Role of ß-catenin in PD-L1 expression of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a particular type of tumor connected to Epstein-Barr virus infection, genetic, and environmental factors. It is typically discovered late, with few therapeutic options and poor clinical outcomes. Cellular immune responses can be attenuated when programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) are combined. Although PD-1 inhibitors have a different anti-tumor response rate than chemotherapy alone, they can nevertheless considerably outperform chemotherapy in patients with metastatic or recurrent NPC. The nuclear ß-catenin can bind to the CD274 promoter region, promoting transcription and upregulating the expression of tumor-specific PD-L1. Separation of ß-catenin from E-cadherin and translocation it into nucleus were both aided by ß-catenin phosphorylates at the Tyr654 site. Its function in NPC and the expression of PD-L1 have not yet been investigated. This study investigated the predictive significance of PD-L1 and p-ß-cateninTyr654 expressions in NPC. Our findings indicated that patients with distant metastases or poor prognoses exhibited higher levels of PD-L1 and p-ß-cateninTyr654 expressions. According to Cox multivariate prognostic analysis, PD-L1 was also an effective indicator for predicting the survival status of patients with NPC. We subsequently demonstrated that PD-L1 transcription and protein production could be downregulated by targeting inhibition of the level of ß-catenin in NPC cells. This is for developing the ß-catenin or TCF4 inhibitor as a potential new option for immune checkpoint immunosuppression in NPC.

Docosahexaenoic acid improves cognition and hippocampal pyroptosis in rats with intrauterine growth restriction.

Background and Objective: Intrauterine growth restriction (IUGR) is defined as the failure of a fetus to reach its genetic growth potential in utero resulted by maternal, placental, fetal, and genetic factors. Previous studies have reported that IUGR is associated with a high incidence of neurological damage, although the precise causes of such damage remain unclear. We aimed to investigate whether cognitive impairment in rats with IUGR is related to pyroptosis of hippocampal neurons and determine the effect of early intervention with docosahexaenoic acid (DHA). Methods: Learning and memory function was assessed using the Morris water maze test. The morphological structure and ultrastructure of the hippocampus was examined via hematoxylin and eosin staining and electron microscopy respectively. The pyroptosis of hippocampal neuron was detected by gasdermin-D (GSDMD) immunofluorescence staining, mRNA and protein expression of nuclear localization leucine-rich-repeat protein 1 (NLRP1), caspase-1, GSDMD, and quantification of inflammatory cytokines interleukin (IL)-1ß and IL-18 in the hippocampus. Results: IUGR rats exhibited decreased learning and memory function, morphological structure and ultrastructural changes in hippocampus compared to controls. IUGR rats also exhibited increased hippocampal quantification of GSDMD immunofluorescence staining, increased mRNA and protein expression of NLRP1, caspase-1, and GSDMD, and increased quantification of IL-1ß and IL-18 in the hippocampus. Intervention with DHA attenuated these effects. Conclusion: Cognitive impairment in rats with IUGR may be related to pyroptosis of hippocampal neurons. Early intervention with DHA may attenuate cognitive impairment and reduce hippocampal pyroptosis in rats with IUGR.

[Risk factors for metabolic bone disease of prematurity in very/extremely low birth weight infants: a multicenter investigation in China].

OBJECTIVE: To investigate the incidence rate and risk factors for metabolic bone disease of prematurity (MBDP) in very low birth weight/extremely low birth weight (VLBW/ELBW) infants. METHODS: The medical data of 61 786 neonates from multiple centers of China between September 1, 2013 and August 31, 2016 were retrospectively investigated, including 504 VLBW/ELBW preterm infants who met the inclusion criteria. Among the 504 infants, 108 infants diagnosed with MBDP were enrolled as the MBDP group and the remaining 396 infants were enrolled as the non-MBDP group. The two groups were compared in terms of general information of mothers and preterm infants, major diseases during hospitalization, nutritional support strategies, and other treatment conditions. The multivariate logistic regression analysis was used to investigate the risk factors for MBDP. RESULTS: The incidence rate of MBDP was 19.4% (88/452) in VLBW preterm infants and 38.5% (20/52) in ELBW preterm infants. The incidence rate of MBDP was 21.7% in preterm infants with a gestational age of < 32 weeks and 45.5% in those with a gestational age of < 28 weeks. The univariate analysis showed that compared with the non-MBDP group, the MBDP group had significantly lower gestational age and birth weight, a significantly longer length of hospital stay, and a significantly higher incidence rate of extrauterine growth retardation (P < 0.05). Compared with the non-MBDP group, the MBDP group had significantly higher incidence rates of neonatal sepsis, anemia, hypocalcemia, and retinopathy of prematurity (P < 0.05). The MBDP group had a significantly lower mean feeding speed, a significantly higher age when reaching total enteral feeding, and a significantly longer duration of parenteral nutrition (P < 0.05). The use rate of caffeine citrate in the MBDP group was significantly higher, but the use rate of erythropoietin was significantly lower than that in the non-MBDP group (P < 0.05). The multivariate logistic regression analysis showed that gestational age < 32 weeks, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis were risk factors for MBDP (P < 0.05). CONCLUSIONS: A lower gestational age, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis may be associated an increased risk of MBDP in VLBW/ELBW preterm infants. It is necessary to strengthen perinatal healthcare, avoid premature delivery, improve the awareness of the prevention and treatment of MBDP among neonatal pediatricians, and adopt positive and reasonable nutrition strategies and comprehensive management measures for preterm infants.

