A Nomogram for Predicting Surgical Risk in Neonates with Necrotizing Enterocolitis: A Retrospective Cohort Study.

OBJECTIVES: To construct a nomogram that predicts the risk of surgery in patients with necrotizing enterocolitis (NEC). METHODS: This retrospective cohort study recruited patients diagnosed with NEC at the Children's Hospital of Soochow University from 2013 to 2023. The neonates were divided into conservative and surgical-treatment groups. Univariate and multivariate logistic regressions were performed to identify factors influencing surgical risk, and a predictive model was constructed. RESULTS: This study comprised 154 cases of NEC, 103 cases (66.9%) in the conservative group and 51 cases (33.1%) in the surgical group. Multivariate logistic regression analysis revealed that increased bloody stools [odds ratio (OR) 5.066; 95% confidence interval (CI) 1.7396-14.7532; p = 0.0029), oxygen inhalation (OR 1.8278; 95% CI 1.2113-2.7581; p = 0.0041), use of vasoconstrictors (OR 4.4446; 95% CI 1.7157-11.5137; p = 0.0021), portal venous gas (OR 4.5569; 95% CI 1.6324-12.7209; p = 0.0038), and blood sodium (OR 0.8339; 95% CI 0.7477-0.9301; p = 0.0011) were independent factors of surgical risk. The area under the nomogram's receiver operating characteristic (ROC) curve was 0.886. Decision curve analysis (DCA) and calibration curves demonstrated good predictive performance for the nomogram. CONCLUSIONS: The nomogram effectively assessed the risk of surgical intervention in NEC patients, providing new insights and references for diagnosing and treating NEC.

Serum cholesterol level as a predictive biomarker for prognosis of Neuroblastoma.

BACKGROUND: Neuroblastoma (NB), a type of solid tumor in children, has a poor prognosis. Few blood biomarkers can accurately predict the prognosis, including recurrence and survival, in children with NB. In this study, we found that the serum total cholesterol (Tchol) level was associated with the prognosis of patients through a retrospective study. METHODS: Multivariate Cox regression model was used to identify the independent risk factors in the children with NB. Kaplan-Meier method was used to analyze the correlation between the common biomarkers, including the serum Tchol level, and the prognosis of the patients. ROC curves were used to predict the accuracy of the International Neuroblastoma Staging System (INSS) stage and Children's Oncology Group (COG) risk stratification after adding the serum Tchol level. RESULTS: Compared with the other patients, serum Tchol level was significantly increased in the relapsed and died patients (P < 0.05). Subsequently, serum Tchol level was found as an independent risk factor to affect the outcome of patients (P < 0.05). Finally, we added serum Tchol level into traditional stage and risk classification system to form the new INSS stage and COG risk classification system. It was found that the areas under the ROC curve (AUC) of recurrence-free survival in the new INSS stage and COG risk classification system were increased to 0.691 (95%CI: 0.535-0.847) and 0.748 (95%CI: 0.622-0.874), respectively. Moreover, the AUC areas of overall survival in the new INSS stage and COG risk classification system were increased to 0.722 (95%CI: 0.561-0.883) and 0.668 (95%CI: 0.496-0.819), respectively. CONCLUSION: We found that serum Tchol level, a clinical biomarker, is a risk factor for recurrence and death among the children with NB. The serum Tchol level could significantly increase the accuracy of the prediction for NB prognosis.

Development of a CT-based radiomics-clinical model to diagnose acute pancreatitis on nonobvious findings on CT in children with pancreaticobiliary maljunction.

