Establishment of cerebral perfusion in a rat model with extracorporeal life support.

Background: Extracorporeal life support echniques as an Adjunct to Advanced Cardiac Life Support is usually suitable for complex heart surgery such as cardiopulmonary bypass (CPB). Cerebral perfusion is a clinically feasible neuroprotective strategy; however, the lack of a reliable small animal model.Methods: Based on the rat model of ECLS we evaluate the effects of ECLS-CP using HE staining, Nissl staining, TUNEL staining and ELISA.Result: We found that ECLS combined with the cerebral perfusion model did not cause brain injury and immune inflammation. There was no difference between the two by a left carotid artery or right carotid artery CP.Conclusion: These experimental results can provide the experimental basis for selecting blood vessels for ECLS patients and clinical CP to offers a trustworthy animal model for future exploration of applying brain perfusion strategies during ECLS-CP.

Bmal1 regulates female reproduction in mice via the hypothalamic-pituitary-ovarian axis.

The hypothalamic-pituitary-gonadal axis (HPG) is the key neuroendocrine axis involved in reproductive regulation. Brain and muscle ARNT-like protein 1 (Bmal1) participates in regulating the metabolism of various endocrine hormones. However, the regulation of Bmal1 on HPG and female fertility is unclear. This study aims to explore the regulation of female reproduction by Bmal1 via the HPG axis in mice. Bmal1-knockout (Ko) mice were generated using the CRISPR/Cas9 technology. The structure, function, and estrous cycle of ovarian in Bmal1 Ko female mice were measured. The key genes and proteins of the HPG axis involved in regulating female reproduction were examined through transcriptome analysis and then verified by RT-PCR, immunohistochemistry, and western blot. Furthermore, the fertility of female mice was detected after intervening prolactin (PRL) and progesterone (Pg) in Bmal1 ko mice. The number of offspring and ovarian weight were significantly lower in Bmal1-Ko mice than in wild-type (Wt) mice. In Bmal1-Ko mice, ovarian cells were arranged loosely and irregularly, and the total number of follicles was significantly reduced. No corpus luteum was found in the ovaries. Vaginal smears revealed that Bmal1-Ko mice had an irregular estrus cycle. In Bmal1-Ko mice, Star expression was decreased, PRL and luteinizing hormone (LH) levels were increased, and dopamine (DA) and Pg levels were decreased. Inhibition of PRL partially recovered the estrous cycle, corpus luteum formation, and Star expression in the ovaries. Pg supplementation promoted embryo implantation in Bmal1-Ko female mice. Bmal1 Ko increases serum PRL levels in female mice likely by reducing DA levels, thus affecting luteal formation, resulting in decreased Star expression and Pg production, hindering female reproduction. Inhibition of PRL or restoration of Pg can partially restore reproductive capacity in female Bmal1-Ko mice. Thus, Bmal1 may regulate female reproduction via the HPG axis in mice, suggesting that Bmal1 is a potential target to treat female infertility.

Effect of blueberry intervention on endothelial function: a systematic review and meta-analysis.

