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Hepatoblastoma is a kind of extreme malignancy frequently diagnosed in children. Although surgical resection is considered as the first-line treatment for hepatoblastoma, a relatively large population of patients have lost the preferred opportunity for surgery. Administration of locoregional ablation enables local tumor control but with the deficiency of insufficient ablation, residual tumor, and rapid progression. In this study, we integrated 219 hepatoblastoma and 121 non-cancer liver tissues to evaluate the expression of NR2F6, from which a higher NR2F6 level was found in hepatoblastoma compared with non-cancer livers with a standard mean difference (SMD) of 1.04 (95% CI: 0.79, 1.29). The overexpression of NR2F6 also appeared to be an efficient indicator in distinguishing hepatoblastoma tissues from non-cancer liver tissues from the indication of a summarized AUC of 0.90, with a pooled sensitivity of 0.76 and a pooled specificity of 0.89. Interestingly, nude mouse xenografts provided direct evidence that overexpressed NR2F6 was also detected in residual tumor compared to untreated hepatoblastoma. Chromatin immunoprecipitation-binding data in HepG2 cells and transcriptome analysis of HepG2 xenografts were combined to identify target genes regulated by NR2F6. We finally selected 150 novel target genes of NR2F6 in residual tumor of incomplete ablation, and these genes appeared to be associated with the biological regulation of lipid metabolism-related pathway. Accordingly, targeting NR2F6 holds a therapeutic promise in treating residual recurrent hepatoblastoma after incomplete ablation., GRAPHICAL ABSTRACT

Purpose This study was performed to establish and validate a nomogram for predicting the overall survival in children with neuroblastoma. Methods The latest clinical data of neuroblastoma in Surveillance, Epidemiology, and End Results (SEER) database was extracted from 2000 to 2016. The cases included were randomly divided into training and validation cohorts. The survival curves were drawn with a Kaplan-Meier estimator to investigate the influences of certain single factors on overall survival. Also, least absolute shrinkage and selection operator regression was applied to further select the prognostic variables for neuroblastoma. Additionally, receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the accuracy of the nomogram. Results In total, 1,262 patients were collected and 8 independent prognostic factors were achieved, including patients' age, sex, race, tumor grade, radiotherapy, chemotherapy, tumor site, and tumor size. Then we constructed a nomogram by using the data of the training cohort with 886 cases. Subsequently, the nomogram was validated internally and externally with 886 and 376 cases, respectively. The internal validation revealed that the area under the curves (AUC) of ROC curves of 1-, 3-, and 5-year overall survival were 0.69, 0.78, and 0.81, respectively. Accordingly, the external validation also showed that the AUC of 1-, 3-, and 5-year overall survival were all ≥0.69. Both methods of validation demonstrated that the predictive calibration curves were consistent with standard curves. Conclusion The nomogram possess the potential to be a new tool in predicting the survival rate of neuroblastoma patients.

