Progress in the treatment of neonatal hypoxic-ischemic encephalopathy with umbilical cord blood mononuclear cells.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a common disease among newborns, which is a leading cause of neonatal death and permanent neurological sequelae. Therapeutic hypothermia (TH) is the only method for the treatment of HIE that has been recognized effective clinically at home and abroad, but the efficacy is limited. Recent research suggests that the cord blood-derived mononuclear cells (CB-MNCs), which the refer to blood cells containing one nucleus in the cord blood, exert anti-oxidative, anti-inflammatory, anti-apoptotic effects and play a neuroprotective role in HIE. This review focuses on safety and efficacy, the route of administration, dose, timing and combination treatment of CB-MNCs in HIE.

Estimating the individual singleton preterm birth risk: nomogram establishment and independent validation.

Background: To establish and independently validate nomograms for predicting singleton preterm birth (PTB) risk based on a large sample size comprising data from two independent datasets. Methods: This cohort study used data from 50 states and the District of Columbia in the National Vital Statistics System (NVSS) database between January 2016 and December 2020. Multivariate logistic regression analysis was used to confirm the independent risk factors for PTB. Statistically significant variables were incorporated into the logistic regression models to establish PTB prediction nomograms. The models were developed using the United States (US)-derived data and were independently validated using data from US Territories. Results: A total of 16,294,529 mother-newborn pairs from the US were included in the training set, and 54,708 mother-newborn pairs from the US Territories were included in the validation set. In all, 4 nomograms were built: 1 to predict PTB probability, and another 3 to predict moderately and late PTB probability, very PTB probability, and extremely PTB probability, respectively. Hypertensive eclampsia and infertility treatment were found to be the top 2 contributors to PTB. Conclusions: We developed and validated nomograms to predict the individualized probability of PTB, which could be useful to physicians for improved early identification of PTB and in making individualized clinical decisions.

T0901317, a liver X receptor agonist, ameliorates perinatal white matter injury induced by ischemia and hypoxia in neonatal rats.

Perinatal white matter injury (PWMI) can lead to permanent neurological damage in preterm infants and bring a huge economic burden to their families and society. Liver X receptors (LXRs) are transcription factors that have been confirmed to mediate the myelination process under physiological conditions and are involved in regulating neurogenesis in adult animal models of acute and chronic cerebral ischemia. However, the role of LXRs in PWMI induced by both ischemic and hypoxic stimulation in the immature brain has not been reported. Herein, we investigated the role of LXRs in a neonatal rat model of white matter loss after hypoxia-ischemia (HI) injury through intraperitoneal injection of the LXR agonist T0901317 (T09) 1 day before and 15 min postinjury. The in vivo data showed that T09 treatment significantly facilitated myelination and ameliorated neurological behavior after PWMI. Moreover, T09 enhanced the proliferation of oligodendrocyte lineage cells and reduced microgliosis and astrogliosis in the microenvironment for oligodendrocytes (OLs), maintaining a healthy microenvironment for myelinating OLs. In vitro data suggested that the expression of the myelin-related genes Plp and Cnpase was increased in OLN-93 cells after T09 intervention compared with OLN-93 cells injured by oxygen and glucose deprivation (OGD). In primary mixed astrocytes/microglia cells, T09 also reduced the expression of Il6, Cox2, Tnfa and Il10 that was induced by OGD. Mechanistically, the mRNA expression level and the protein level of ATP binding cassette subfamily A member 1 (Abca1) decreased after HI injury, and the protective effect of T09 might be related to the activation of the LXRß-ABCA1 signaling pathway. Our study revealed the protective role of LXRs in myelination and white matter homeostasis, providing a potential therapeutic option for PWMI.

Construction and validation of a m6A RNA methylation and ferroptosis-related prognostic model for pancreatic cancer by integrated bioinformatics analysis.