Introduction: Endothelial dysfunction indicates blood vessel injury and is a risk factor for cardiovascular diseases. Blueberry has been approved for its benefits on human health, especially on cardiovascular function. However, its effect on endothelial function remains unclear. We conducted a systematic review and meta-analysis to explore the impact of blueberries on endothelial function in adults. Methods: We searched PubMed, Web of Science, Embase, and the Cochrane Library, 16 studies were included in the systematic review, and 11 were used for the meta-analysis. Data associated with endothelial function were extracted and pooled as mean differences (MD) with 95% confidence intervals (CI). Results: Blueberry consumption significantly improved flow-mediated dilation (FMD) by 1.50% (95% CI: 0.81, 2.20; I2 = 87%) and reactive hyperemia index (RHI) by 0.26 (95% CI: 0.09, 0.42; I2 = 72%). A significant decrease in diastolic blood pressure (DBP) was also observed (MD: -2.20 mm Hg; 95% CI: -4.13, -0.27; I2 = 11%). Subgroup analysis indicated a significant decrease in blood pressure (Systolic blood pressure [SBP]: -3.92 mmHg; 95% CI: -6.88, -0.97; I2 = 20% and DBP: -2.20 mmHg; 95% CI: -4.13, -0.27; I2 = 11%) in the smoking population. However, SBP levels (MD: -1.43 mm Hg; 95% CI: -3.11, 0.26; I2 = 20%) and lipid status (high-density lipoprotein cholesterol [HDL-C]: 0.06; 95% CI: -0.04, 0.16; I2 = 77%; low-density lipoprotein cholesterol [LDL-C]: 0.05; 95% CI: -0.14, 0.24; I2 = 0%) did not significantly improve. Conclusion: Blueberry intervention improved endothelial function and DBP. Subgroup analysis revealed a notable improvement in blood pressure among the smoking population. However, no significant effects were observed on SBP, HDL-C, and LDL-C levels. Future research should delve into the mechanisms of endothelial improvement and verify blood pressure reduction in specific subpopulations through large-scale trials. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/, Identifier CRD42023491277.

Association between methyltransferase-like 3 and non-small cell lung cancer: pathogenesis, therapeutic resistance, and clinical applications.

Non-small cell lung cancer (NSCLC) is a malignant cancer that with high incidence, recurrence, and mortality rates in human beings, posing significant threats to human health. Moreover, effective early diagnosis of NSCLC remains limited primarily by the lack of accurate biomarkers. Therefore, there is an urgent need to understand the mechanisms underlying NSCLC pathogenesis and treatment failure. Methyltransferase-like 3 (METTL3) is a prototypical member of a family of which its members transfer methyl groups. It has been implicated in modulating the pathogenesis of NSCLC, as well as conferring resistance to NSCLC therapeutics. The targeting of METTL3 for NSCLC treatment has been reported. However, the relationship between METTL3 and NSCLC remains to be demonstrated. In this review, we discuss relevant interrelationships by summarising the studies on METTL3 in NSCLC pathogenesis, therapeutic resistance, and clinical applications. Current research suggests that the upregulation of METTL3 expression propels the tumorigenesis, progression, and treatment resistance of NSCLC. Therefore, we propose that METTL3 is an excellent candidate biomarker for NSCLC diagnosis and prognosis. Therapeutic targeting of METTL3 has significant potential for NSCLC treatment. This review provides a summary of the association between METTL3 and NSCLC, which would be a valuable reference for both basic and clinical research.

Diagnostic and therapeutic potentials of methyltransferase-like 3 in liver diseases.

Methyltransferase-like 3 (METTL3), a component of the RNA N6-methyladenosine (m6A) modification with a specific catalytic capacity, controls gene expression by actively regulating RNA splicing, nuclear export, stability, and translation, determines the fate of RNAs and assists in regulating biological processes. Studies conducted in recent decades have demonstrated the pivotal regulatory role of METTL3 in liver disorders, including hepatic lipid metabolism disorders, liver fibrosis, nonalcoholic steatohepatitis, and liver cancer. Although METTL3's roles in these diseases have been extensively investigated, the regulatory network of METTL3 and its potential applications remain unexplored. In this review, we provide a comprehensive overview of the roles and mechanisms of METTL3 implicated in these diseases, establish a regulatory network of METTL3, evaluate the potential for targeting METTL3 for diagnosis and treatment, and discuss avenues for future development and research. We found relatively upregulated expressions of METTL3 in these liver diseases, demonstrating its potential as a diagnostic biomarker and therapeutic target.

A retrospective cohort study on mortality, morbidity, and care practices for 1750 very low birth weight infants, 2016-2021.