OBJECTIVES: Since neither abdominal pain nor pancreatic enzyme elevation is specific for acute pancreatitis (AP), the diagnosis of AP in patients with pancreaticobiliary maljunction (PBM) may be challenging when the pancreas appears normal or nonobvious on CT. This study aimed to develop a quantitative radiomics-based nomogram of pancreatic CT for identifying AP in children with PBM who have nonobvious findings on CT. METHODS: PBM patients with a diagnosis of AP evaluated at the Children's Hospital of Soochow University from June 2015 to October 2022 were retrospectively reviewed. The radiological features and clinical factors associated with AP were evaluated. Based on the selected variables, multivariate logistic regression was used to construct clinical, radiomics, and combined models. RESULTS: Two clinical parameters and 6 radiomics characteristics were chosen based on their significant association with AP, as demonstrated in the training (area under curve [AUC]: 0.767, 0.892) and validation (AUC: 0.757, 0.836) datasets. The radiomics-clinical nomogram demonstrated superior performance in both the training (AUC, 0.938) and validation (AUC, 0.864) datasets, exhibiting satisfactory calibration (P > .05). CONCLUSIONS: Our radiomics-based nomogram is an accurate, noninvasive diagnostic technique that can identify AP in children with PBM even when CT presentation is not obvious. ADVANCES IN KNOWLEDGE: This study extracted imaging features of nonobvious pancreatitis. Then it developed and evaluated a combined model with these features.

Preterm Birth and Infantile Appendicitis.

OBJECTIVE: To investigate the potential association between preterm birth and infantile appendicitis. METHODS: We conducted a retrospective, multicenter, matched case-control study. This study included consecutive patients <1 year of age with surgery- or autopsy-confirmed appendicitis, admitted between December 2007 and May 2023. For each case, 10 healthy infants were randomly selected and matched by age. Infants were categorized as neonates (0 to 28 days) or older infants (>28 days and <1 year). RESULTS: The study included 106 infants diagnosed with appendicitis (median age 2.4 months) and 1060 age-matched healthy controls. In the univariate analysis, preterm birth was significantly associated with the development of appendicitis within the first year of life (odds ratio [OR], 4.23; 95% confidence interval [CI], 2.67-6.70). Other factors associated with a higher risk of infantile appendicitis included being male (OR, 1.91; 95%CI, 1.25-2.94), weight-for-age z-score (OR, 0.72; 95%CI, 0.64-0.81), and exclusively fed on formula (OR, 2.95; 95%CI, 1.77-4.91). In multivariable analyses, preterm remained significantly associated with appendicitis (adjusted OR, 3.32; 95%CI, 1.76-6.24). Subgroup analysis revealed that a preterm birth history increased the risk of appendicitis in both neonates (adjusted OR, 4.56; 95%CI, 2.14-9.71) and older infants (adjusted OR, 3.63; 95%CI, 1.72-7.65). However, preterm did not significantly influence the incidence of appendiceal perforation. CONCLUSIONS: Preterm infants have an increased risk of appendicitis during the first year of life. A preterm birth history may help improve the timely diagnosis of infantile appendicitis.

Identification and validation of PCSK9 as a prognostic and immune-related influencing factor in tumorigenesis: a pan-cancer analysis.

