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Carbapenem- and colistin-resistant Escherichia coli (CCREC) cause high mortality rates and health costs, and have become serious health concerns. Total 1764 samples were collected from 60 animal farms in 2019 and 2021, including worker and animal faeces, wastewater, well water, air, vegetables, human hands, object surfaces, throat swabs, soil, and flies to investigate the prevalence and potential transmission pathways of CCREC. Eleven CCREC were detected: 9 (5 in 2019 and 4 in 2021) from 5 worker faeces, 3 animal faeces, 1 wastewater, and 2 from 1 flies sample. Chicken farms had the highest number of CCREC (n = 9). The detection rate was low (<1.1%) overall, and there was no significant difference in both years, indicating that CCREC existed stably after 4 years of colistin ban. The combinations of chromosomes and plasmids harbouring bla NDM and mcr-1.1 were divided into 4 patterns: IncX3 plasmid-bla NDM & chromosome-mcr.1.1 (n = 5); IncX3 plasmid-bla NDM & IncHI2 plasmid-mcr.1.1 (n = 3); IncFII plasmid-bla NDM & IncI2 plasmid-mcr.1.1 (n = 2); both chromosome (n = 1). The bla NDM located on plasmids was surrounded by similar genetic structures: Tn3-IS-bla NDM -bleMBL-TrpF-DsbD-IS. The genetic contexts of mcr-1.1 were highly similar, with 'ISApl1-mcr-1.1-PAP2' and 'mcr-1.1-PAP2'. All plasmids can be successfully transferred into E. coli J53, except for the IncHI2 plasmids with the transfer rate of 33.3%. The IncFII and IncI2 plasmids from same strain of flies could be co-transferred. The clonal spread of CCREC from humans to humans occurred on the same pig farm (P4) or different chicken farms (BC9 and LH7). This study suggested that flies, chromosomes, and plasmids jointly contribute to the steady existence of CCREC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Phosphoinositide-3-kinase (PI3K) is overexpressed in many tumors and is, thus, an ideal target for cancer treatments. Accordingly, there is an urgent need for the development of PI3K inhibitors with high potency and low toxicity., Methods: In this study, we designed and synthesized a series of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency., Results and Discussion: Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC 50 : 31.8 ± 4.1 nM) to the positive control, BKM-120 (IC 50 : 44.6 ± 3.6 nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC 50 : 15.4 ± 1.9 nM) and significant isoform selectivity against PI3Kβ, PI3Kγ, and mTOR. Furthermore, 17p exhibited good antiproliferative activities against cancer cell activity and good safety in the Ames and hERG tests while having outstanding liver microsomal stability in vitro , with half-lives of 38.5 min in rats and 127.9 min in humans. In addition, in an apoptosis assay, 17p could induce dose-dependent cytotoxicity in the ovarian cancer cell line A2780. In a pharmacokinetic study, 17p was stable ( T ½ : 2.03 h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment., Competing Interests: Authors QZ and JL were employed by the Shanghai Institute of Pharmaceutical Industry Co., Ltd. Author YW was employed by Shijiazhuang Vortech Biotech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Yang, Zhang, Zhou, Wang, Shang, Li and Zhang.)

