostic models are urgently warranted. We hunted and identified prognostic variables associated with recurrence-free survival (RFS) for renal cancer patients. PATIENTS AND METHODS: In this retrospective study, 187 renal cancer patients who had received curative radical/partial nephrectomy between November 2011 and January 2017 were enrolled in the current study. These patients were randomly split into the training (n = 95) and validation sets (n = 92) by the ratio of 1:1. Univariate and multivariable Cox regression analyses were used to establish the nomogram, which was then evaluated by receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses. RESULTS: Patient characteristics and outcomes were well balanced between the training and validation sets; the median RFS values were 54.1 months and 58.9 months for the training and validation cohorts, respectively. The final nomogram included six independent prognostic variables (prothrombin time (%), prothrombin time (second), albumin/globulin ratio, platelets, sex and fibrinogen). The mean values of RFS for the low- and high-risk groups defined by a prognostic formula were 56.22 ± 18.50 months and 49.54 ± 23.57 months, respectively, in the training cohort and were 59.00 ± 19.50 months and 53.32 ± 19.95 months, respectively, in the validation cohort. The significance and stability of the model were tested by the time-dependent K-M model and ROC curves, respectively. CONCLUSION: Our validated prognostic model incorporates variables routinely collected from renal cancer patients, identifying subsets of patients with different survival outcomes, which provides useful information for patient care and clinical trial design.

Laparoscopic ureterolithotomy, flexible ureteroscopic lithotripsy and percutaneous nephrolithotomy for treatment of upper urinary calculi in patients with autosomal dominant polycystic kidney disease.

OBJECTIVES: Patients with autosomal dominant polycystic kidney disease (ADPKD) showed relatively high incidence of urinary stones. Enlarged kidneys occupied by cysts could make the stone-removal surgery relatively difficult. This study aimed to compare the efficacy and safety of retroperitoneal laparoscopic ureterolithotomy (RPLU), flexible ureteroscopic lithotripsy (FURL) and percutaneous nephrolithotomy (PCNL) in the ADPKD patients with upper urinary stones. METHODS: In this study, 45 patients with ADPKD who underwent RPLU, FURL and PCNL procedures were evaluated. Demographic and serum parameters, stone features, outcomes and complications were analyzed. RESULTS: 45 patients were included in the present study, 13 received RPLU, 21 received FURL, and 11 received PCNL. There were no significant differences in demographic and serum parameters between the three groups. Stone-free rates of the three approaches are 100%, 85.7% and 90.9%, respectively. Patients who underwent FURL had shorter mean operative time and postoperative hospital stay. Compared to RPLU and PCNL, FURL resulted in fewer complications, but the difference is statistically non-significant. CONCLUSIONS: RPLU, FURL and PCNL are commonly used surgical methods to solve upper urinary calculi in ADPKD patients and could achieve satisfactory stone clearance. Among them, FURL showed a relative high safety and faster recovery.

Transparenchymal Renal Pelvis Injection of Recombinant Adeno-Associated Virus Serotype 9 Vectors Is a Practical Approach for Gene Delivery in the Kidney.

Gene therapy has great potential in treating human diseases, but little progress has been made in preclinical and clinical studies of renal diseases. To find an effective gene delivery approach in the kidney, transparenchymal renal pelvis injection was developed. Using adeno-associated virus serotype 9 (AAV9) vectors, the gene delivery efficiency and safety of this administration method were evaluated. The results showed that the exogenous gene was expressed in the tubular epithelial cells of the injected kidney, with a much lower expression level in the contralateral kidney. Extra-renal transduction in the liver was also observed in this study, with the liver function of AAV9-injected mice comparable to that of control mice. Altogether, the administration of AAV9 vectors by newly established transparenchymal renal pelvis injection achieved the desired exogenous gene expression in renal tubular cells, and hence might be one possible way for gene therapy in renal diseases.

Polymorphism of MMP-9 gene is not associated with the risk of urinary cancers: Evidence from an updated meta-analysis.

OBJECTIVE: Matrix metalloproteinases 9 (MMP-9) is a zinc-dependent gelatinase, which could decrease the expression of extracellular matrix proteins and influence the metastatic behavior of tumors. In order to draw a comprehensive and precise result about the relationship of MMP-9 and urinary cancers, we presented the current meta-analysis. METHODS: We searched the PubMed, EMbase, Web of Science, CBM, CNKI and Wanfang databases, the cited references were also manually searched again, covering all the papers published until August 2018. Quality assessment was conducted using the Newcastle-Ottawa Scale. All the meta-analysis was conducted with Stata version 12.0 software to assess the strength of the association. Linkage disequilibrium (LD) analyses of gene polymorphisms and in-silico analysis of MMP-9 expression were also conducted to illustrate the relationship. RESULTS: 17 case-control studies comprise of more than 6154 cases and 6330 controls were enrolled and analyzed. After analyzed, we found that there is no significant association between rs3918241, rs2250889, rs17576 and rs17577 of MMP-9 and urinary cancers. LD analysis uncovered a significant LD between rs3918241 and rs17577 in CEU, CHB&CHS, ESN, and JPT populations (CEU: r2 = 1.0; CHB&CHS: r2 = 1.0; ESN: r2 = 0.74; JPT: r2 = 0.77), as well as a remarkable LD between rs17576 and rs2250889 in CHB&CHS and JPT populations (CHB&CHS: r2 = 0.81; JPT: r2 = 0.82). Furthermore, in-silico results indicated that the expression of MMP-9 in cancer tissue was higher than that in normal tissue in prostate cancer (Transcripts Per Kilobase Million (TPM) = 7.14 vs. 1.36, P < 0.001), bladder cancer (TPM = 14.2 vs. 2.47, P < 0.001), kidney renal clear cell carcinoma (TPM = 7.43 vs. 1.61, P < 0.001), kidney renal papillary cell carcinoma (TPM = 5.52 vs. 1.74, P = 0.002). CONCLUSIONS: rs3918241, rs2250889, rs17576 and rs17577 polymorphisms of MMP-9 are not associated with altered risk of urinary cancer. More studies with large sample size focused on the combined effect of two or more polymorphisms of MMP-9 are necessary in the future.