Preoperative serum cortisone levels are associated with cognition in preschool-aged children with tetralogy of Fallot after corrective surgery: new evidence from human populations and mice.

BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Children with TOF would be confronted with neurological impairment across their lifetime. Our study aimed to identify the risk factors for cerebral morphology changes and cognition in postoperative preschool-aged children with TOF. METHODS: We used mass spectrometry (MS) technology to assess the levels of serum metabolites, Wechsler preschool and primary scale of intelligence-Fourth edition (WPPSI-IV) index scores to evaluate neurodevelopmental levels and multimodal magnetic resonance imaging (MRI) to detect cortical morphological changes. RESULTS: Multiple linear regression showed that preoperative levels of serum cortisone were positively correlated with the gyrification index of the left inferior parietal gyrus in children with TOF and negatively related to their lower visual spaces index and nonverbal index. Meanwhile, preoperative SpO2 was negatively correlated with levels of serum cortisone after adjusting for all covariates. Furthermore, after intervening levels of cortisone in chronic hypoxic model mice, total brain volumes were reduced at both postnatal (P) 11.5 and P30 days. CONCLUSIONS: Our results suggest that preoperative serum cortisone levels could be used as a biomarker of neurodevelopmental impairment in children with TOF. Our study findings emphasized that preoperative levels of cortisone could influence cerebral development and cognition abilities in children with TOF.

Spongioplasty with Buck's fascia covering dorsal inlay graft urethroplasty for primary hypospadias repair.

INTRODUCTION: Neourethral covering is an essential technique for preventing complications such as fistula and glans dehiscence in hypospadias repairs. The spongioplasty has been reported for neourethral coverage about 20 years ago. However, reports of the outcome are limited. OBJECTIVE: This study aimed to retrospectively evaluate the short-term outcome of spongioplasty with Buck's fascia covering dorsal inlay graft urethroplasty (DIGU). METHODS: From December 2019 to December 2020, 50 patients with primary hypospadias (median age at surgery, 37 months; range, 10 months-12 years) were treated by a single pediatric urologist. The patients underwent spongioplasty with Buck's fascia covering dorsal inlay graft urethroplasty in single stage. The penile length, glans width, urethral plate width and length, and the location of the meatus of the patients were recorded preoperatively. The patients were followed up,complications noted, and postoperative uroflowmetries at the one-year follow-up time were evaluated. RESULTS: The average width of glans was 12.92 ± 1.86 mm. A minor penile curvature was observed in all patients (≤30°). The patients were followed up for 12-24 months, and 47 patients (94%) were free from complications. A neourethra formed with a slit-like meatus at the tip of the glans, and the urinary stream was straight. Three patients had coronal fistulae (3/50) and no glans dehiscence, and the mean ± SD Qmax of postoperative uroflowmetry was 8.13 ± 3.8 ml/s. DISCUSSION: This study estimated the short-term outcome of the DIGU covered using spongioplasty with Buck's fascia as the second layer in patients diagnosed with primary hypospadias with a relatively small glans (average width <14 mm). However, only a few reports emphasize spongioplasty with Buck's fascia as the second layer and the DIGU procedure performed on a relatively small glans. The major limitations of this study were its short follow-up time and the retrospective data collection. CONCLUSIONS: Dorsal inlay graft urethroplasty combined with spongioplasty with Buck's fascia as coverage is an effective procedure. In our study, this combination had good short-term outcomes for primary hypospadias repair.

Altered brain structure in preschool-aged children with tetralogy of Fallot.

BACKGROUND: Neurodevelopmental abnormalities are prevalent in children with tetralogy of Fallot. Our aim was to investigate the structural brain alterations of preschool-aged children with tetralogy of Fallot and its correlation with neurodevelopmental outcome. METHODS: T1-weighted structural images were obtained from 25 children with tetralogy of Fallot who had undergone cardiopulmonary bypass surgery and from 24 normal controls. Cortical morphological indices including gray matter volume, cortical thickness, sulcal depth, gyrification, and cortical surface complexity were compared between the two groups. Neurodevelopmental assessments of the children with tetralogy of Fallot were performed with the Wechsler Preschool and Primary Scale of Intelligence. RESULTS: Cortical morphological differences between groups were distributed throughout the right caudal middle frontal gyrus, right fusiform gyrus, right lateral occipital gyrus, right precuneus, and left inferior parietal lobule. Among children with tetralogy of Fallot, altered cortical structures were correlated with the visual spatial index, working memory index, and perioperative variables. CONCLUSION: Our results suggested that abnormal cortical structure in preschool-aged children with tetralogy of Fallot may be the persistent consequence of delayed cortical development in fetuses and cortical morphology can be used as an early potential biomarker to capture regional brain abnormalities that are relevant to neurodevelopmental outcomes. IMPACT: Altered cortical structures in preschool-aged children with ToF were correlated with both neurodevelopmental outcomes and clinical risk factors. Cortical morphology can be used as an effective tool to evaluate neuroanatomical changes and detect underlying neural mechanisms in ToF patients. Abnormal cortical structure may be the continuous consequence of delayed fetal brain development in children with ToF.