Background: Prolonged Field Care (PFC) is a military adaptation of Tactical Combat Casualty Care providing extended pre-hospital management during delayed extrication. Effects of addition of Valproic Acid (VPA) to Fresh Frozen Plasma (FFP) in a PFC model of hemorrhagic shock and traumatic brain injury (TBI) are not known. We hypothesized that VPA is associated with decreased neurological impairment, and its protective changes are detected at the transcriptomic level., Study Design: Swine underwent TBI and 40%-blood volume hemorrhage. After 2-hours of shock, they were randomized to: 1)normal saline (NS), 2)NS+250 ml FFP (NS+FFP), or 3)NS+FFP+150 mg/kgVPA(NS+FFP+VPA). At 72-hours, they were transfused packed red blood cells before being euthanized. Intraoperative variables and neurological outcomes were compared. Brain lesion size was measured, and gene expression profiles were analyzed using RNA-sequencing. Pathway and network analyses were performed on differentially expressed genes. Real-time PCR was performed to validate key genes., Results: NS+FFP and NS+FFP+VPA required significantly less crystalloid resuscitation(974 ml-NS+FFP; 1461ml-NS+FFP+VPA vs. 4540 ml-NS, p<0.001), had smaller brain lesion size(2477mm3-NS+FFP; 3018.0mm3-NS+FFP+VPA vs. 4517.0mm3-NS, p<0.01), and less functional neurologic impairment compared to NS. Per pathway analysis of differentially expressed genes, VPA was associated with enrichment of numerous metabolic changes in injured brains, which were not observed with FFP. Network analysis showed enrichment of various gene networks. MT-ATP8 gene was downregulated in VPA-treated animals., Conclusions: The addition of FFP to the resuscitation protocol resulted in a significant reduction in crystalloid requirements. Both, the FFP and FFP+VPA groups showed improved neurological recovery compared to NS alone and had distinctive transcriptomic profiles in injured brains at 72-hours. MT-ATP8, involved in worsening ischemia following brain injury, was down-regulated in VPA-treated animals., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Chemotherapy is the main treatment for bladder cancer, but drug resistance and side effects limit its application and therapeutic effect. Herein, we constructed doxorubicin (DOX)/COOH-mesoporous silica nanoparticle/polyethylenimine (PEI)/nucleic acid chimeras (DOX/MSN/Chimeras) to reduce the toxicity of chemotherapy drugs and the resistance of bladder cancer cells. Transmission electron microscopy showed that PEI was coated on the DOX/MSN/BSA nanoparticles with a diameter of about 150 nm. DOX/MSN/PEI could control DOX release for over 48 h, and the sudden release rate was significantly lower than DOX/MSN. Immunohistochemical results showed that DOX/MSN/Chimera specifically bound to bladder cancer cells, and markedly inhibited PI3K expression and proliferation of DOX-resistant bladder cancer cells. DOX/MSN/Chimera promoted the apoptosis of drug-resistant bladder cancer cells, which was superior to DOX/MSN/Aptamer or DOX/MSN. We further carried out animal experiments and found that DOX/MSN/Chimera could reduce the volume of transplanted tumors in vivo. Compared with DOX/MSN/Aptamer group, the proliferation rate was significantly decreased and the proportion of apoptotic cells was highly increased. Through the histological observation of kidneys and lungs, we believed that DOX/MSN/Chimera can effectively reduce the damage of chemotherapy drugs to normal tissues. In conclusion, we constructed a COOH-MSN/nucleic acid chimera conjugate for the targeted delivery of siRNA and anti-cancer drugs. Our study provides a new method for personalized and targeted treatment of drug-resistant bladder cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: DNA damage response (DDR) mutation-related genes and composition of immune cells are core factors affecting the effectiveness of immune checkpoint inhibitor therapy. The aim of this study is to combine DDR with immune-related genes to screen the prognostic signature for prostate cancer (PCa). Methods: Gene expression profile and somatic mutation were downloaded from The Cancer Genome Atlas (TCGA). DDR-related genes were obtained from published study. After identification of prognostic-related DDR genes, samples were divided into mutation and nonmutation groups. Differentially expressed genes between these two groups were screened, followed by selection of immune-related DDR genes. Univariate and multivariate Cox analyses were performed to screen genes for constructing prognostic model. Nomogram model was also developed. The expression level of signature was detected by quantitative real-time PCR (qPCR). Results: Two genes ( MYBBP1A and PCDHA9 ) were screened to construct the prognostic model, and it showed good risk prediction of PCa prognosis. Survival analysis showed that patients in high-risk group had worse overall survival than those in low-risk group. Cox analyses indicated that risk score could be used as an independent prognostic factor for PCa. qPCR results indicated that MYBBP1A was upregulated, whereas PCDHA9 was downregulated in PCa cell lines. Conclusions: A prognostic model based on DDR mutation-related genes for PCa was established, which serves as an effective tool for prognostic differentiation in patients with PCa.

Mer and c-Met kinases, which are commonly overexpressed in various tumors, are ideal targets for the development of antitumor drugs. This study focuses on the design, synthesis, and evaluation of several 2-substituted aniline pyrimidine derivatives as highly potent dual inhibitors of Mer and c-Met kinases for effective tumor treatment. Compound 18c emerged as a standout candidate, demonstrating robust inhibitory activity against Mer and c-Met kinases, with IC 50 values of 18.5 ± 2.3 nM and 33.6 ± 4.3 nM, respectively. Additionally, compound 18c displayed good antiproliferative activities on HepG2, MDA-MB-231, and HCT116 cancer cells, along with favorable safety profiles in hERG testing. Notably, it exhibited exceptional liver microsomal stability in vitro, with a half-life of 53.1 min in human liver microsome. Compound 18c also exhibited dose-dependent cytotoxicity and hindered migration of HCT116 cancer cells, as demonstrated in apoptosis and migration assays. These findings collectively suggest that compound 18c holds promise as a dual Mer/c-Met agent for cancer treatment.

Background: Neurogenic bladder (NB) following suprasacral spinal cord injury (SSCI) is an interstitial disease with the structural remodeling of bladder tissue and matrix over-deposition. Circular RNAs (circRNAs) are involved in fibrotic disease development through their post-transcriptional regulatory functions. This study aimed to use transcriptome high-throughput sequencing to investigate the process of NB and bladder fibrosis after SSCI., Methods: Spinal cord transection at the T10-T11 level was used to construct the SSCI model in rats (10-week-old female Wistar rats, weighing 200 ± 20 g). The bladders were collected without (sham group) and with (SSCI 1-3 groups) NB status. Morphological examination was conducted to assess the extent of bladder fibrosis. Additionally, RNA sequencing was utilized to determine mRNAs and circRNAs expression patterns. The dynamic changes of differentially expressed mRNAs (DEMs) and circRNAs (DECs) in different periods of SSCI were further analyzed., Results: Bladder weight, smooth muscle cell hypertrophy, and extracellular matrix gradually increased after SSCI. Compared with the sham group, 3,255 DEMs and 1,339 DECs, 3,449 DEMs and 1,324 DECs, 884 DEMs, and 1,151 DECs were detected in the SSCI 1-3 groups, respectively. Specifically, circRNA3621, circRNA0617, circRNA0586, and circRNA4426 were significant DECs common to SSCI 1-3 groups compared with the sham group. Moreover, Gene Ontology (GO) enrichment suggested that inflammatory and chronic inflammatory responses were the key events in NB progression following SSCI. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment associated with the "Chemokine signaling pathway", the "IL-17 signaling pathway", and the "TGF-beta signaling pathway" suggests their potential involvement in regulating biological processes. The circRNA-miRNA-mRNA interaction networks of DECs revealed rno-circ-2239 (micu2) as the largest node, indicating that the rno-circ-2239-miRNA-mRNA-mediated network may play a critical role in the pathogenesis of SSCI-induced NB., Conclusions: This study offers a comprehensive outlook on the possible roles of DEMs and DECs in bladder fibrosis and NB progression following SSCI. These findings have the potential to serve as novel biomarkers and therapeutic targets., Competing Interests: The authors declare there are no competing interests., (©2023 Ruan et al.)