BACKGROUND: Very low birth weight (VLBW) infants are the key populations in neonatology, wherein morbidity and mortality remain major challenges. METHODS: A retrospective cohort study conducted aiming to analyze the clinical characteristics of VLBW in our hospital between January 2016 and December 2021. Neonates with a birth weight of <1500 g were included. Mortality, care practices, and major morbidities were analyzed, and compared with that of previous 7 years (2009-2015). RESULTS: Of the total 1750 VLBW, 1386 infants born with birth weight between 1000-1499 g and 364 were below 1000 g, 42.9% (751/1750) required delivery room resuscitation, 53.9% (943/1750) received non-invasive ventilation only, 38.2% (669/1750) received invasive ventilation; 1517 VLBW infants received complete treatment. Among them, 60.1% (912/1517) of neonates had neonatal respiratory distress syndrome (NRDS), 28.7% (436/1517) had bronchopulmonary dysplasia (BPD), 22.0% (334/1517) had apnea, 11.1% (169/1517) had culture-confirmed sepsis, 8.4% (128/1517) had pulmonary hemorrhage, 7.6% (116/1517) had severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL), 5.7% (87/1517) had necrotizing enterocolitis (NEC), 2.0% (31/1517) had severe retinopathy of prematurity. The total and in-hospital mortality rates were 9.7% (169/1750) and 3.0% (45/1517), respectively. The top three diagnoses of death among those who had received complete treatment were sepsis, NRDS, and NEC. In 2009-2015, 1146 VLBW were enrolled and 895 infants received complete treatment. The incidences of apnea, IVH, and IVH stage ≥3/PVL, were higher in 2009-2015 compared with those in 2016-2021, while the incidences of NRDS and BPD were characterized by significant increases in 2016-2021. The total and in-hospital mortality rates were 16.7% (191/1146) and 5.6% (50/895) respectively in 2009-2015. CONCLUSION: Among VLBW infants born in 2016-2021, the total and in-hospital mortality rates were lower than those of neonates born in 2009-2015. Incidences of NRDS and BPD increased in 2016-2021, which affected the survival rates and long-term prognosis of VLBW.

A case report on deficiency of adenosine deaminase 2 with relapse-remission course and analysis of genotype-phenotype correlation.

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in adenosine deaminase 2 (ADA2). The varying phenotypes of the disease often lead to delayed diagnosis or misdiagnosis. We report an 11-year-old boy with DADA2 and provide a preliminary analysis of genotype-phenotype correlation. The age of onset of the disease was 8 years old. The disease successively involved the brainstem, muscles, joints, and cerebrum. After three relapse-remission episodes over 3 years, the patient was finally diagnosed with DADA2 by whole-exome sequencing. Compound heterozygous variants in the ADA2 gene (NM_001282225.2: c.1072G>A, p.Gly358Arg; c.419dupC, p.Arg141Lysfs*37) were found in the patient. He did not receive anti-TNF therapy and had no relapse after a 8-month follow-up. We identified a novel variant of the ADA2 gene, and the associated disease course may follow a relapse-remission pattern. Homozygous mutations of p.Gly358Arg can cause pure red cell aplasia, whereas compound heterozygous variations may lead to different phenotypes. Variants in the catalytic domain and frameshift mutations may also cause relatively benign phenotypes besides causing hematological disorders. Further studies are needed to clarify the genotypic-phenotypic relationship of this disease.

Methyltransferase-like 3 mediated RNA m6 A modifications in the reproductive system: Potentials for diagnosis and therapy.

Several studies have highlighted the functional indispensability of methyltransferase-like 3 (METTL3) in the reproductive system. However, a review that comprehensively interprets these studies and elucidates their relationships is lacking. Therefore, the present work aimed to review studies that have investigated the functions of METTL3 in the reproductive system (including spermatogenesis, follicle development, gametogenesis, reproductive cancer, asthenozoospermia and assisted reproduction failure). This review suggests that METTL3 functions not only essential for normal development, but also detrimental in the occurrence of disorders. In addition, promising applications of METTL3 as a diagnostic or prognostic biomarker and therapeutic target for reproductive disorders have been proposed. Collectively, this review provides comprehensive interpretations, novel insights, potential applications and future perspectives on the role of METTL3 in regulating the reproductive system, which may be a valuable reference for researchers and clinicians.

Methyltransferase-like 3 modifications of RNAs: Implications for the pathology in the endocrine system.