Introduction: Proprotein convertase subtilisin/kexin-9 (PCSK9) has been primarily studied in the cardiovascular field however, its role in cancer pathophysiology remains incompletely defined. Recently, a pivotal role for PCSK9 in cancer immunotherapy was proposed based on the finding that PCSK9 inhibition was associated with enhancing the antigen presentation efficacy of target programmed cell death-1 (PD-1). Herein, we provide results of a comprehensive pan-cancer analysis of PCSK9 that assessed its prognostic and immunological functions in cancer. Methods: Using a variety of available online cancer-related databases including TIMER, cBioPortal, and GEPIA, we identified the abnormal expression of PCSK9 and its potential clinical associations in diverse cancer types including liver, brain and lung. We also validated its role in progression-free survival (PFS) and immune infiltration in neuroblastoma. Results: Overall, the pan-cancer survival analysis revealed an association between dysregulated PCSK9 and poor clinical outcomes in various cancer types. Specifically, PCSK9 was extensively genetically altered across most cancer types and was consistently found in different tumor types and substages when compared with adjacent normal tissues. Thus, aberrant DNA methylation may be responsible for PCSK9 expression in many cancer types. Focusing on liver hepatocellular carcinoma (LIHC), we found that PCSK9 expression correlated with clinicopathological characteristics following stratified prognostic analyses. PCSK9 expression was significantly associated with immune infiltrate since specific markers of CD8+ T cells, macrophage polarization, and exhausted T cells exhibited different PCSK9-related immune infiltration patterns in LIHC and lung squamous cell carcinoma. In addition, PCSK9 was connected with resistance of drugs such as erlotinib and docetaxel. Finally, we validated PCSK9 expression in clinical neuroblastoma samples and concluded that PCSK9 appeared to correlate with a poor PFS and natural killer cell infiltration in neuroblastoma patients. Conclusion: PCSK9 could serve as a robust prognostic pan-cancer biomarker given its correlation with immune infiltrates in different cancer types, thus potentially highlighting a new direction for targeted clinical therapy of cancers.

A multicenter prospective study on the management of hepatoblastoma in children: a report from the Chinese Children's Cancer Group.

BACKGROUND: This study aimed to identify survival risk factors in Chinese children with hepatoblastoma (HB) and assess the effectiveness of the new treatment protocol proposed by the Chinese Children's Cancer Group (CCCG) in 2016. METHODS: A multicenter, prospective study that included 399 patients with HB from January 2015 to June 2020 was conducted. Patient demographics, treatment protocols, and other related information were collected. Cox regression models and Kaplan-Meier curve methods were used. RESULTS: The 4-year event-free survival (EFS) and overall survival (OS) were 76.9 and 93.5%, respectively. The 4-year EFS rates for the very-low-risk, low-risk, intermediate-risk, and high-risk groups were 100%, 91.6%, 81.7%, and 51.0%, respectively. The 4-year OS was 100%, 97.3%, 94.4%, and 86.8%, respectively. Cox regression analysis found that age, tumor rupture (R +), and extrahepatic tumor extension (E +) were independent prognostic factors. A total of 299 patients had complete remission, and 19 relapsed. Patients with declining alpha-fetoprotein (AFP) > 75% after the first two cycles of neoadjuvant chemotherapy had a better EFS and OS than those ≤ 75%. CONCLUSIONS: The survival outcome of HB children has dramatically improved since the implementation of CCCG-HB-2016 therapy. Age ≥ 8 years, R + , and E + were independent risk factors for prognosis. Patients with a declining AFP > 75% after the first two cycles of neoadjuvant chemotherapy had better EFS and OS.

Clinical presentations and outcomes of pancreaticobiliary maljunction in different pediatric age groups.

BACKGROUND: Pancreaticobiliary maljunction (PBM) is a congenital defect, with risk of developing various pancreaticobiliary and hepatic complications. The presentations of PBM in children and adults are believed to be different, but studies on PBM children of different age groups are limited. This study was to evaluate clinicopathologic characteristics and outcomes in PBM children of different ages. METHODS: A total of 166 pediatric patients with PBM were reviewed retrospectively. Clinicopathological, imaging, laboratory, surgical, and follow-up data were collected and analyzed. The patients were divided into three age groups, namely, group A (< 1 year, n = 31), group B (1-3 years, n = 63), and group C (> 3 years, n = 72). RESULTS: The major clinical manifestation was jaundice in group A and abdominal pain and vomiting in groups B and C. Acute pancreatitis was more often seen in group C than group A. The length of common channel was significantly longer in group C than group A, while the maximum diameter of common bile duct in group C was smaller than that in group A. Cholangitis and cholecystitis were more commonly performed in groups B and C, while hepatic fibrosis in group A. Whether preoperatively or postoperatively, group C was more likely to have elevated serum amylase, while groups A and B were more likely to present with abnormal liver function indicators, including the increase of aspartate transaminase, alanine transaminase, and gamma-glutamyl transpeptidase. CONCLUSION: Presentation of PBM varies among different pediatric age groups, thus suggesting that targeted management should be carried out according to these differences.