Background: Growing evidence has indicated that long non-coding RNAs (lncRNAs) are important regulators of pathological and physiological processes through various mechanisms. However, the signature of lncRNA expression and the possible roles of lncRNAs in spinal cord injury (SCI) rat neurogenic bladder (NB) have not been comprehensively explored. In this study, the expression profiles of lncRNAs and mRNAs were explored in the bladder tissue of SCI rats using next-generation sequencing (NGS)., Methods: Twenty female Wistar rats were randomly divided into SCI 1-3 and normal control (NC) groups. The spinal cord was completely transected at the T9-T10 level to establish the SCI model. Bladder tissues were collected on days 7, 14, and 28 after the operation. The expression profiles of lncRNAs were detected by NGS. Differentially expressed lncRNAs (DELs) were chosen for qRT-PCR verification to validate the RNA sequencing results. The functions of the predicted target genes were then evaluated using Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis., Results: Compared with the NC group, the SCI 1-3 groups had 468, 117, and 408 DELs [fold change (FC) >2], including 247, 38, and 201 up-regulated and 163, 79, and 207 down-regulated lncRNAs, respectively. Likewise, 6,654, 2,133, and 5,706 mRNAs (FC >2) were differentially expressed between SCI 1-3 and NC rats, of which 4,821, 1,195, and 3,695 were up-regulated, and 1,833, 938, and 2,011 were down-regulated, respectively. Specifically, Miat, Mir155hg, and H19 were significant DELs in all SCI groups. Moreover, GO revealed that the DELs were related to several terms, including immune response, and KEGG was mainly enriched in 10 pathways, such as the transforming growth factor β signaling pathway., Conclusions: The results revealed the expression profiles and possible roles of lncRNAs in SCI rat NB. This study may help identify possible NB mechanisms following SCI from the perspective of lncRNAs and provides new potential lncRNAs for the early diagnosis and treatment of human NB in the future., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-21-1161/coif). The authors have no conflicts of interest to declare., (2022 Translational Andrology and Urology. All rights reserved.)

Background: Intradetrusor botulinum toxin A injection is recommended for the treatment of refractory detrusor overactivity (DO) in patients with neurogenic bladder, however, whether it could inhibit neurogenic bladder fibrosis is uncertain. This study aimed to investigate the effect of botulinum toxin A on neurogenic bladder fibrosis and the underlying mechanism., Methods: Forty eight Female Wistar rats were evenly randomized into 4 groups: Sham, T10 transection, Early and Late groups. The last three groups were subjected to T10 spinal cord transection, while the Sham group was treated with sham surgery. 0.9% saline was injected into the detrusor in the Sham and T10 transection groups simultaneously with the surgery, while 2 U/rat botulinum toxin A was injected into the detrusor simultaneously with the surgery in the Early group and 4 weeks following the surgery in the Late group. Body/bladder weight, cystometric parameters, bladder Hematoxylin-eosin staining were used to evaluate the bladder fibrosis. Western blot and quantitative Real-time PCR were used to evaluate the expression of bladder transforming growth factor β1., Results: Compared with the T10 transection group, the bladder/body weight was decreased significantly in the Early and Late groups (P<0.05), along with the significant inhibition of non-voiding contraction (NVC) frequency and amplitude (P<0.05), and the significant increase of bladder volume (P<0.05). The detrusor connective tissue percentage (P<0.05) and the expression of transforming growth factor β1 (P<0.05) also decreased significantly in the Early and Late groups. Those changes were more obviously in the Early group than in the Late group., Conclusions: Intradetrusor botulinum toxin A injection reduced bladder fibrosis in rats with spinal cord injury (SCI), which was more obviously in the Early group than in the Late group. The mechanisms might be mediated by suppression of transforming growth factor β1 (TGF-β1) expression., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-21-62). All authors report grants from National Natural Science Foundation of China [grant numbers: 81500578; 82070787], grants from Beijing Municipal Administration of Hospitals Clinical Medicine Development of special Funding Support [grant number: ZYLX201801], during the conduct of the study., (2021 Translational Andrology and Urology. All rights reserved.)