Background: Both N6-methyladenosine (m6A) ribonucleic acid (RNA) methylation and ferroptosis regulators are demonstrated to have significant effects on the malignant clinicopathological characteristics of pancreatic adenocarcinoma (PAAD) patients. However, the currently available clinical indexes are not sufficient to predict precise prognostic outcomes pf PAAD patients accurately. This study aims to examine the clinicopathologic features of m6A RNA methylation and ferroptosis regulators in predicting the outcomes of different types of cancer. Methods: As the foundation for this research, the differentially expressed genes (DEGs) between PAAD tissues and adjacent normal tissues were first identified. Next, dimensional reduction analysis (DCA) based on m6A RNA methylation regulators and ferroptosis regulators were performed and DEGs between good/poor prognosis PAAD patient clusters were identified. DEGs were then screened by Cox analysis, and finally a risk signature was established by least absolute shrinkage and selection operator (LASSO) analyses. The prediction model based on risk score was further evaluated by a validation set from Gene Expression Omnibus (GEO) database. Results: In total, 4 m6A RNA methylation regulator genes and 29 ferroptosis regulator genes were found to have close causal relationships with the prognosis of PAAD, and a risk score with 3 m6A methylation regulators (i.e., IGF2BP2, IGF2BP3, and METTL16) and 4 ferroptosis regulators (i.e., ENPP2, ATP6V1G2, ITGB4, and PROM2) was constructed and showed to be highly involved in PAAD progression and could serve as effective markers for prognosis with AUC value equaled 0.753 in training set and 0.803 in validation set. Conclusions: The combined prediction model, composed of seven regulators of m6A methylation and ferroptosis, in this study more effectively reflects the progression and prognosis of PAAD than previous single genome or epigenetic analysis. Our study provides a broader perspective for the subsequent establishment of prognostic models and the patients may benefit from more precision management.

Factors associated with short-term survival in neonates with hyperammonemia.

Background: Hyperammonemia due to inherited metabolic disease can lead to neurological sequelae and death in neonates. Metabolite scavenger (MS) administration and dialysis can be helpful. We aim at analyzing the factors affecting short-term survival in neonates with hyperammonemia. Methods: We conducted a retrospective study including all neonates with hyperammonemia admitted to the neonatal intensive care unit (NICU) of the Children's Hospital of Fudan University between April 2013 and June 2020. Results: Sixty-two neonates were enrolled in the study. Of these, 32 neonates were included in the non-survival group, and 30 neonates in the survival group. Compared to the survival group, the non-survival group had a higher peak ammonia level (882.2 vs. 433.4 µmol/L) (P=0.002), a shorter length of stay (5.7 vs. 22.3 d) (P<0.000), and higher rates of acidosis (19 vs. 10) (P=0.047), electrolyte disturbance (15 vs. 6) (P=0.033), coma (12 vs. 2) (P=0.005), and invasive mechanical ventilation (28 vs. 8) (P=0.000). A longer length of stay was the most significant protective factors in the multivariate logistic regression analysis, followed by MS administration. Factors of invasive mechanical ventilation, Δ<0 (Δ= last ammonia level - first ammonia level), coma and electrolyte disturbance established a risk score model that performed well in survival analysis. Area under ROC curve for survival length of hyperammonemia combined with peak ammonia levels was 0.737 (95% CI: 0.603-0.870). Conclusions: MS administration is an effective treatment method for hyperammonemia in neonates, and increasing the length of stay in the NICU could help improve short-term survival. Further intervention should be administered when peak ammonia levels >406.5 µmol/L.

Derivation and validation of a prediction model for neonate unplanned rehospitalization in a tertiary center in China.

BACKGROUND: To construct and externally validate a prediction model for neonate unplanned rehospitalization within 31 days of discharge. METHODS: A retrospective study was performed in the Department of Neonatology of the Children's Hospital of Fudan University. A binominal regression method was applied to construct and validate the prediction model. Analysis was performed on a total of 11,116 neonates with an index admission between 11/1/2016 and 12/31/2018. Neonates admitted from 11/1/2016 to 1/31/2018 were used for the selection of prognostic variables and construction of the model. Model validation was then performed with neonates admitted from 2/1/2018 to 12/31/2018. RESULTS: The rehospitalization rate for neonates was 3.27% (373/11,116). A total of 512 neonates were enrolled for the construction of the prediction model. Gestational age (GA), NICU length of stay (LOS), nonmedical order discharge and younger maternal age were strongly correlated with rehospitalization. By incorporating these 4 strong risk factors, we constructed a model to predict neonate unplanned rehospitalization within 31 days of discharge. The formula was turned into a nomogram for use in clinical practice. The nomogram has a total score of 180, with a predicted risk from 0 to 100%. Neonates are at high risk for rehospitalization if they have a total score greater than 39 points, according to the cutoff point established by the Youden index. The model was shown to have good discriminatory ability, with area under the receiver operating characteristic curves of 0.68 and 0.65 in the model construction and validation datasets, respectively. A total of 39 points is the cutoff for follow-up. CONCLUSIONS: The model is able to predict neonate unplanned rehospitalization well. A total score greater than 39 indicates that follow-up is necessary.