Clinical features and treatment outcomes of infantile appendicitis: a multicentre study.

Appendicitis in infants is a life-threatening condition that is seldom studied. Our purpose was to conduct a comprehensive evaluation of appendicitis in this age group. This was a multicenter retrospective study. Patients aged under one year with surgically confirmed appendicitis during January, 2010 to May, 2022 were identified from four institutional databases. The patients were grouped as neonates or older infants based on their age at the onset of symptoms associated with acute appendicitis. The study encompassed 98 infants, with median age of 66.5 (IQR, 13.8-176.0) days. Neonates were more likely to exhibit abdominal distension (64.9%) and fever (56.8%), while older infants more frequently presented with fever (88.5%) and vomiting (49.2%). Most patients (76.5%) were misdiagnosed during their initial clinical encounter, with a -rate was 3.1% (3 deaths), with neonates exhibiting a rate of 5.4%, and older infants 1.6%. Compared to older infants, neonates showed a higher incidence of appendiceal perforation (OR, 2.9; 95%CI, 1.1-8.1), mechanical ventilation (OR, 9.5; 95%CI, 3.1-29.2), and ICU admission (OR, 16.1; 95%CI, 5.6-45.7). However, there were no significant differences in mortality rates, 30-day readmission rates, and surgical complications between the two groups. CONCLUSION: Although most infants with appendicitis were misdiagnosed during the first clinical encounter, the observed mortality rates were considerably lower than previously reported. While neonates and infants over 28 days displayed differing clinical presentations and disease severity, their outcomes were similar. WHAT IS KNOWN: • Appendicitis in infants is a critical yet underemphasized health concern, often misdiagnosed at initial clinical encounters due to its atypical presentation and non-specific symptoms. • The mortality rates in the neonates with appendicitis was 23% during the past decades. WHAT IS NEW: • The neonates and older infants displayed differing clinical presentations and disease severity. The treatment outcomes were similar. • The mortality rate for infantile appendicitis (3.1%) was significantly lower than historically reported.

Identification and validation of radiomic features from computed tomography for preoperative classification of neuroblastic tumors in children.

BACKGROUND: To identify radiomic features that can predict the pathological type of neuroblastic tumor in children. METHODS: Data on neuroblastic tumors in 104 children were retrospectively analyzed. There were 14 cases of ganglioneuroma, 24 cases of ganglioneuroblastoma, and 65 cases of neuroblastoma. Stratified sampling was used to randomly allocate the cases into the training and validation sets in a ratio of 3:1. The maximum relevance-minimum redundancy algorithm was used to identify the top 10 of two clinical features and 851 radiomic features in portal venous-phase contrast-enhanced computed tomography images. Least absolute shrinkage and selection operator regression was used to classify tumors in two binary steps: first as ganglioneuroma compared to the other two types, then as ganglioneuroblastoma compared to neuroblastoma. RESULTS: Based on 10 clinical-radiomic features, the classifier identified ganglioneuroma compared to the other two tumor types in the validation dataset with sensitivity of 100.0%, specificity of 81.8%, and an area under the receiver operating characteristic curve (AUC) of 0.875. The classifier identified ganglioneuroblastoma versus neuroblastoma with a sensitivity of 83.3%, a specificity of 87.5%, and an AUC of 0.854. The overall accuracy of the classifier across all three types of tumors was 80.8%. CONCLUSION: Radiomic features can help predict the pathological type of neuroblastic tumors in children.

Using machine learning models to predict the surgical risk of children with pancreaticobiliary maljunction and biliary dilatation.