Methyltransferase-like 3 (METTL3) is the most well-known element of N6-methyladenosine modification on RNAs. METTL3 deposits a methyl group onto target RNAs to modify their expression, ultimately regulating various physiological and pathological events. Numerous studies have suggested the significant role of METTL3 in endocrine dysfunction and related disorders. However, reviews that summarize and interpret these studies are lacking. In this review, we systematically analyze such studies, including obesity, type 2 diabetes mellitus (T2DM), T2DM-induced diseases, pancreatic cancer, and thyroid carcinoma. This review indicates that METTL3 contributes remarkably to the endocrine dysfunction and progression of obesity, T2DM, T2DM-induced diseases, pancreatic cancer, and thyroid carcinoma. In conclusion, this review provides a comprehensive interpretation of the mechanism via which METTL3 functions on RNAs and regulates various endocrine dysfunction events and suggest potential associated correlations. Our review, thus, provides a valuable reference for further fundamental studies and clinical applications.

Long-term follow-up of neuropsychological complications in neonates undergoing extracorporeal membrane oxygenation: a systematic review and meta-analysis.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been widely used in severe neonatal diseases for approximately 50 years, while few studies have concentrated on the long-term follow-up of its neuropsychological development. OBJECTIVE: To assess the long-term neuropsychological complications in children who underwent ECMO in infancy. METHODS: The PubMed, Web of Science, Cochrane, and EMBASE databases were searched for retrieving studies published in the recent 10 years (until June 10, 2022). All studies were eligible that concentrated on the long-term follow-up of neuropsychological complications in neonates undergoing ECMO. Excluding animal studies, neonates with congenital craniocerebral dysplasia and studies with data from the same center performed at different times. Statistical analysis was performed using RevMan 5.3 and Stata/SE 12.0 software. A random-effects model was used to report results. The sensitivity analysis was utilized to identify sources of heterogeneity. RESULTS: The meta-analysis of 10 studies that enrolled 1199 patients was conducted, showing the pooled morbidity of intelligence (pooled morbidity: 20.3%, 95% CI: 0.16-0.25, I2: 9.5%, P=0.33), motor activity (pooled morbidity: 10.3%, 95%CI: 0.07-0.14, I2: 43.5%, P=0.15), learning (pooled morbidity: 9.0%, 95%CI: -0.03-0.21, I2: 63.2%, P=0.10), hearing (pooled morbidity: 15.7%, 95%CI: 0.02-0.29, I2: 94.2%, P=0.00), vision (pooled morbidity: 18.5%, 95%CI: 0.12-0.25, I2: 0%, P=0.46), cognition (pooled morbidity: 26.3%, 95%CI: 0.19-0.34, I2: 0%, P=0.32), attention (pooled morbidity: 7.4%, 95%CI: 0.02-0.13, I2: 38.9%, P=0.20), speed in attention (pooled morbidity: 69.9%, 95%CI: 0.62-0.78), and accuracy in attention (pooled morbidity: 39.0%, 95%CI: 0.30-0.48) in neonates undergoing ECMO. The results of the Begg's test and sensitivity analysis indicated that the heterogeneity was originated from factors other than sample size. CONCLUSION: This systematic review and meta-analysis showed that neonates undergoing ECMO were associated with various neuropsychological complications. Additional randomized controlled trials (RCTs) with a larger sample size and a higher quality are needed.

Human Placenta Derived Mesenchymal Stem Cells Transplantation Reducing Cellular Apoptosis in Hypoxic-Ischemic Neonatal Rats by Down-Regulating Semaphorin 3A/Neuropilin-1.