Src Family Kinases Inhibition Ameliorates Hypoxic-Ischemic Brain Injury in Immature Rats.

Hypoxic-ischemic (HI) injury is one of the initial factors contributing to neonatal brain injury. Src family kinases (SFKs) are considered to act as molecular hubs for N-methyl-d-aspartate receptor (NMDAR) regulation and participate in the HI injury process. The objectives of this study were to evaluate the levels of phospho-Src (p-Src), the relationship between NMDARs and SFKs, and the effects of SFK inhibition on an immature rat HI brain injury model. The model was induced in 3-day-old Sprague-Dawley rats using the Rice-Vannucci model operation. The level of p-Src was evaluated using Western blotting. The association of NMDARs with SFKs was detected using Western blotting and coimmunoprecipitation. After intraperitoneal injection of 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2), an SFK-selective inhibitor, neuropathological changes were observed by performing H&E and immunofluorescence staining, and the neurological functions were assessed using the following behavioral tests: modified neurological severity score, open field test, and Morris water maze test. The levels of p-Src first decreased at 0 h after injury, increased at 2 h after injury, and continuously decreased from 6 h to 3 days. Along with the increased p-Src levels observed at 2 h after injury, the phosphorylation of NMDAR subunit NR2B at tyrosine 1472 was increased. Following the administration of PP2, the increased p-Src and NMDAR-2B levels detected at 2 h after injury were decreased, and tissue injury and myelin basic protein expression were improved at 7 days after injury. The PP2 intervention improved the performance of injured rats on behavioral tests. In conclusion, we determined the patterns of p-Src expression after HI brain injury in immature rats and showed a relationship with the activated NMDA receptor. The inhibition of p-Src ameliorates neuropathological changes and damages neurological functions induced by HI injury.

Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options.

Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia-ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long-term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti-inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.

Serum galectin-3 as a biomarker for screening, early diagnosis, prognosis and therapeutic effect evaluation of pancreatic cancer.

Galectin-3 plays an important role in cell-cell adhesion, macrophage activation, angiogenesis, metastasis and apoptosis and is overexpressed in pancreatic cancer. We explored the importance of galectin-3 in the screening, early diagnosis, prognosis and therapeutic effect evaluation of pancreatic cancer. A time-resolved fluorescence immunoassay was performed to detect serum galectin-3 level. Serum samples were collected from healthy controls and patients with pancreatic cancer before and after different treatments, and the relationships between galectin-3 level and clinical parameters were analysed. Among the healthy controls, one individual with an abnormally high concentration of galectin-3 (9.85 µg/L) was diagnosed with pancreatic cancer. Compared to the pre-operative level, galectin-3 concentration significantly decreased in patients with radical excision 1 month after surgery (P < .05), but showed no obvious change in patients who underwent palliative resection. Additionally, among patients with radical excision, carcinoma recurrence rate was significantly higher in those with increased or unchanged galectin-3 level. Retrospective analysis revealed the extraordinarily high value and high specificity of galectin-3 for predicting 3-year survival (P < .001). Thus, galectin-3 may serve as a potential biomarker for the screening and early diagnosis of pancreatic cancer and as an independent prognostic indicator in patients with pancreatic cancer.

The AKR1B1 inhibitor epalrestat suppresses the progression of cervical cancer.

Cervical cancer is the leading cause of cancer-related death among women worldwide. Identifying an effective treatment with fewer side effects is imperative, because all of the current treatments have unique disadvantages. Aldo-keto reductase family 1 member B1 (AKR1B1) is highly expressed in various cancers and is associated with tumor development, but has not been studied in cervical cancer. In the current study, we used CRISPR/Cas9 technology to establish a stable HeLa cell line with AKR1B1 knockout. In vitro, AKR1B1 knockout inhibited the proliferation, migration and invasion of HeLa cells, providing evidence that AKR1B1 is an innovative therapeutic target. Notably, the clinically used epalrestat, an inhibitor of aldose reductases, including AKR1B1, had the same effect as AKR1B1 knockout on HeLa cells. This result suggests that epalrestat could be used in the clinical treatment of cervical cancer, a prospect that undoubtedly requires further research. Moreover, aiming to determine the underlying regulatory mechanism of AKR1B1, we screened a series of differentially regulated genes (DEGs) by RNA sequencing and verified selected DEGs by quantitative RT-PCR. In addition, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the DEGs revealed a correlation between AKR1B1 and cancer. In summary, epalrestat inhibits the progression of cervical cancer by inhibiting AKR1B1, and thus may be a new drug for the clinical treatment of cervical cancer.