PURPOSE: To develop machine learning (ML) models to predict the surgical risk of children with pancreaticobiliary maljunction (PBM) and biliary dilatation. METHODS: The subjects of this study were 157 pediatric patients who underwent surgery for PBM with biliary dilatation between January, 2015 and August, 2022. Using preoperative data, four ML models were developed, including logistic regression (LR), random forest (RF), support vector machine classifier (SVC), and extreme gradient boosting (XGBoost). The performance of each model was assessed via the area under the receiver operator characteristic curve (AUC). Model interpretations were generated by Shapley Additive Explanations. A nomogram was used to validate the best-performing model. RESULTS: Sixty-eight patients (43.3%) were classified as the high-risk surgery group. The XGBoost model (AUC = 0.822) outperformed the LR (AUC = 0.798), RF (AUC = 0.802) and SVC (AUC = 0.804) models. In all four models, enhancement of the choledochal cystic wall and an abnormal position of the right hepatic artery were the two most important features. Moreover, the diameter of the choledochal cyst, bile duct variation, and serum amylase were selected as key predictive factors by all four models. CONCLUSIONS: Using preoperative data, the ML models, especially XGBoost, have the potential to predict the surgical risk of children with PBM and biliary dilatation. The nomogram may provide surgeons early warning to avoid intraoperative iatrogenic injury.

Weighted gene co-expression network analysis and CIBERSORT screening of key genes related to m6A methylation in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a neural crest disease that results from the failure of enteric neural crest cells (ENCCs) to migrate to the corresponding intestinal segment. The RET gene, which regulates enteric neural crest cell proliferation and migration, is considered one of the main risk factors for HSCR and is commonly used to construct HSCR mouse models. The epigenetic mechanism of m6A modification is involved in HSCR. In this study, we analyzed the GEO database (GSE103070) for differentially expressed genes (DEGs) and focused on m6A-related genes. Comparing the RNA-seq data of Wide Type and RET Null, a total of 326 DEGs were identified, of which 245 genes were associated with m6A. According to the CIBERSORT analysis, the proportion of Memory B-cell in RET Null was significantly higher than that of Wide Type. Venn diagram analysis was used to identify key genes in the selected memory B-cell modules and DEGs associated with m6A. Enrichment analysis showed that seven genes were mainly involved in focal adhesion, HIV infection, actin cytoskeleton organization and regulation of binding. These findings could provide a theoretical basis for molecular mechanism studies of HSCR.

Prediction of post-operative acute pancreatitis in children with pancreaticobiliary maljunction using machine learning model.

PURPOSE: This study aimed to develop a prediction model to identify risk factors for post-operative acute pancreatitis (POAP) in children with pancreaticobiliary maljunction (PBM) by pre-operative analysis of patient variables. METHODS: Logistic regression (LR), support vector machine (SVM), and extreme gradient boosting (XGBoost) models were established using the prospectively collected databases of patients with PBM undergoing surgery which was reviewed in the period comprised between August 2015 and August 2022, at the Children's Hospital of Soochow University. Primarily, the area beneath the receiver-operating curves (AUC), accuracy, sensitivity, and specificity were used to evaluate the model performance. The model was finally validated using the nomogram and clinical impact curve. RESULTS: In total, 111 children with PBM met the inclusion criteria, and 21 children suffered POAP. In the validation dataset, LR models showed the highest performance. The risk nomogram and clinical effect curve demonstrated that the LR model was highly predictive. CONCLUSION: The prediction model based on the LR with a nomogram could be used to predict the risk of POAP in patients with PBM. Protein plugs, age, white blood cell count, and common bile duct diameter were the most relevant contributing factors to the models.

Automated quantitative assessment of pediatric blunt hepatic trauma by deep learning-based CT volumetry.

