Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors.

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 IC50 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.

Using genomic resources for linkage analysis in Peromyscus with an application for characterizing Dominant Spot.

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.

Injecting RNA interference lentiviruses targeting the muscarinic 3 receptor gene into the bladder wall inhibits neurogenic detrusor overactivity in rats with spinal cord injury.

AIMS: To investigate the effects of injecting RNA interference (RNAi) lentiviruses targeting the muscarinic 3 (M3 ) receptor gene into the bladder wall on bladder activity in rats with spinal cord injury (SCI). METHODS: Four M3 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 M3 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 M3 RNAi lentivirus with the highest interference efficiency (78.9%) was constructed and identified. Three weeks after injecting M3 RNAi lentiviruses into the bladder wall, Western blotting and qRT-PCR showed that the M3 receptor was significantly downregulated in the experimental group. Cystometric evaluation suggested that downregulating M3 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 M3 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.

An uncommon manifestation of paraneoplastic cerebellar degeneration in a patient with high grade urothelial, carcinoma with squamous differentiation: A case report and literature review.

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.

Amino acid-PEGylated resveratrol and its influence on solubility and the controlled release behavior.

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.

Gypenosides protected the neural stem cells in the subventricular zone of neonatal rats that were prenatally exposed to ethanol.

Fetal alcohol spectrum disorder (FASD) can cause severe mental retardation in children who are prenatally exposed to ethanol. The effects of prenatal and early postnatal ethanol exposure on adult hippocampal neurogenesis have been investigated; however, the effects of prenatal ethanol exposure on the subventricular zone (SVZ) have not. Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The effects of GPs on neural stem cells (NSCs) in the FASD model are unknown. Here, we test the effect of prenatal ethanol exposure on the neonatal SVZ, and the protection potential of GPs on NSCs in FASD rats. Our results show that prenatal ethanol exposure can suppress the cell proliferation and differentiation of neural stem cells in the neonatal SVZ and that GPs (400 mg/kg/day) can significantly increase the cell proliferation and differentiation of neural stem cells inhibited by ethanol. Our data indicate that GPs have neuroprotective effects on the NSCs and can enhance the neurogenesis inhibited by ethanol within the SVZ of neonatal rats. These findings provide new evidence for a potential therapy involving GPs for the treatment of FASD.

Nanoemulsion for solubilization, stabilization, and in vitro release of pterostilbene for oral delivery.

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 Prognostic Model for Prostate Cancer Patients Based on Two DNA Damage Response Mutation-Related Immune Genes.

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.

Expression profiles of circular RNAs and interaction networks of competing endogenous RNAs in neurogenic bladder of rats following suprasacral spinal cord injury.

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.

Methyl 2-[2-(benzyl-oxycarbon-ylamino)-propan-2-yl]-5-hy-droxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxyl-ate.

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.

Benzyl 2-benzyl-4-[(3aS,7aR)-2,3,3a,4,5,6,7,7a-octa-hydro-1H-isoindol-2-yl]-4-oxobutano-ate.

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°.

Expression profiles of long non-coding RNAs in neurogenic bladder of spinal cord injured rats: a transcriptomic analysis.

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 ß 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.

Methyl 2-(2-{[(benz-yloxy)carbon-yl]amino}-propan-2-yl)-5-hy-droxy-6-meth-oxy-pyrimidine-4-carboxyl-ate.

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.

Methyl 2-(2-{[(benz-yloxy)carbon-yl]amino}-propan-2-yl)-5-hy-droxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxyl-ate.

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.

Botulinum toxin A improves neurogenic bladder fibrosis by suppressing transforming growth factor ß1 expression in rats.

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 ß1. 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 ß1 (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 ß1 (TGF-ß1) expression.

The Diagnostic Values of Pretreatment Serum Inflammation Markers and Lipoprotein in Men With Total Prostate-Specific Antigen Between 4 and 10 ng/ml.

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.

Predictive Values of Preoperative Prognostic Nutritional Index and Systemic Immune-Inflammation Index for Long-Term Survival in High-Risk Non-Muscle-Invasive Bladder Cancer Patients: A Single-Centre Retrospective Study.

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 (109/L)×5+albumin concentration (g/L). SII was calculated as neutrophil count (109/L)×platelet count (109/L)/lymphocyte count (109/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.

LncRNA RNF144A-AS1 Promotes Bladder Cancer Progression via RNF144A-AS1/miR-455-5p/SOX11 Axis.

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.

MicroRNA expression profile in the spinal cord injured rat neurogenic bladder by next-generation sequencing.

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.

The level of zinc finger of the cerebellum 2 is predictive of overall survival in clear cell renal cell carcinoma.

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.