Jing-Xiao Li,1 Jin-Shu Pang,2 Bin-Tong Yin,1 Gang Chen,1 Jun-Hong Chen,1 Jia-Yuan Luo,1 Xia Yang,1 Li-Ting Qin,1 Jiang-Hui Zeng,3 Peng Chen,4 Jia-Bo Chen,4 Deng Tang1 1Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3Department of Clinical Laboratory, The Third Affiliated Hospital of Guangxi Medical University/Nanning Second People’s Hospital, Nanning, Guangxi Zhuang Autonomous Region, 530031, People’s Republic of China; 4Department of Pediatric Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530031, People’s Republic of ChinaCorrespondence: Deng TangDepartment of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaTel +86-7715356534Email tdnever@163.comPurpose: The molecular mechanisms and signal pathways of ferroptosis in hepatoblastoma (HB) have not yet been clarified. In previous studies, activating transcription factor 3 (ATF3) was reported to be correlated with several tumors, but the clinical significance of ATF3 has never been determined. Herein, we investigated the clinicopathological value and mechanisms of ATF3 in regulating ferroptosis in HB.Methods: The mRNA microarray and RNA-sequencing data of 402 samples from our hospital and public databases were used to estimate ATF3 expression and assess its clinical role in HB. The standard mean difference (SMD) and summary receiver operating characteristic curves were utilized to judge the discrimination ability of ATF3 between HB and non-HB liver tissues. We examined the expression variation of ATF3 in HB cells after the treatment with erastin. We also predicted the target genes of ATF3 as a transcriptional factor from public Chromatin Immunoprecipitation-sequencing data and selected the ferroptosis-related genes for a signaling pathway analysis.Results: In ten series, the pooled SMD for ATF3 was − 0.91, demonstrating that ATF3 expression was predominantly lower in HB than in non-HB liver tissues. ATF3 down-regulation showed moderate potential to distinguish HB from non-HB liver tissues (area under curves = 0.83, 95% confidence interval = 0.79– 0.86). Altogether, 4855 putative targets of ATF3 as a transcriptional factor were collected, among which, 60 genes were ferroptosis-related.Conclusion: The down-regulated ATF3 expression may play a vital role in the occurrence of HB possible partially by regulating ferroptosis.Keywords: transcription factor, ATF3, hepatoblastoma, ferroptosis

BACKGROUND Primitive neuroectodermal tumors are rare, highly malignant small round cell tumors belonging to the Ewing sarcoma family. The purpose of this article is to present clinical manifestation, histology, treatment, and prognosis of two primitive neuroectodermal tumors (PNETs) in extremely rare anatomic locations, the abdominal wall and vulva. CASE SUMMARY Case 1 was a 66-month-old girl with lesions on the abdominal wall; tumor size was about 3.4 cm × 6.1 cm × 2 cm. The patient underwent radical resection of the tumor. After the operation, an alternating vincristine, doxorubicin, and cyclophosphamide/ifosfamide and etoposide (IE) regimen was given for eight cycles, and the patient survived for 66 mo without progression. Case 2 was a 40-month-old girl, with a vulvar lesion; tumor size was about 3.3 cm × 5 cm × 2.5 cm. The tumor was partially resected by surgery. The family left treatment after two cycles of vincristine, pirarubicin, and cyclophosphamide/IE chemotherapy, and the patient died at home six months after surgery. CONCLUSION PNET is a rare, fast-growing, highly malignant tumor that requires histologic and molecular analyses for exact diagnosis, and multimodal treatment is required to achieve a good prognosis.

Background: Wilms tumour is the most common childhood renal cancer that requires development of better treatments. Nitidine chloride, a Chinese traditional medicine, could have therapeutic potential for Wilms tumour, however there have been no studies to date. Methods: In-house RNA-seq was performed and public RNA-seq plus microarrays datasets were incorporated for identifying the landscape of differentially expressed genes (DEGs) in Wilms tumour. Meanwhile, the potential targets of nitidine chloride in Wilms tumour were acquired through combined analysis of computational prediction and DEG, which was further validated by molecular docking. The molecular mechanism of nitidine chloride-putative targets was investigated through transcription factors and gene set enrichment analysis. Findings: As a result, a total of 1819 upregulated DEGs and 1942 downregulated DEGs were identified in Wilms tumour. Twenty-three putative targets of nitidine chloride in Wilms tumour were determined and nine showed strong binding force with nitidine chloride in molecular docking. IMPDH2 and MAP4K4 exhibited significant value of prognostic signification. The upregulation of these putative targets in Wilms tumour may be induced by transcription factors (TFs) such as MYC, E2F1, SOX2, MYCN, MITF and CREM. The hub putative targets of nitidine chloride in Wilms tumour were enriched in pathways such as cell cycle, chemokine signaling pathway, glycolysis and gluconeogenesis. Interpretation: In conclusion, the putative pharmacologic targets and molecular pathways of nitidine chloride in Wilms tumour were unveiled in this study. Further research is necessary for confirming the therapeutic effect of nitidine chloride in Wilms tumour. Funding: This work was supported by Natural Science Foundation of Guangxi, China (2018GXNSFAA294025); Guangxi Medical High-level Key Talents Training "139" Program (2020); Guangxi Medical University Training Program for Distinguished Young Scholars ; Medical Excellence Award Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University; Guangxi Degree and Postgraduate Education Reform and Development Research Projects, China (JGY2019050); Innovation Project of Guangxi Graduate Education; Guangxi Zhuang Autonomous Region Health and Family Planning Commission Self-financed Scientific Research Project (Z20200317); Innovation Project of Guangxi Graduate Education (YCSW2021121 Declaration of Interests: The authors have declared no competing interests. Ethics Approval Statement: All patients provided informed consent and approval of this research project was granted by the medical ethics committee of the First Affiliated Hospital of Guangxi Medical University (2020-ky-guoji-135). All experiments involving animals were conducted according to the ethical policies and procedures approved by the ethics committee of the First Affiliated Hospital of Guangxi Medical Univeristy (Approval no. 2020-ky-guoji-135).