BACKGROUND: To develop an end-to-end deep learning method for automated quantitative assessment of pediatric blunt hepatic trauma based on contrast-enhanced computed tomography (CT). METHODS: This retrospective study included 170 children with blunt hepatic trauma between May 1, 2015, and August 30, 2021, who had undergone contrast-enhanced CT. Both liver parenchyma and liver trauma regions were manually segmented from CT images. Two deep convolutional neural networks (CNNs) were trained on 118 cases between May 1, 2015, and December 31, 2019, for liver segmentation and liver trauma segmentation. Liver volume and trauma volume were automatically calculated based on the segmentation results, and the liver parenchymal disruption index (LPDI) was computed as the ratio of liver trauma volume to liver volume. The segmentation performance was tested on 52 cases between January 1, 2020, and August 30, 2021. Correlation analysis among the LPDI, trauma volume, and the American Association for the Surgery of Trauma (AAST) liver injury grade was performed using the Spearman rank correlation. The performance of severity assessment of pediatric blunt hepatic trauma based on the LPDI and trauma volume was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The Dice, precision, and recall of the developed deep learning framework were 94.75, 94.11, and 95.46% in segmenting the liver and 72.91, 72.40, and 76.80% in segmenting the trauma regions. The LPDI and trauma volume were significantly correlated with AAST grade (rho = 0.823 and rho = 0.831, respectively; p < 0.001 for both). The area under the ROC curve (AUC) values for the LPDI and trauma volume to distinguish between high-grade and low-grade pediatric blunt hepatic trauma were 0.942 (95% CI, 0.882-1.000) and 0.952 (95% CI, 0.895-1.000), respectively. CONCLUSIONS: The developed end-to-end deep learning method is able to automatically and accurately segment the liver and trauma regions from contrast-enhanced CT images. The automated LDPI and liver trauma volume can act as objective and quantitative indexes to supplement the current AAST grading of pediatric blunt hepatic trauma.

Clinical outcomes of fetal ovarian masses diagnosed by prenatal ultrasonography and literature review.

With the advancement of prenatal examination technology, more and more fetus with ovarian masses are diagnosed. However, whether such children need intervention measures after delivery, there is no more unified diagnosis and treatment measures in the world. In this study, postnatal data and clinical outcome of fetal diagnosed with ovarian masses were analyzed. We also combined with relevant literature to explore the postpartum intervention measures and timing of such children. A total of 57 cases of abdominal masses from the reproductive system were included in the study. These children were diagnosed with ovarian masses after birth. We collected from 2012 to 2020, the prenatal examination revealed the presence of abdominal masses from the reproductive system, and diagnosis was confirmed by imaging examinations after childbirth. We counted the fetal period data of these children, compared the changes in the postnatal pathology and intervention measures. A total of 57 cases of ovarian masses were diagnosed prenatally, 1 case was lost to follow-up, and 56 cases were finally included in the study. After birth a total of 21 cases of ovarian masses were treated conservatively, of which 18 cases resolved spontaneously during the follow-up process, with an average follow-up period of 30.88 ±â€…18.16 weeks. There were statistically significant differences in the nature and the maximum diameter of the mass between the two groups receiving conservative treatment or surgical treatment after delivery (P < .05).Univariate and multivariate Logistic regression analysis showed that there were significant differences in the nature and diameter of the mass between two groups (P < .05). In addition, we divided the children undergoing postpartum surgery into a laparoscopic surgery group and a conventional open surgery group. Through data analysis, we found that there were statistically significant differences in the age of operation, operation time, and hospitalization days in the two groups of these children (P < .05). Children diagnosed with ovarian masses prenatally generally have a good prognosis. For these children, the treatment plan should be developed according to the child general condition. If child with ovarian mass is treated with surgery, the preservation of ovarian tissue should be emphasized regardless of the size, nature, and torsion of the mass.

Cathepsin L promotes chemresistance to neuroblastoma by modulating serglycin.