Neonatal hypoxic-ischemic encephalopathy (HIE) is an abnormal neurological condition caused by hypoxic-ischemic damage during the perinatal period. Human placenta derived mesenchymal stem cells (hPMSCs) have been shown to have protective and reparative effects in various neurological diseases; however, the research on HIE is insufficient. This study aimed to establish a rat model of HIE and transplant hPMSCs through the lateral ventricle after hypoxic-ishcemic (HI) brain damage to observe its protective effects and mechanisms, with a focus on brain apoptosis compared among groups. Differentially expressed apoptosis-related proteins were screened using a rat cytokine array and subsequent verification. Neuropilin-1 (NRP-1) and Semaphorin 3A (Sema 3A) were selected for further investigation. Western blotting was used to quantify the expression of Sema 3A and the proteins related to PI3K/Akt/mTOR signaling pathway. Exogenous Sema 3A was added to evaluate the effects of Sema 3A/NRP-1 on hPMSCs following HI injury. hPMSCs transplantation ameliorated HI-induced pathological changes, reduced apoptosis, and improved long-term neurological prognosis. Furthermore, Sema 3A/NRP-1 was a key regulator in reducing HI-induced apoptosis after hPMSCs transplantation. hPMSCs inhibited the expression of Sema 3A/NRP-1 and activated the PI3K/Akt/mTOR signaling pathway. Additionally, exogenous Sema 3A abolished the protective effects of hPMSCs against HI. In conclusion, hPMSCs transplantation reduced apoptosis and improved long-term neurological prognosis after HI by downregulating Sema 3A/NRP-1 expression and activating the PI3K/Akt/mTOR signaling pathway.

High-flow nasal cannula (HFNC) vs continuous positive airway pressure (CPAP) vs nasal intermittent positive pressure ventilation as primary respiratory support in infants of ≥ 32 weeks gestational age (GA): study protocol for a three-arm multi-center randomized controlled trial.

BACKGROUND: Health problems in neonates with gestational age (GA) ≥ 32 weeks remain a major medical concern. Respiratory distress (RD) is one of the common reasons for admission of neonates with GA ≥ 32 weeks. Noninvasive ventilation (NIV) represents a crucial approach to treat RD, and currently, the most used NIV modes in neonatal intensive care unit include high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and nasal intermittent positive pressure ventilation. Although extensive evidence supports the use of NIPPV in neonates with a GA < 32 weeks, limited data exist regarding its effectiveness in neonates with GA ≥ 32 weeks. Therefore, the aim of this study is to compare the clinical efficacy of HFNC, CPAP, and NIPPV as primary NIV in neonates with GA ≥ 32 weeks who experience RD. METHODS: This trial is designed as an assessor-blinded, three-arm, multi-center, parallel, randomized controlled trial, conducted in neonates ≥ 32 weeks' GA requiring primary NIV in the first 24 h of life. The neonates will be randomly assigned to one of three groups: HFNC, CPAP or NIPPV group. The effectiveness, safety and comfort of NIV will be evaluated. The primary outcome is the occurrence of treatment failure within 72 h after enrollment. Secondary outcomes include death before discharge, surfactant treatment within 72 h after randomization, duration of both noninvasive and invasive mechanical ventilation, duration of oxygen therapy, bronchopulmonary dysplasia, time to achieve full enteral nutrition, necrotizing enterocolitis, duration of admission, cost of admission, air leak syndrome, nasal trauma, and comfort score. DISCUSSION: Currently, there is a paucity of data regarding the utilization of NIPPV in neonates with GA ≥ 32 weeks. This study will provide clinical evidence for the development of respiratory treatment strategies in neonates at GA ≥ 32 weeks with RD, with the aim of minimizing the incidence of tracheal intubation and reducing the complications associated with NIV. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2300069192. Registered on March 9, 2023, https://www.chictr.org.cn/showproj.html?proj=171491 .

Volume-targeted ventilation vs pressure-controlled ventilation for very low birthweight infants: a protocol of a randomized controlled trial.