BACKGROUND Wilms tumor, or nephroblastoma, is a malignant pediatric embryonal renal tumor that has a poor prognosis. This study aimed to use bioinformatics data, RNA-sequencing, connectivity mapping, molecular docking, and ligand-protein binding to identify potential targets for drug therapy in Wilms tumor. MATERIAL AND METHODS Wilms tumor and non-tumor samples were obtained from high throughput gene expression databases, and differentially expressed genes (DEGs) were analyzed using the voom method in the limma package. The overlapping DEGs were obtained from the intersecting drug target genes using the Connectivity Map (CMap) database, and systemsDock was used for molecular docking. Gene databases were searched for gene expression profiles for complementary analysis, analysis of clinical significance, and prognosis analysis to refine the study. RESULTS From 177 cases of Wilms tumor, there were 648 upregulated genes and 342 down-regulated genes. Gene Ontology (GO) enrichment analysis showed that the identified DEGs that affected the cell cycle. After obtaining 21 candidate drugs, there were seven overlapping genes with 75 drug target genes and DEGs. Molecular docking results showed that relatively high scores were obtained when retinoic acid and the cyclin-dependent kinase inhibitor, alsterpaullone, were docked to the overlapping genes. There were significant standardized mean differences for three overlapping genes, CDK2, MAP4K4, and CRABP2. However, four upregulated overlapping genes, CDK2, MAP4K4, CRABP2, and SIRT1 had no prognostic significance. CONCLUSIONS RNA-sequencing, connectivity mapping, and molecular docking to investigate ligand-protein binding identified retinoic acid and alsterpaullone as potential drug candidates for the treatment of Wilms tumor.

We explored the difference in expression of tubulin alpha 1b (TUBA1B) between Wilms’ tumor (WT) and normal tissues (NT) from in-house patients and databases, to determine TUBA1B expression in WT and the predictive pathways of coexpressed genes. In-house RNA-sequencing data were performed with WT and NT from three patients from our institute. Other four RNA-sequencing and microarray data were also downloaded from multiple public databases. The TUBA1B expression between WT and NT was analyzed by Student’s t-test and meta-analysis. The correlation between the expression of TUBA1B and other genes in each study was analyzed. Genes with p<0.05 and r>0.5 were considered as the coexpressing genes of TUBA1B. Overlapping the coexpressed genes of the five studies, including three in-house patients (3 WT vs. 3 NT), GTEx-TARGET (126 WT vs. 51 NT), GSE2172 (18 WT vs. 3 NT), GSE11024 (27 WT vs. 12 NT), and GSE73209 (32 WT vs. 6 NT), were performed with limma and VennDiagram packages in R software. The website of WEB-based GEne SeT AnaLysis toolkit were used to analyze the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations for the overlapped genes. The results showed that the relative expression of TUBA1B in WT tissues from in-house three patients was 280.0086, 141.7589, and 303.8292 and that in NT was 16.5836, 104.8141, and 12.79 (3 WT vs. 3 NT, p=0.0285, ROC=100%, SMD=2.74). Student’s t-test and meta-analysis in all studies revealed that the expression of TUBA1B was upregulated in WT tissues compared to that in NT (p<0.05, SMD=2.89, sROC=0.98). Finally, the research identified the expression of TUBA1B in WT tissues was significantly upregulated than that in NT. The coexpressed genes of TUBA1B were enriched in the pathway of DNA replication, mismatch repair, cell cycle, pathogenic Escherichia coli infection, and spliceosome.