Cathepsin L (CTSL), a lysosomal acid cysteine protease, is found to play a critical role in chemosencitivity and tumor progression. However, the potential roles and molecular mechanisms of CTSL in chemoresistance in neuroblastoma (NB) are still unclear. In this study, the correlation between clinical characteristics, survival and CTSL expression were assessed in Versteeg dataset. The chemoresistant to cisplatin or doxorubicin was detected using CCK-8 assay. Western blot was employed to detect the expression of CTSL, multi-drug resistance proteins, autophagy-related proteins and apoptosis-related proteins in NB cells while knocking down CTSL. Lysosome staining was analyzed to access the expression levels of lysosomes in NB cells. The expression of apoptosis markers was analyzed with immunofluorescence. Various datasets were analyzed to find the potential protein related to CTSL. In addition, a subcutaneous tumor xenografts model in M-NSG mice was used to assess tumor response to CTSL inhibition in vivo. Based on the validation dataset (Versteeg), we confirmed that CTSL served as a prognostic marker for poor clinical outcome in NB patients. We further found that the expression level of CTSL was higher in SK-N-BE (2) cells than in IMR-32 cells. Knocking down CTSL reversed the chemoresistance in SK-N-BE (2) cells. Furthermore, combination of CTSL inhibition and chemotherapy potently blocked tumor growth in vivo. Mechanistically, CTSL promoted chemoresistance in NB cells by up-regulating multi-drug resistance protein ABCB1 and ABCG2, inhibiting the autophagy level and cell apoptpsis. Furthermore, we observed six datasets and found that Serglycin (SRGN) expression was positively associated with CTSL expresssion. CTSL could mediate chemoresistance by up-regulating SRGN expression in NB cells and SRGN expression was positively correlated with poor prognosis of NB patients. Taken together, our findings indicate that the CTSL promotes chemoresistance to cisplatin and doxorubicin by up-regulating the expression of multi-drug resistance proteins and inhibiting the autophagy level and cell apoptosis in NB cells. Thus, CTSL may be a therapeutic target for overcoming chemoresistant to cisplatin and doxorubicin in NB patients.

Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury.

Necrotizing enterocolitis (NEC), an acute intestinal inflammatory disease of premature infants, is one of the leading causes of death in neonates. Effective measures for clinical treatment are limited and there is a pressing need in searching for new therapeutic strategies. Jumonji domain-containing protein D3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase plays a proinflammatory role in sepsis and neuroinflammation. However, whether JMJD3 is involved in the pathogenesis of NEC has not been elucidated. Here we report that overexpressed JMJD3 was revealed in the intestine of NEC patients by bioinformatic analysis. Moreover, upregulated JMJD3 and suppressed H3K27me3 were detected in both NEC patients and neonatal mice subjected to experimental NEC. Importantly, administration of GSK-J4, a specific JMJD3 inhibitor, rescued neonatal mice from NEC-associated lethality by suppressing proinflammatory response with attenuated IL-6, TNF-α, and MCP-1 levels and ameliorating intestinal injury with reversed claudin-1, occludin, and E-cadherin expression. Remarkably, administration of GSK-J4 attenuated intestinal injury by inhibiting activation of intestinal necroptosis in NEC mice. Administration of GSK-J4 regulated intestinal inflammation via NF-κB and JAK2/STAT3 pathway. These results indicate that JMJD3 is involved in the development of NEC and inhibition of JMJD3 overexpression by mean of GSK-J4 could be a potential therapeutic approach in the prevention and treatment of NEC.

Systematic screen of potential circular RNA biomarkers of Hirschsprung's disease.