BACKGROUND: Mechanical ventilation (MV) is essential in the management of critically ill neonates, especially preterm infants. However, inappropriate or prolonged use of invasive MV may result in ventilator-associated lung injury. A systemic review comparing pressure control ventilation (PCV) with volume-targeted ventilation mode (VTV) approved that VTV reduces the incidence of death or bronchopulmonary dysplasia (BPD) in neonates; however, this study did not analyze subgroups of very low birthweight (VLBW) infants. Therefore, the aim of this study was to compare the use of VTV and PCV in VLBW infants and to provide clinical evidence for reducing mortality and complications of MV in VLBW infants. METHOD: A single-center randomized controlled trial will be performed. All eligible infants will be randomized and assigned to either VTV or PCV group with 1:1 ratio using sealed envelopes. Death or BPD at 36 weeks' postmenstrual age will be used as the primary outcome. Secondary outcomes include BPD, death, length of invasive MV, noninvasive mechanical ventilation, and oxygen use, length of hospital stay, failure of conventional MV, rate of using high-frequency oscillatory ventilation (HFOV) as rescue therapy, rate of reintubation within 48 h, and hospital expenses. DISCUSSION: Systemic review suggested that VTV decreases the incidence of death or BPD in neonates compared to PLV; however, this study did not specifically analyze subgroups of VLBW infants. We designed this single-center randomized controlled trials (RCT) to add a significant contribution regarding the benefits of VTV for VLBW patients.

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets.

Methyltransferase-like 3 (METTL3) is a typical component of N6-methyladenosine writers that exhibits methyltransferase activity and deposits methyl groups on RNA. Currently, accumulating studies have demonstrated the involvement of METTL3 in the regulation of neuro-physiological and pathological events. However, no reviews have comprehensively summarized and analyzed the roles and mechanisms of METTL3 in these events. Herein, we are focused on reviewing the roles of METTL3 in regulating normal neurophysiological (Neurogenesis, Synaptic Plasticity and Glial Plasticity, Neurodevelopment, Learning and Memory,) and neuropathological (Autism Spectrum Disorder, Major Depressive Disorder, Neurodegenerative disorders, Brain Tumors, Brain Injuries, and Other Brain Disorders) events. Our review found that although the down-regulated levels of METTL3 function through different roles and mechanisms in the nervous system, it primarily inactivates neuro-physiological events and triggers or worsens neuropathological events. In addition, our review suggests that METTL3 could be used as a diagnostic biomarker and therapeutic target in the nervous system. Collectively, our review has provided an up-to-date research outline of METTL3 in the nervous system. In addition, the regulatory network for METTL3 in the nervous system has been mapped, which could provide directions for future research, biomarkers for clinical diagnosis, and targets for disease treatment. Furthermore, this review has provided a comprehensive view, which could improve our understanding of METTL3 functions in the nervous system.

Diagnostic performance of adenosine deaminase for abdominal tuberculosis: A systematic review and meta-analysis.

Background and aim: Abdominal tuberculosis (TB) is a common type of extrapulmonary TB with an insidious onset and non-specific symptoms. Adenosine deaminase (ADA) levels increase rapidly in the early stages of abdominal TB. However, it remains unclear whether ADA serves as a diagnostic marker for abdominal TB. Methods: We performed a systematic literature search for relevant articles published in PubMed, Web of Science, Cochrane Library, and Embase up to April 2022. First, we used the Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2), to evaluate the quality of the included articles. Bivariate and hierarchical summary receiver operating characteristic (HSROC) models were then utilized to analyze pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC). In addition, we explored a subgroup analysis for potential heterogeneity and publication bias among the included literature. Results: Twenty-four articles (3,044 participants, 3,044 samples) which met the eligibility criteria were included in this study. The pooled sensitivity and specificity of ADA for abdominal TB detection were 93% [95% confidence interval (CI): 0.89-0.95] and 95% (95% CI: 0.93-0.96), respectively. PLR and NLR were 18.6 (95% CI: 14.0-24.6) and 0.08 (95% CI: 0.05-0.12), respectively. DOR and AUROC were 236 (95% CI: 134-415) and 0.98 (95% CI: 0.96-0.99), respectively. Furthermore, no heterogeneity or publication bias was found. Conclusions: Our meta-analysis found ADA to be of excellent diagnostic value for abdominal TB and could be used as an auxiliary diagnostic tool. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022297931.

Synthetic lethality between TP53 and ENDOD1.