Long Non-Coding RNA CRNDE Functions as a Tumor Promoter by Modulating the ERK/MAPK Signaling Pathway in Neuroblastoma Cells.

OBJECTIVE: The long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) is considered a carcinogenic promoter in various human malignancies. However, the role and underlying mechanism of action of CRNDE during carcinogenesis in neuroblastoma remain unknown. METHODS: CRNDE transcript levels were detected in neuroblastoma tissues and adjacent normal tissues. The effects of CRNDE overexpression and knockdown on the viability of SH-SY5Y and SK-N-AS cells were determined using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was performed to measure the role of CRNDE in apoptosis and the cell cycle in neuroblastoma cells. Moreover, the transwell assay was used to evaluate the role of CRNDE in the migration and invasion of tumor cells. The levels of ERK/MAPK pathway-related proteins were evaluated using western blotting. The in vivo role of CRNDE in tumor growth and apoptosis was evaluated in a xenograft mouse model of human neuroblastoma. RESULTS: The relative expression of CRNDE was significantly higher in neuroblastoma tissues than in the adjacent normal tissues. Moreover, knockdown of CRNDE inhibited tumor cell proliferation and induced apoptosis and cell cycle arrest, whereas elevation of CRNDE promoted cell growth and inhibited apoptosis in neuroblastoma cells. In addition, depletion of CRNDE suppressed migration and invasion, whereas overexpression of CRNDE enhanced the migratory and invasive potential of SH-SY5Y and SK-N-AS cells. At the mechanistic level, western blotting showed that CRNDE exerted its oncogenic role by affecting the ERK/MAPK signaling pathway. Furthermore, animal experiments confirmed that CRNDE promotes tumor growth and inhibits apoptosis in neuroblastoma in vivo. CONCLUSION: The present study revealed that CRNDE plays a critical role in the proliferation, apoptosis, migration, and invasion of neuroblastoma by altering the ERK/MAPK signaling pathway, representing a novel molecular target for the treatment of neuroblastoma.

PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of MYCN or c-Myc.

Neuroblastoma (NB) is one of the most common solid tumors in childhood. To date, targeting MYCN, a well-established driver gene in high-risk neuroblastoma, is still challenging. In recent years, inhibition of bromodomain and extra terminal (BET) proteins shows great potential in multiple of Myc-driven tumors. ARV-825 is a novel BET inhibitor using proteolysis-targeting chimera (PROTAC) technology which degrades target proteins by the proteasome. In this study, we investigated the effect of ARV-825 in neuroblastoma in vitro and in vivo. Our results showed that ARV-825 treatment robustly induced proliferative suppression, cell cycle arrest, and apoptosis in NB cells. Moreover, ARV-825 efficiently depleted BET protein expression, subsequently repressing the expression of MYCN or c-Myc. In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and MYCN expression in mice. Taken together, these findings provide evidence that PROTAC BET inhibitor is an efficient way to achieve MYCN/c-Myc manipulation, and ARV-825 can be used as a potential therapeutic strategy for the treatment of neuroblastoma.

Nuclear paraspeckle assembly transcript 1 promotes the metastasis and epithelial-mesenchymal transition of hepatoblastoma cells by inhibiting miR-129-5p.