Neuroblastoma (NBL) is the most frequently encountered extracranial solid neoplasm and impacts significantly on the survival of patients, especially in cases of advanced tumor stage or relapse. A long noncoding RNA (lncRNA) signature to predict the survival of patients with NBL is proposed in this paper. Differentially expressed lncRNA (DElncRNA) was selected using the Limma plus Voom package in R based on the RNA-sequencing data downloaded from the Therapeutically Applicable Research To Generate Effective Treatments database and Genotype-Tissue Expression database. Univariate cox regression analysis, least absolute shrinkage and selection operator regression analysis, and multivariate cox regression analysis were conducted to identify candidate DElncRNAs for the risk signature. Consequently, 10 DElncRNAs were designated as candidate DElncRNAs for the risk signature. Time-dependent receiver operating characteristic curves and Kapan-Meier survival curves confirmed the efficacy of the risk signature in predicting the survival of patients with NBL (area under the curve = 0.941; p ≤ .001). One of the DElncRNA constituent subparts (LINC01010) was significantly associated with the survival outcome of patients with NBL in GSE62564 (p = .004). Thus, a risk signature comprising 10 DElncRNAs was identified as effective for individual risk stratification and the survival prediction outcomes of patients with NBL.

We compare the effects of staged tranverse preputial island flap urethroplasty and the Byars 2-stage procedure in patients with proximal hypospadias and severe chordee.We studied 87 consecutive children referred for proximal hypospadias with severe chordee between March 2011 and March 2014. Of the cases 42 were repaired with staged tranverse preputial island flap (group 1) and 45 were managed by 2-stage Byars urethroplasty (group 2). Mean ± SD age at first stage surgery was 26.6 ± 13.3 months in group 1 and 24.8 ± 14.7 months in group 2. Postoperative complications in both groups were assessed regarding fistulas, urethral strictures, diverticula, meatal stenosis and glanular dehiscence.After the second stage 2 patients (4.8%) in group 1 and 10 (23.2%) in group 2 had urethrocutaneous fistulas (p0.05). One patient (2.4%) in group 1 and 2 patients (4.4%) in group 2 had urethral strictures (p0.05). All patients with stricture were cured by repeated dilation and no patient required reoperation. One patient (2.4%) in group 1 and no patient in group 2 had diverticulum (p0.05). No patient in either group had signs or symptoms of meatal stenosis or residual chordee. Three patients (7.1%) in group 1 and 12 (26.7%) in group 2 needed reoperation (p0.05).Two-stage urethroplasty, particularly tranverse preputial island flap partial urethroplasty, is appropriate for treating patients with proximal hypospadias and severe chordee. Use of the tranverse preputial island flap can decrease complications associated with the second stage and significantly improve the success rate.