Background: The purpose of this study was to analyze the values of pretreatment serum inflammation markers, lipid, and lipoprotein for predicting the pathological results in men with total prostate-specific antigen between 4 and 10 ng/ml. Materials and method: A total of 611 eligible patients diagnosed with total prostate-specific antigen between 4 and 10 ng/ml and who received a transrectal ultrasound-guided prostate biopsy between January 2014 and December 2019 were included in our study. All the patients were divided into groups according to their pathological results and we collected the data of their pretreatment indicators of the blood routine and biochemistry. Results: The pathological results from prostate biopsies from 160 patients with prostate cancer and 451 patients with benign lesions. Age and total prostate-specific antigen values were significantly higher in patients with prostate cancer than those with benign lesions ( P < 0.05). Red blood cell, platelet count, prealbumin, and triglyceride were significantly lower in patients with prostate cancer than those with benign lesions. Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte- monocyte ratio, and apolipoprotein B were lower and apolipoprotein A-I was higher in the prostate cancer group than in the benign lesions group but not significantly ( P > 0.05). Multivariate logistic regression revealed that age and total prostate-specific antigen could be independent predictors for pathological results (OR, 1.064, 95%CI, 1.031-1.098, P < 0.001; OR, 1.232, 95%CI, 1.061-1.429, P = 0.006). Conclusion: Higher age and total prostate-specific antigen were closely related to the pathological results. Prospective studies conducted with a large number of patients are needed to evaluate the diagnostic value of non-invasively pretreatment serum inflammation markers and lipoprotein for predicting the pathological results in men with total prostate-specific antigen between 4 and 10 ng/ml., (Copyright © 2020 Li, Shang, Liu, Yan and Ou.)

Background: Bladder cancer (BC) is the most commonly occurring malignant tumor of the urinary system worldwide. Long non-coding RNAs (lncRNAs), including lncRNA RNF144A-AS1 (RNF144A-AS1), perform an oncogenic role in BC progression. However, how RNF144A-AS1 is regulated in BC has not been fully investigated, and its role in BC is mostly obscure. In this study, we explore its role in BC progression., Materials and Methods: The expression level of RNF144A-AS1 in BC tissues was explored via bioinformatics analysis and quantitative real-time PCR (qRT-PCR). We used RNF144A-AS1 siRNA (si-RNF144A-AS1) to inhibit the RNF144A-AS1 level in BC cell lines (J82 and 5637 cells). A series of experimental studies in vitro (CCK-8 assay, colony formation assay and Transwell assay) was performed to explore the role of si-RNF144A-AS1 on the proliferation, migration and invasion of J82 and 5637 cells. A BC xenograft model was established, and the effect of si-RNF144A-AS1 on xenograft growth was explored in vivo. The interactions among RNF144A-AS1, miR-455-5p and SOX11 were predicted by bioinformatics miRanda and Targetscan database, and verified by the luciferase reporter assay and RNA pull-down assay. Finally, miR-455-5p inhibitor and si-RNF144A-AS1 were cotransfected into J82 and 5637 cells., Results: RNF144A-AS1 is overexpressed in BC tumors and cells, and its overexpression is correlated with poor prognosis. Knockdown of RNF144A-AS1 markedly suppressed the proliferation, migration and invasion of J82 and 5637 cells and significantly inhibited xenograft growth in nude mice, compared to si-NC. We found that RNF144A-AS1 serves as a sponge for miR-455-5p. Furthermore, a binding site of miR-455-5p was found in 3' UTR of SOX11 gene, and overexpression of miR-455-5p suppressed SOX11 levels. RNF144A-AS1 knockdown markedly decreased SOX11 expression levels, while miR-455-5p inhibitor restored this repressive effect. Restoration of SOX11 could reverse this repressive effect of RNF144A-AS1 on cell proliferation, migration and invasion abilities., Conclusion: Overall, our findings underline the critical role of RNF144A-AS1 in BC development, and our study reveals for the first time that RNF144A-AS1 promotes BC progression via the RNF144A-AS1/miR-455-5p/SOX11 axis., Competing Interests: The authors declare that there are no competing interests associated with this manuscript., (© 2020 Bi et al.)

Purpose: This study aimed to investigate the associations between the preoperative prognostic nutritional index (PNI), systemic immune-inflammation index (SII) and overall survival (OS) and cancer-specific survival (CSS) in high-risk non-muscle-invasive bladder cancer (NMIBC) patients who received intravesical instillation of Bacillus Calmette-Guerin (BCG) after transurethral resection of bladder tumour (TURBT)., Patients and Methods: We retrospectively collected data from 387 high-risk NMIBC patients between January 2004 and December 2014. PNI was calculated as total lymphocyte count (10 9 /L)×5+albumin concentration (g/L). SII was calculated as neutrophil count (10 9 /L)×platelet count (10 9 /L)/lymphocyte count (10 9 /L). The cutoff values of PNI and SII were determined through receiver operating characteristic (ROC) analysis. OS and CSS were estimated by Kaplan-Meier analysis. The Log rank test was used to compare differences between the groups. Univariate and multivariate Cox regression analyses were performed to assess the predictive values of PNI and SII for OS and CSS. Additionally, highest-risk NMIBC patients were also divided into low or high groups according to PNI and SII. The OS and CSS of highest-risk NMIBC patients were estimated using Kaplan-Meier analysis with the Log rank test., Results: The patients were divided into two groups according to the cutoff values of PNI (<50.17 vs ≥50.17) and SII (<467.76 vs ≥467.76). Kaplan-Meier analysis revealed that low PNI and high SII were associated with poorer OS and CSS in high-risk NMIBC patients. Univariate and multivariate Cox regression analyses revealed that PNI and SII were independent predictive factors for OS and CSS. Kaplan-Meier analysis also revealed that low PNI and high SII were related to poorer OS and CSS in highest-risk NMIBC patients., Conclusion: These results suggest that preoperative PNI and SII, based on standard laboratory measurements, may be useful noninvasive, inexpensive and simple tools for predicting the long-term survival of high-risk NMIBC patients who received intravesical instillation of BCG after TURBT., Competing Interests: The authors report grants from Beijing Municipal People’s Government, during the conduct of the study; and grants from Beijing Municipal People’s Government, outside the submitted work. The authors declare that there are no other conflicts of interest in this study., (© 2020 Bi et al.)