The atypical nuclease ENDOD1 functions with cGAS-STING in innate immunity. Here we identify a previously uncharacterized ENDOD1 function in DNA repair. ENDOD1 is enriched in the nucleus following H2O2 treatment and ENDOD1-/- cells show increased PARP chromatin-association. Loss of ENDOD1 function is synthetic lethal with homologous recombination defects, with affected cells accumulating DNA double strand breaks. Remarkably, we also uncover an additional synthetic lethality between ENDOD1 and p53. ENDOD1 depletion in TP53 mutated tumour cells, or p53 depletion in ENDOD1-/- cells, results in rapid single stranded DNA accumulation and cell death. Because TP53 is mutated in ~50% of tumours, ENDOD1 has potential as a wide-spectrum target for synthetic lethal treatments. To support this we demonstrate that systemic knockdown of mouse EndoD1 is well tolerated and whole-animal siRNA against human ENDOD1 restrains TP53 mutated tumour progression in xenograft models. These data identify ENDOD1 as a potential cancer-specific target for SL drug discovery.

Early Vitamin A Supplementation for Prevention of Short-Term Morbidity and Mortality in Very-Low-Birth-Weight Infants: A Systematic Review and Meta-Analysis.

Background: Vitamin A plays an important role in the development and maintenance of the normal function of organs and systems. Premature infants have low levels of vitamin A, which may be associated with an increased risk of developing disease. This study aimed to evaluate the effects of vitamin A supplementation on short-term morbidity and mortality in very-low-birth-weight (VLBW) infants. Methods: We used PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and Web of Science to conduct a literature search of studies published before January 1, 2022, to be included in our meta-analysis. The analysis included randomized controlled trials that compared the effects of vitamin A supplementation on VLBW infants (birth weight <1,500 g) and controls given a placebo or no treatment. The certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines. Results: Twelve randomized controlled trials were included in the meta-analysis, and 2,111 infants were pooled and analyzed. The overall risk of bias was not serious in the included studies. Vitamin A supplementation for reducing the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age seems to be limited [risk ratio (RR):0.85; 95% confidence intervals (CI): 0.70-1.04; 8 studies, 1,595 infants, very-low-certainty evidence], which is different from the previous systematic review. Length of hospital stay (mean difference: -12.67, 95% CI: -23.55 to -1.79; 6 studies, 739 infants, low-certainty evidence), and the incidence of vitamin A deficiency at 28 days postnatal age (RR: 0.08; 95% CI: 0.02-0.38; 3 studies, 358 infants, low-certainty evidence) were reduced in the vitamin A group. Besides, vitamin A supplementation seems to reduce the incidence of periventricular leukomalacia (RR: 0.68; 95% CI: 0.47-0.97; 4 studies, 1,224 infants, low-certainty evidence) and retinopathy of prematurity of any grade (RR: 0.61; 95% CI: 0.48-0.76; 4 studies, 463 infants, moderate-certainty evidence). Conclusions: There is no sufficient evidence regarding vitamin A supplementation preventing BPD in VLBW infants. Vitamin A supplementation can reduce the incidence of vitamin A deficiency and retinopathy of prematurity of any grade, and may exert an effect of preventing periventricular leukomalacia. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42020211070.

Atorvastatin inhibits neuronal apoptosis via activating cAMP/PKA/p-CREB/BDNF pathway in hypoxic-ischemic neonatal rats.