A modeling system that couples a land-use-based export coefficient model, a stream nutrient transport equation, and Bayesian statistics was developed for stream nitrogen source apportionment. It divides a watershed into several sub-catchments, and then considers the major land-use categories as stream nitrogen sources in each sub-catchment. The runoff depth and stream water depth are considered as the major factors influencing delivery of nitrogen from land to downstream stream node within each sub-catchment. The nitrogen sources and delivery processes are lumped into several constant parameters that were calibrated using Bayesian statistics from commonly available stream monitoring and land-use datasets. This modeling system was successfully applied to total nitrogen (TN) pollution control scheme development for the ChangLe River watershed containing six sub-catchments and four land-use categories. The temporal (across months and years) and spatial (across sub-catchments and land-use categories) variability of nonpoint source (NPS) TN export to stream channels and delivery to the watershed outlet were assessed. After adjustment for in-stream TN retention, the time periods and watershed areas with disproportionately high-TN contributions to the stream were identified. Aimed at a target stream TN level of 2 mg L−1, a quantitative TN pollution control scheme was further developed to determine which sub-catchments, which land-use categories in a sub-catchment, which time periods, and how large of NPS TN export reduction were required. This modeling system provides a powerful tool for stream nitrogen source apportionment and pollution control scheme development at the watershed scale and has only limited data requirements.

To review the indications, techniques and complications of reoperation for failed hypospadias repair using modified Mathieu urethroplasty.Using modified Mathieu urethroplasty, we treated 24 hypospadias patients aged 3-12 (mean 4.5) years for whom the first (n = 20) or the second hypospadias repair (n = 4) had failed, including 13 cases of large coronary sulcus urethrocutaneous fistula, 5 cases of urethral meatus retraction and 6 cases of anterior urethra dehiscence. The modified procedure involved median longitudinal incision of the urethral posterior wall, dorsal tunica albuginea plication under the vascular and nerve bundle, and double dartos flap protection of the neourethra.Of the 24 patients, 19 (79.2%) were successfully treated by the first operation, which achieved desirable straightness, good cosmetic appearance and normal urethral meatus of the penis, without postoperative complications. Small urethrocutaneous fistula developed in 4 cases, of which 3 were cured by fistula repair and 1 self-healed. Urethral meatus stenosis occurred in 1 case, which was restored by meatal dilation. Urethrocele and urethrostenosis were not found in any of the cases. Two cases received urethroscopy postoperatively, which revealed no hypertrophic cicatrix at the site of median longitudinal incision in the urethral posterior wall.Modified Mathieu urethroplasty can be applied to hypospadias reoperation, particularly in such cases as large coronary sulcus urethrocutaneous fistula, urethral meatus retraction and anterior urethra dehiscence. The modified procedure includes median longitudinal incision of the urethral posterior wall, dorsal tunica albuginea plication under the vascular and nerve bundle, and double dartos flap protection of the neourethra.

Based on the hydrological difference between the point source (PS) and nonpoint source (NPS) pollution processes and the major influencing mechanism of in-stream retention processes, a bivariate statistical model was developed for relating river phosphorus load to river water flow rate and temperature. Using the calibrated and validated four model coefficients from in-stream monitoring data, monthly phosphorus input loads to the river from PS and NPS can be easily determined by the model. Compared to current hydrologica methods, this model takes the in-stream retention process and the upstream inflow term into consideration; thus it improves the knowledge on phosphorus pollution processes and can meet the requirements of both the district-based and watershed-based wate quality management patterns. Using this model, total phosphorus (TP) input load to the Changle River in Zhejiang Province was calculated. Results indicated that annual total TP input load was (54.6 +/- 11.9) t x a(-1) in 2004-2009, with upstream water inflow, PS and NPS contributing to 5% +/- 1%, 12% +/- 3% and 83% +/- 3%, respectively. The cumulative NPS TP input load during the high flow periods (i. e. , June, July, August and September) in summer accounted for 50% +/- 9% of the annual amount, increasing the alga blooming risk in downstream water bodies. Annual in-stream TP retention load was (4.5 +/- 0.1) t x a(-1) and occupied 9% +/- 2% of the total input load. The cumulative in-stream TP retention load during the summer periods (i. e. , June-September) accounted for 55% +/- 2% of the annual amount, indicating that in-stream retention function plays an important role in seasonal TP transport and transformation processes. This bivariate statistical model only requires commonly available in-stream monitoring data (i. e. , river phosphorus load, water flow rate and temperature) with no requirement of special software knowledge; thus it offers researchers an managers with a cost-effective tool for quantifying TP pollution processes in both district and watershed scales.