Background: Peromyscus are the most common mammalian species in North America and are widely used in both laboratory and field studies. The deer mouse, P. maniculatus and the old-field mouse, P. polionotus, are closely related and can generate viable and fertile hybrid offspring. The ability to generate hybrid offspring, coupled with developing genomic resources, enables researchers to conduct linkage analysis studies to identify genomic loci associated with specific traits., Results: We used available genomic data to identify DNA polymorphisms between P. maniculatus and P. polionotus and used the polymorphic data to identify the range of genetic complexity that underlies physiological and behavioral differences between the species, including cholesterol metabolism and genes associated with autism. In addition, we used the polymorphic data to conduct a candidate gene linkage analysis for the Dominant spot trait and determined that Dominant spot is linked to a region of chromosome 20 that contains a strong candidate gene, Sox10. During the linkage analysis, we found that the spot size varied quantitively in affected Peromyscus based on genetic background., Conclusions: The expanding genomic resources for Peromyscus facilitate their use in linkage analysis studies, enabling the identification of loci associated with specific traits. More specifically, we have linked a coat color spotting phenotype, Dominant spot, with Sox10, a member the neural crest gene regulatory network, and that there are likely two genetic modifiers that interact with Dominant spot. These results establish Peromyscus as a model system for identifying new alleles of the neural crest gene regulatory network.

Background: An increasing amount of evidence has indicated that microRNAs (miRs) are involved in most biological conditions, including the neurogenic bladder (NB). However, to our knowledge, no studies have investigated these miR expressions in spinal cord-injured (SCI) rat NB. The goal of the study was to explore the miR expression profile in the SCI rat NB by next-generation sequencing (NGS)., Methods: Female Wistar rats underwent spinal cord transection at T9-10 and were randomly divided into the SCI-1, SCI-2 and SCI-3 groups (n=5 for each group) whose bladder tissues were collected 1, 2, and 4 weeks after transection, respectively. The normal rats were used as the normal control (NC) group. MiRs microarray assays were used to detect the differentially expressed miRs between the groups by NGS, which was then verified by quantitative real-time polymerase chain reaction (qRT-PCR). Those significantly differently expressed miRs were analyzed with Gene Ontology categories and Kyoto Encyclopedia of Genes and Genomes bioinformatical analyses., Results: Compared with the NC group, 96, 28 and 51 miRs were downregulated in the rats' bladder in the SCI-1, SCI-2, and SCI-3 groups, respectively, and 133, 49, and 76 miRs were upregulated respectively. Specifically, miR-21-5p was the most significantly upregulated miR in all SCI groups. Also, 121 miRs (SCI-1 vs. SCI-2), 98 miRs (SCI-1 vs. SCI-3), and 26 miRs (SCI-2 vs. SCI-3) were of significantly different expression. Furthermore, a large set of genes implicated in essential signaling pathways were targeted by these miRs, including PI3K-Akt, MAPK, Rap1, and cGMP-PKG signaling pathways, along with the tight junction and metabolic pathways., Conclusions: This is the first demonstration of differentially expressed miRs, which may potentially serve as new molecular targets in the SCI rat NB., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-415). The authors have no conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

Background: The zinc finger of the cerebellum 2 (ZIC2) has been reported to function as an oncogenic transcription factor. However, the level and prognostic value of ZIC2 in patients with clear cell renal cell carcinoma (ccRCC) remain unclear., Methods: UALCAN was employed to analyze the level of ZIC2 mRNA in ccRCC samples compared to normal kidney tissues and to explore the impacts of ZIC2 expression according to tumor-node-metastasis (TNM) stages and histologic grades. The correlations between ZIC2 expression and clinicopathological parameters were investigated by bioinformatic analysis using UCSC Xena Browser in the light of data from The Cancer Genome Atlas. We used Kaplan-Meier analysis to assess the association between the level of ZIC2 and overall survival (OS), disease-free survival (DFS) in ccRCC patients. Moreover, Cox analyses were adopted to evaluate its prognostic value in ccRCC patients., Results: ZIC2 expression was much higher in ccRCC samples than that in normal ones and increased with the escalation of TNM stages and histologic grades. In addition, the high ZIC2 expression group had significantly advanced age (age >65), T, N, M, TNM stage, histologic grade and lower 5-years OS (19.40% vs. 31.74%, P=0.006) than the low one. High ZIC2 expression was related to remarkably worse OS (P<0.001) in ccRCC patients, whereas no statistical relation was detected between the level of ZIC2 and DFS. Moreover, multivariate analysis indicated high level of ZIC2 is an independent factor of prognosis for worse OS (HR: 1.625, 95% CI, 1.146-2.302, P=0.006)., Conclusions: The level of ZIC2 expression is an independent predictor for OS in ccRCC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau.2020.01.12). The authors have no conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