The abnormal expression of nuclear paraspeckle assembly transcript 1 (NEAT1) may serve critical functions for the development and progression of various types of human tumor. However, the expression and biological function of NEAT1 in hepatoblastoma (HB) and the underlying mechanisms for the function of NEAT1 in HB remain largely uncharacterized. In the present study, the results of reverse transcription-quantitative polymerase chain reaction revealed that the expression of NEAT1 was significantly elevated in HB tissues. HB tissues with metastasis also exhibited significantly increased levels of NEAT1 compared with tissues without metastasis. The biological functions of NEAT1 were then assessed using gain-/loss-of-function studies. The results of in vitro assays revealed that inhibiting NEAT1 expression reduced the migration and invasion of HepG2 cells. By contrast, the induced expression of NEAT1 exhibited the opposite effect. The present study also demonstrated that the inhibition of NEAT1 expression prevented the epithelial-mesenchymal transition of HepG2 cells, whereas forced expression of NEAT1 exhibited the opposite effect. In addition, it was confirmed that NEAT1 could modulate the expression of microRNA (miR)-129-5p in HepG2 cells, and that NEAT1 may exert its effect on the metastatic behaviors and epithelial-mesenchymal transition of HepG2 cells by inhibiting miR-129-5p. In conclusion, the present study indicated that NEAT1 expression was aberrantly increased in HB and that it may promote the metastasis of HB cells by inhibiting miR-129-5p. Targeting NEAT1 may potentially be a novel therapeutic option for treating patients with HB.

MiR-513c suppresses neuroblastoma cell migration, invasion, and proliferation through direct targeting glutaminase (GLS).

Neuroblastoma is a malignancy [corrected] of childhood and accounts for 7-10% of childhood cancers, leading to approximately 15% of pediatric cancer deaths. MicroRNAs (miRNAs) are a family of short (about 18-25 nucleotides), noncoding and single stranded endogenous RNAs, which complementarily bind to the 3' untranslated regions of their target genes. Recently, glutamine metabolism has been recognized as an important nutrition source for tumor cells, and hence targeting glutamine metabolism could benefit to development of anti-cancer agents. In this study, we investigate the roles of miR-513c in human neuroblastoma. We report miR-513c is significantly downregulated in human neuroblastoma tissues compared with their adjacent normal tissues. Moreover, miR-513c is significantly downregulated in neuroblastoma cell lines compared with normal neuroblast cells. Overexpression of miR-513c suppresses neuroblastoma cells' migration, invasion, and proliferation. We demonstrate the glutaminase (GLS) is a direct target of miR-513c in human neuroblastoma cells. In addition, we found restoration of GLS expression recovered the neuroblastoma cells' migration, invasion, and proliferation. In summary, this study illustrates a miR-513c mediated neuroblastoma cells suppression, providing a new aspect on the miRNA-based therapeutic approach for the treatments of neuroblastoma.

Histone deacetylase 5 promotes Wilms' tumor cell proliferation through the upregulation of c-Met.

The histone deacetylase (HDAC) family is comprised of enzymes, which are involved in modulating the majority of critical cellular processes, including transcriptional regulation, apoptosis, proliferation and cell cycle progression. However, the biological function of HDAC5 in Wilms' tumor remains to be fully elucidated. The present study aimed to investigate the expression and function of HDAC5 in Wilm's tumor. It was demonstrated that the mRNA and protein levels of HDAC5 were upregulated in human Wilms' tumor tissues. Overexpression of HDAC5 in G401 cells was observed to significantly promote cellular proliferation, as demonstrated by the results of an MTT assay and bromodeoxyuridine incorporation assay. By contrast, HDAC5 knockdown using small interfering RNA suppressed the proliferation of the G401 cells. At the molecular level, the present study demonstrated that HDAC5 promoted the expression of c­Met, which has been previously identified as an oncogene. In addition, downregulation of c­Met inhibited the proliferative effects of HDAC5 in human Wilms' tumor cells. Taken together, these results suggested that HDAC5 promotes cellular proliferation through the upregulation of c­Met, and may provide a novel therapeutic target for the treatment of patients with Wilms' tumor.

Stat3 inhibits WTX expression through up-regulation of microRNA-370 in Wilms tumor.

Wilms tumor (WT) is a genetically heterogeneous childhood kidney tumor. Several genetic mutations have been identified in WT patients, including inactivation of WTX, somatic stabilizing CTNNB1, and p53 mutations. However, the molecular mechanisms in tumorigenesis remain largely unexplored. Stat3 is a transcription factor that can promote oncogenesis. Stat3 activation is commonly viewed as crucial for multiple tumor proliferation and metastasis. We show that Stat3 is highly activated in Wilms tumor tissues compared to those in adjacent tissues. IL-6 treatment or transfection of a constitutively activated Stat3 in G401 cells promotes cell proliferation. At the molecular level, we further elucidate that Stat3 inhibits WTX expression through up-regulation of microRNA-370. Our results suggest that Stat3/miR-370/WTX regulatory axis might be a critical mechanism in Wilms tumor cells.