Mechanisms Underlying Neurologic Injury in Intrauterine Growth Restriction.

Intrauterine growth restriction is a condition that prevents normal fetal development, and previous studies have reported that intrauterine growth restriction is caused by adverse intrauterine factors. This condition affects both short- and long-term neurodevelopmental disorders. Studies have revealed that neurodevelopmental disorders can contribute to gray and white matter damage and decrease the brain volume of affected individuals. Further, these disorders are associated with increased risks of mental retardation, cognitive impairment, and cerebral palsy, which seriously affect the quality of life. Although the mechanisms underlying the neurologic injury associated with intrauterine growth restriction are not completely clear, studies have revealed that neuronal apoptosis, neuroinflammation, oxidative stress, excitatory toxicity, disruption of blood-brain barrier, and epigenetics may be involved in this process. This article reviews the manifestations and possible mechanisms underlying neurologic injury in intrauterine growth restriction and provides a theoretical basis for the effective prevention and treatment of this condition.

Bone Turnover Markers and Bone Histomorphometry in Pubertal Rats with Intrauterine Growth Restriction.

OBJECTIVE: To investigate the effect of malnutrition during pregnancy on bone development in rat pups with intrauterine growth restriction (IUGR). Methods: IUGR offspring were induced with a 10% low protein diet, while the control group was given a 21% protein diet during pregnancy. Serum biomarkers including bone glutamyl protein (BGP), amino-terminal propeptide of type 1 procollagen (P1NP), cross linked N-telopeptide of type I collagen (NTX), and insulin like growth factor 1 (IGF-1) levels were measured at 7, 21 and 56 d. Left femurs taken at 56 d were used for bone histomorphometry analysis by micro-computed tomography (micro-CT). Results: Compared with the control group, the IUGR group had lower IGF-1 and BGP levels at 7 and 21 d, and higher P1NP and NTX levels at 7 d. The IUGR group had thinner trabecular thickness (Tb.Th), lower trabecular number (Tb.N), and increased trabecular separation (Tb.Sp) at 56 d. Conclusion: The effect of IUGR on bone development may persist after birth.

Association of vitamin D status at birth with pulmonary disease morbidity in very preterm infants.

OBJECTIVE: We aimed to assess whether serum 25-hydroxyvitamin D (25(OH)D) levels at birth are associated with pulmonary disease morbidities in very preterm infants. METHODS: This prospective cohort analysis included 93 infants born before 32 weeks of gestation in the Second Xiangya Hospital of Central South University between March 2016 and February 2017. Participants were classified into three groups according to their 25(OH)D levels at birth. The groups were compared in terms of demographic variables and pulmonary disease morbidities. RESULTS: The mean serum 25(OH)D level at birth was 35.7 ± 19.1 nmol/L, and 38 (40.9%), 31 (33.3%), and 24 (25.8%) infants had 25(OH)D levels of less than 25 nmol/L, 25-50 nmol/L, and more than or equal to 50 nmol/L, respectively. There was a statistically significant difference in neonatal respiratory distress syndrome (RDS) rates among the three groups (43.6% vs. 35.9% vs. 20.5%, p = .029). The rates of bronchopulmonary dysplasia, apnea, respiratory failure, persistent pulmonary hypertension, and pulmonary hemorrhage did not differ significantly among the groups. Logistic analysis, adjusted for gestational age and birth weight, showed that a low serum 25(OH)D level (<50 nmol/L) was a risk factor for RDS (odds ratio, 0.195; p = .017). CONCLUSION: There was a high prevalence of low 25(OH)D levels (<50 nmol/L) and an association between vitamin D status and RDS in very preterm infants. However, more research on this association is required.

Application of a modified electrocardiogram-guided technique for umbilical venous catheterisation in neonates: A retrospective trial.