Aims: To investigate the effects of injecting RNA interference (RNAi) lentiviruses targeting the muscarinic 3 (M 3 ) receptor gene into the bladder wall on bladder activity in rats with spinal cord injury (SCI)., Methods: Four M 3 RNAi lentiviruses were constructed and used to infect primary cultured bladder smooth muscle cells (BSMCs). Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were performed to determine the optimal RNAi lentivirus with the highest interference efficiency. Female Wistar rats were subjected spinal cord transection at T9-10 and randomly divided into three groups (n = 8), namely, blank control, negative control, and experimental groups, and injected into the bladder wall with saline, negative control shRNA, and M 3 RNAi lentiviruses, respectively, 1 week after spinal cord transection. The normal rats were used as normal control group. Urodynamic parameters and bladder tissues were evaluated in the different groups., Results: An M 3 RNAi lentivirus with the highest interference efficiency (78.9%) was constructed and identified. Three weeks after injecting M 3 RNAi lentiviruses into the bladder wall, Western blotting and qRT-PCR showed that the M 3 receptor was significantly downregulated in the experimental group. Cystometric evaluation suggested that downregulating M 3 receptor expression could substantially decrease basal pressure, residual volume, and non-voiding contraction number, increase intercontraction interval, and significantly improve bladder compliance in rats with SCI., Conclusion: Injecting RNAi lentiviruses targeting the M 3 receptor gene into the bladder wall could effectively inhibit neurogenic detrusor overactivity (NDO) due to SCI. Thus, this approach may be a potential treatment for NDO in SCI., (© 2018 Wiley Periodicals, Inc.)

Background: Epidemiological evidences regarding the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of prostate cancer (PC) is still controversial. Therefore, we conducted a meta-analysis to explore the controversy that exists. Methods: Electronic databases including Medline, EMBASE, Web of Science, Cochrane Library, BIOSIS, Scopus, CBM, CNKI, WANFANG, and CQVIP were used to search for and identify eligible studies published until December 31, 2017. Pooled effect estimates for the relative risk (RR) were computed through fixed-effects or random-effects models as appropriate. Publication bias was evaluated by Egger's and Begg's tests and potential sources of heterogeneity were investigated in subgroup analyses. Results: A total of 43 observational studies were eligible for this meta-analysis. A protective effect was identified for the intake of any NSAIDs on the risk of PC (pooled RR = 0.89, 95% CI = 0.81-0.98). Moreover, the long-term intake of NSAIDs (≥5 years rather than ≥4 years) was associated with reduced PC incidence (pooled RR = 0.882, 95% CI = 0.785-0.991). Aspirin intake was also associated with a 7.0% risk reduction of PC (pooled RR = 0.93, 95% CI = 0.89-0.96). The inverse association became stronger for advanced PC and PC with a Gleason score ≥7 compared to the association with total PC. Interestingly, it was the daily dose (≥1 pill/day) rather than, long-term aspirin intake (≥4 or ≥5 years) that was associated with reduced PC incidence (pooled RR = 0.875, 95% CI = 0.792-0.967). The pooled effects for non-aspirin NSAIDs demonstrated no significantly adverse or beneficial effects on total PC, advanced PC, or PC with Gleason score ≥7, though all pooled RRs were >1. Conclusions: Our findings suggested a protective effect of the intake of any NSAIDs on the risk of PC, especially in those who took the NSAIDs for a long period. Moreover, aspirin intake was also associated with a decreased risk of PC, and there was a dose related association between aspirin intake and the risk of PC, while no significant effects of long-term aspirin intake were found on the PC incidence.