Neuronal apoptosis is one of the main pathological processes of hypoxic-ischemic brain damage (HIBD) and is involved in the development of hypoxic-ischemic encephalopathy (HIE) in neonates. Atorvastatin has been found to have neuroprotective effects in some nervous system diseases, but its role in regulating the pathogenesis of neonatal HIBD remains elusive. Thus, this study aimed to explore the effects and related mechanisms of atorvastatin on the regulation of neuronal apoptosis after HIBD in newborn rats. The rat HIBD model and the neuronal oxygen glucose deprivation (OGD) model were established routinely. Atorvastatin, cAMP inhibitor (SQ22536), and BDNF inhibitor (ANA-12) were used to treat HIBD rats and OGD neurons. Cerebral infarction, learning and memory ability, cAMP/PKA/p-CREB/BDNF signaling molecules, and apoptosis-related indicators (TUNEL, cleaved caspase-3, and Bax/Bcl2) were then examined. In vivo, atorvastatin reduced cerebral infarction, improved learning and memory ability, decreased the number of TUNEL-positive neurons, inhibited the expression of cleaved caspase-3 and Bax/Bcl2, and activated the cAMP/PKA/p-CREB/BDNF pathway in the cerebral cortex after HIBD. In vitro, atorvastatin also decreased the apoptosis-related indicators and activated the cAMP/PKA/p-CREB/BDNF pathway in neurons after OGD. Furthermore, inhibition of cAMP or BDNF attenuated the effect of atorvastatin on the reduction of neuronal apoptosis, suggesting that atorvastatin inhibits HIBD-induced neuronal apoptosis and alleviates brain injury in neonatal rats mainly by activating the cAMP/PKA/p-CREB/BDNF pathway. In conclusion, atorvastatin may be developed as a potential drug for the treatment of neonatal HIE.

Intensive phototherapy vs. exchange transfusion for the treatment of neonatal hyperbilirubinemia: a multicenter retrospective cohort study.

BACKGROUND: Intensive phototherapy (IPT) and exchange transfusion (ET) are the main treatments for extreme hyperbilirubinemia. However, there is no reliable evidence on determining the thresholds for these treatments. This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia. METHODS: This retrospective cohort study was conducted in seven centers from January 2015 to January 2018. Patients with extreme hyperbilirubinemia that met the criteria of ET were included. Patients were divided into three subgroups (low-, medium-, and high- risk) according to gestational week and risk factors. Propensity score matching (PSM) was performed to balance the data before treatment. Study outcomes included the development of bilirubin encephalopathy, duration of hospitalization, expenses, and complications. Mortality, auditory complications, seizures, enamel dysplasia, ocular motility disorders, athetosis, motor, and language development were evaluated during follow-up at age of 3 years. RESULTS: A total of 1164 patients were included in this study. After PSM, 296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-, medium-, and high-risk subgroups with 188, 364, and 40 matched patients, respectively. No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity, complications, and sequelae. Hospitalization duration and expenses were lower in the low- and medium-risk subgroups in the IPT only group. CONCLUSIONS: In this study, our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia. The indication of ET for patients with hyperbilirubinemia could be stricter. However, it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors. If IPT can be guaranteed and proved to be therapeutic, ET should be avoided as much as possible.

[Role and mechanism of histone deacetylases in mouse neuronal development].

OBJECTIVE: To study the role and mechanism of histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2) in mouse neuronal development. METHODS: The mice with Synapsin1-Cre recombinase were bred with HDAC1&2flox/flox mice to obtain the mice with neuron-specific HDAC1&2 conditional knockout (knockout group), and their littermates without HDAC1&2 knockout were used as the control group. The general status of the mice was observed and survival curves were plotted. Brain tissue samples were collected from the knockout group and the control group. Western blot and immunohistochemistry were used to measure the protein expression of related neuronal and axonal markers, neuronal nuclear antigen (NeuN), non-phosphorylated neurofilament heavy chain (np-NF200), and phosphorylated neurofilament heavy chain (p-NF200), as well as the downstream effector of the mTOR signaling pathway, phosphorylated S6 ribosomal protein (p-S6). RESULTS: The mice with HDAC1&2 conditional knockout usually died within one month after birth and were significantly smaller than those in the control group, with motor function abnormalities such as tremor and clasping of hindlimbs. Compared with the control group, the knockout group had significant reductions in the protein expression levels of NeuN, np-NF200, p-NF200, and p-S6 (P < 0.05; n=3). CONCLUSIONS: Deletion of HDAC1 and HDAC2 in mouse neurons results in reduced neuronal maturation and axonal dysplasia, which may be associated with the mTOR signaling pathway.