BACKGROUND: Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system in which enteric ganglia are missing along a portion of the intestine. Aberrant expression of several circular RNAs (circRNAs) has been identified in the disease, but the full range of dysregulated circRNAs and their potential roles in its pathogenesis remain unclear. We used microarray profiling to systematically screen for circRNAs that were differentially expressed in HSCR, and we comprehensively analyzed the potential circRNA-miRNA-mRNA regulatory network to identify molecular mechanisms involved in the disorder. METHODS: We identified circRNAs that were differentially expressed between diseased tissue and paired normal intestinal tissues from patients with HSCR. The most strongly upregulated circRNAs were then validated by quantitative reverse-transcription-PCR (RT-PCR). We also constructed a circRNA-miRNA-mRNA interaction network to determine functional interactions between miRNAs and mRNAs. RESULTS: We identified 17 circRNAs that were upregulated and 10 that were downregulated in HSCR tissue compared with normal tissues. The five circRNAs that showed the greatest upregulation were verified by RT-PCR: hsa_circRNA_092493, hsa_circRNA_101965, hsa_circRNA_103118, hsa_circRNA_103279, and hsa_circRNA_104214. These five circRNAs were successfully adopted to diagnose HSCR based on receiver operating characteristic curves, and they were used to generate a circRNA-miRNA-mRNA network. The network revealed a potential function of the circRNAs as molecular sponges targeting miRNAs and mRNAs in HSCR. CONCLUSIONS: This first-ever systematic dissection of the circRNA profile in HSCR may provide useful insights into improving diagnosis and therapy.

Two-phase releasing immune-stimulating composite orchestrates protection against microbial infections.

Sepsis, a syndrome of acute organ dysfunction induced by various infections, could lead to a very high mortality in hospitals despite the development of advanced medical technologies. Herein, a type of two-phase releasing immune-stimulating composite is developed by mixing alginate (ALG) with muramyl dipeptide (MDP) and the nanoparticle formulation of monophosphoryl lipid A (MPLA), the latter two are immunomodulatory agents with different release rates from the formed ALG hydrogel. The obtained two phase-releasing composite could provide instantaneous sepsis protection by the rapid release of MDP to enhance the phagocytic and bactericidal function of macrophages. Later on, such composite could further offer long-term sepsis protection by the sustained release of MPLA to continuously activate the immune system, via up-regulating the production of various pro-inflammatory cytokines, promoting the polarization of macrophages, and increasing the percent of natural killer (NK) cells in the lesion after sepsis challenge. Mice survived from sepsis challenge after such treatment could resist a second infection. Notably, treatment with our composite could increase the mouse survival rate in a cecal ligation and puncture (CLP) induced polymicrobial sepsis model. This work provides an easy-translatable immune-stimulating formulation for effective protection against sepsis under various triggering causes. Our strategy may be promising for long-term broad prevention against various infections, and could potentially be used to protect medical workers under a new pandemic before a reliable vaccine is available.

Machine learning-based quantitative analysis of barium enema and clinical features for early diagnosis of short-segment Hirschsprung disease in neonate.

OBJECTIVE: To develop a mathematical model based on a combination of clinical and radiologic features (barium enema) for early diagnosis of short-segment Hirschsprung disease (SHSCR) in neonate. METHODS: The analysis included 54 neonates with biopsy-confirmed SHSCR (the cases) and 59 neonates undergoing barium enema for abdominal symptoms but no Hirschsprung disease (the control). Colon shape features extracted from barium enema images and clinical features were used to develop diagnostic models using support vector machine (SVM) and L2-regularized logistic regression (LR). The training cohort included 32 cases and 37 controls; testing cohort consisted 22 cases and 22 controls. Results were compared to interpretation by 2 radiologists. RESULTS: In the analysis by radiologists, 87 out of 113 cases were correctly classified. Six SHSCR cases were mis-classified into the non-HSCR group. In the remaining 20 cases, radiologists were unable to make a decision. Both the SVM and LR classifiers contained five clinical features and four shape features. The performance of the two classifiers was similar. The best model had 86.36% accuracy, 81.82% sensitivity, and 90.91% specificity. The AUC was 0.9132 for the best-performing SVM classifier and 0.9318 for the best-performing LR classifier. CONCLUSION: A combination of clinical features and colon shape features extracted from barium enemas can be used to improve early diagnosis of SHSCR in neonate.