Introduction: The aim of this study was to elucidate the association between apolipoprotein A-I (Apo A-I) and overall survival (OS) as well as cancer-specific survival (CSS) in non-muscle-invasive bladder cancer (NMIBC) patients undergoing transurethral resection of bladder tumor (TURBT)., Patients and Methods: We retrospectively collected data of 470 eligible patients diagnosed with NMIBC and who received TURBT between January 2004 and December 2011. Pretreatment blood indexes were examined. The association of Apo A-I with clinicopathological characteristics was further analyzed by dichotomizing our sample into those with Apo A-I ≤ 1.19 g/L (low Apo A-I group) and those with Apo A-I > 1.19 g/L (high Apo A-I group). OS and CSS were estimated by Kaplan-Meier analysis and the log-rank test was used to compare differences between groups. Univariate and multivariate Cox regression analyses were plotted to assess the prognostic value of Apo A-I in NMIBC patients. In addition, subgroup analyses were performed according to the risk classification of the International Bladder Cancer Group., Results: In the overall population, patients in the high Apo A-I group had greater 5-year OS and 5-year CSS rates as compared to those in the low Apo A-I group. Kaplan-Meier survival analysis revealed that higher albumin, Apo A-I, and hemoglobin levels were associated with greater OS and CSS while elevated neutrophil-lymphocyte ratio was associated with worse OS and CSS in the overall and high-risk population rather than low- and intermediate-risk population. Furthermore, Apo A-I was shown to be an independent predictor in the overall population (for OS, hazard ratio [HR], 0.364, 95% confidence interval [CI], 0.221-0.598, p < 0.001; for CSS, HR, 0.328, 95% CI, 0.185-0.583, p < 0.001) and high-risk patients (for OS, HR, 0.232, 95% CI 0.121-0.443, p < 0.001; for CSS, HR, 0.269, 95% CI, 0.133-0.541, p < 0.001)., Conclusion: These results suggest that Apo A-I level could potentially serve as a useful prognostic indicator for therapeutic decision making in NMIBC patients., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Most plant bacterial pathogens rely on type III effectors to cause diseases. Although it is well known that the plant hormone salicylic acid (SA) plays an essential role in defense, whether the master regulator of SA signaling, NPR1, is targeted by any plant pathogen effectors is unknown. SA facilitates the reduction of cytosolic NPR1 oligomers into monomers, which enter the nucleus and function as transcriptional coactivators of plant defense genes. We show that SA promotes the interaction between the Pseudomonas syringae type III effector AvrPtoB and NPR1. In the presence of SA, AvrPtoB mediates the degradation of NPR1 via the host 26S proteasome in a manner dependent on AvrPtoB's E3 ligase activity. Intriguingly, we found that NPR1 plays an important role in MAMP-triggered immunity (MTI), inducing the expression of MTI marker genes. Thus, this work uncovers a strategy in which AvrPtoB targets NPR1 and represses NPR1-dependent SA signaling, thereby subverting plant innate immunity., (Published by Elsevier Inc.)

Objectives: The widespread use of partial nephrectomy (PN) has led to the preservation of functional renal parenchyma. However, the benefits of PN on renal function and cardiovascular outcomes remain controversial. Thus, a meta-analysis was performed to reconcile the conflicting results., Materials and Methods: PubMed, Embase, and the Cochrane Library were searched from inception to August 2015, and databases with all relevant comparative studies were included. The Mantel-Haenszel method with random-effects models was used to determine the pooled hazard ratios (HRs) for each outcome., Results: In total, 26 studies were pooled for new-onset chronic kidney disease, and 6 studies were pooled for cardiovascular outcomes. According to the pooled estimates, PN correlated with a 73% risk reduction of new-onset chronic kidney disease in all included patients (HR = 0.27, P<0.0001) and a 65% risk reduction in patients with tumors>4cm (HR = 0.35, P<0.0001) compared with radical nephrectomy. There were no significant differences between groups regarding postsurgery cardiovascular events (HR = 0.86, P = 0.238) and cardiovascular death (HR = 0.79, P = 0.196). Despite inherent selection biases, the pooled estimates were robust in sensitivity and subgroup analyses., Conclusions: Our findings suggest that PN lowers the postoperative risk of new-onset chronic kidney disease. Nevertheless, the protection of renal function by PN did not reduce the risk of cardiovascular outcomes. However, this result remains controversial, and additional large-scale evaluations are warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Paraneoplastic neurological syndromes (PNS) are rare disorders associated with malignant tumours, which are triggered by autoimmune reactions. Paraneoplastic cerebellar degeneration (PCD) is the PNS type most commonly associated with ovarian and breast cancer. Two bladder cancers manifesting in PCD were previously reported. However, the cancers in these cases had poor outcomes., Case Presentation: Here, we present a 68-year old man with history of high-grade papillary urothelial carcinoma of the bladder. The patient suffered from persistent cerebellar ataxia accompanied by bladder cancer recurrence five months after transurethral resection of the bladder tumour (TURBt). Laboratory screening for the specific antibodies of paraneoplastic neurological syndromes revealed no positive results. Symptoms were not remitted after a 7-day-course of high-dose glucocorticoid therapy. To our surprise, the patient recovered fully after laparoscopic radical cystectomy. Postoperative pathology revealed that surgical specimens were urothelial carcinoma in situ (CIS) and squamous cell carcinoma of the bladder. The patient remained asymptomatic and there was no evidence of recurrence after the followup period of 11 months., Conclusion: To our knowledge, this is the third report of PCD in a patient with bladder cancer. This case showed that tumour resection cured the PCD. To assist clinical evaluation and management, literature regarding basic PNS characteristics and bladder cancers was reviewed.

Objective: A meta-analysis was undertaken to provide an evidence-based basis of clinical trials comparing extralevator abdominoperineal excision with conventional abdominoperineal excision for low rectal tumor., Methods: We searched through the major medical databases such as PubMed, EMBASE, Medline, Science Citation Index, Web of Science for all published studies without any limit on language from January 2009 until January 2015. The following search terms were used: extralevator abdominoperineal excision or cylindrical abdominoperineal resection or conventional abdominoperineal excision or abdominoperineal excision or rectal cancer. Furthermore, Additional related studies were manually searched in the reference lists of all published reviews and retrieved articles., Results: In this meta-analysis, there are a total number of 1797 patients included: 1099 patients in the ELAPE group and 698 in the APE group, and there are not statistically differences between groups in CRM [RR=0.65, 95% CI (0.41, 1.04), P=0.07] and wound complications [RR=1.14, 95% CI (1.09, 1.66), P=0.45] between ELAPE and APE. However, ELAPE has a lower rate of intraoperation perforation [RR=0.44; 95% CI (0.33, 0.60); P<0.00001] and local recurrence [RR=0.45, 95% CI (0.27, 0.77), P=0.003] than APE in terms of short follow-up time.

Rapid and high-resolution imaging of large tissues is essential in biological research, like brain neuron connectivity research and cancer margins imaging. Here a novel stage-scanning confocal microscopy was developed for rapid imaging of large tissues. Line scanning methods and strip imaging strategy were used to increase the imaging speed. The scientific CMOS was used as line detector in sub-array mode and the optical sectioning ability can be easily adjusted by changing the number of line detectors according to different samples. Fluorescent beads imaging showed resolutions of 0.47 μm, 0.56 μm, and 1.56 μm in the X, Y, and Z directions, respectively, with a 40 × objective lens. A 10 × 10 mm(2) coronal plane with enough signal intensity could be imaged in about 88 sec at a sampling resolution of 0.16 μm/pixel. Rapid imaging of mouse brain slices demonstrated the applicability of this system in visualizing neuronal details at high frame rate.

We report a novel fluorescence imaging approach to imaging nonfluorescence-labeled biological tissue samples. The method was demonstrated by imaging neurons in Golgi-Cox-stained and epoxy-resin-embedded samples through the excitation of the background fluorescence of the specimens. The dark neurons stood out clearly against background fluorescence in the images, enabling the tracing of a single dendritic spine using both confocal and wide-field fluorescence microscopy. The results suggest that the reported fluorescence imaging method would provide an effective alternative solution to image nonfluorescence-labeled samples, and it allows tracing the dendritic spine structure of neurons.

Pterostilbene, being extracted from many plants, has significant biological activities in preventing cancer, diabetes, and cardiovascular diseases so as to have great potential applications in pharmaceutical fields. But the poor solubility and stability of pterostilbene strictly restrained its applications. As a good protection and oral delivery system, an optimal nanoemulsion for pterostilbene was developed by using low-energy emulsification method. Systematic pseudo-ternary phase diagrams have been studied in optimization of nanoemulsion formulations. The prepared pterostilbene nanoemulsion was characterized by transmission electron microscope, Fourier transform Raman spectrum, and laser droplet size analyzer. Nanoemulsion droplets are circular with smooth margin, and the mean size is 55.8 ± 10.5 nm. The results illustrated that the nanoemulsion as oral delivery system dramatically improved the stability and solubility of pterostilbene, and in vitro release of pterostilbene was significantly improved (96.5% in pH 3.6 buffer; 13.2% in pH 7.4 buffer) in comparison to the pterostilbene suspension (lower than 21.4% in pH 3.6 buffer; 2.6% in pH 7.4 buffer).

A set of polyethylene glycol (PEG)-resveratrol (RES) conjugates with amino acid as spacers was designed and synthesized to improve certain defects of resveratrol, such as poor solubility, its short half-life and the difficulty of obtaining controlled release. Amino acids, which are released along with RES, are necessary for human health and likely have a facilitating effect on the absorption of the drug. The prepared PEG conjugates were characterized by FT-IR, (1)H-NMR, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Evaluation of free RES, loading capability, solubility and in vitro release of conjugates was also conducted. The results show that solubility in water of all the conjugates is over 900 mg·mL(-1) and controlled release of RES was achieved. Therefore, the developed PEG conjugate is a favorable system for modifying the solubility and bioavailability of RES.

The title pyrimidine derivative, C(18)H(21)N(3)O(6), was obtained by the reaction of methyl 2-[2-(benzyl-oxycarbon-yl)amino-propan-2-yl]-5-hy-droxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxyl-ate with dimethyl sulfate in dimethyl sulfoxide. The mol-ecule has a V-shaped structure, the phenyl and the pyrimidine rings making a dihedral angle of 43.1 (1)°. The methyl group substituting the pyrimidine ring deviates slightly from the ring mean-plane [C-N-C-C torsion angle = 5.49 (15)°], and the methyl ester substituent has a conformation suitable for the formation of an intra-molecular O-H⋯O hydrogen bond with the hydroxyl functionality. In the crystal, molecules are linked into chains along the b axis by N-H⋯O hydrogen bonds.

In the title compound, C(26)H(31)NO(3), the octa-hydro-1H-isoindole ring is not planar and the two rings are twisted with a C-C-C-C torsion angle of 73.6 (4)°. The six-membered ring has a chair conformation while the five-membered ring has an envelope conformation on the C-atom in position 7a. The H atoms in the 3a- and 7a-psitions are cis and the H-C-C-H torsion angle is 42.36°.

In the title compound, C(18)H(21)N(3)O(6), the dihedral angle between the two aromatic rings is 61.1 (1)°. The crystal structure is stabilized by inter-molecular O-H⋯O hydrogen bonds. An intra-molecular O-H⋯O hydrogen bonds is also present.

In the title compound, C(17)H(19)N(3)O(6), the dihedral angle between the two aromatic rings is 45.9 (1)°. The crystal structure is stabilized through inter-molecular N-H⋯O hydrogen bonds and intra-molecular O-H⋯O hydrogen bonds are also present.