AIM: To investigate the effectiveness and safety of modified electrocardiogram (ECG)-guided technique in umbilical venous catheterisation in neonates. METHODS: Sixty-six critically ill neonates underwent umbilical venous catheterisation with (ECG group) or without (control group) ECG guidance from January 2017 to March 2019. We retrospectively analysed and compared the rate of correct tip placement on first try, unplanned extubation rate and incidence of catheter-related complications between the two groups. RESULTS: There were 33 patients in each group. The ECG group showed significantly higher rate of correct tip placement on first try (P < 0.001), lower unplanned extubation rate (P < 0.001), but identical incidence of catheter-related complications (P = 0.492) comparing with the control group. CONCLUSION: The ECG-guided technique is an effective and safe method for umbilical venous catheterisation. The connecting method we modified made this technique more practical and can be promoted to areas without access to specific ECG adaptors.

MiR-199a-5p regulates sirtuin1 and PI3K in the rat hippocampus with intrauterine growth restriction.

In humans, malnutrition during pregnancy results in intrauterine growth restriction (IUGR) and an increased risk of neurological morbidities; altered miRNA characteristics have been suggested to contribute to IUGR neurological pathogenesis. A miRNA microarray was used to identify differentially expressed miRNA molecules in the hippocampi of rats with IUGR. Five of the molecules in question were selectively validated using real-time PCR in rats with IUGR. We then investigated the role of miR-199a-5p in hippocampal pathology. Bioinformatics analysis results suggested that TNF-α, caspase-3 and SIRT1 were potential targets of miR-199a-5p. Changes in PI3K, SIRT1 and caspase-3 protein expressions levels in the hippocampus were confirmed by Western blot analysis (all P < 0.05). Studies using the pheochromocytoma cell line PC12 cells and primary neurons demonstrated that miR-199a-5p modulated PI3K, caspase-3 and SIRT1 expression. Additionally, there was an inverse correlation between miR-199a-5p and caspase-3 expression, though dual-luciferase reporter assays showed that caspase-3 is not a target of miR-199a-5p. We conclude that IUGR affects hippocampal miRNAs characteristics. Our results also indicated that aberrantly high expression levels of miR-199a-5p may play an important role in the pathogenesis of IUGR by regulating SIRT1 and PI3K.

Effect of L-arginine supplementation on the hepatic phosphatidylinositol 3-kinase signaling pathway and gluconeogenic enzymes in early intrauterine growth-restricted rats.

The present study aimed to investigate the response of the phosphatidylinositol 3-kinase (PI3K) signaling pathway and gluconeogenic enzymes in intrauterine growth-restricted rats to dietary L-arginine (L-Arg) supplementation during the lactation period early in life. Pregnant Sprague-Dawley rats were randomly divided into a control group (CON), an intrauterine growth restriction group (IUGR) and an L-Arg group (LA). The pregnant rats in the CON group were fed a 21% protein diet, and those in the IUGR and LA groups were fed a 10% low protein diet, and all rats were fed a 21% protein diet after delivery. Water was available ad libitum to the pregnant rats during the 21-day lactation period, and the water provided to the LA group included 200 mg/kg/day L-Arg. Blood glucose, serum insulin, homeostasis model of assessment for insulin resistance (HOMA-IR), PI3K and protein kinase B (PKB) protein expression, and phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) mRNA expression in the offspring rats were measured postnatally at 1, 3 and 8 weeks. No significant difference in blood glucose, serum insulin and HOMA-IR were identified at any time point among the three groups. PI3K and PKB expression was lower in the IUGR group offspring compared with that in the CON group offspring, but both were increased by dietary L-Arg supplementation. PEPCK mRNA and G-6-Pase mRNA expression levels in the offspring of the IUGR group were higher compared with those in the CON group but were downregulated following L-Arg supplementation. These results suggest that dietary L-Arg supplementation during the early lactation period promoted catch-up growth and reversed abnormalities in hepatic insulin signaling and gene expression of gluconeogenic enzymes in IUGR offspring rats.

Effect of L-arginine and sildenafil citrate on intrauterine growth restriction fetuses: a meta-analysis.

BACKGROUND: Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and mortality. Several clinical trials have reported L-arginine and sildenafil citrate had effect on intrauterine growth restriction fetuses. A meta-analysis of available randomized controlled trials (RCTs) was conducted to investigate the effects of L-arginine and sildenafil citrate on major clinical outcomes of IUGR fetuses. METHODS: Systematically searched Medline, Embase, the Cochrane Library, and Clinical Trials, references of retrieved articles, and conference proceedings from 1960 to 2015. We included randomized controlled trials assessing the effects of L-arginine and sildenafil citrate on IUGR. Outcomes analyzed were the birth weight, gestational age at labor, Apgar score at 1and 5 min, the ratio of NRDS, the ratio of ICH and neonatal death, etc. RESULTS: Ten trials were included. Nine trials (576 patients) compared L-arginine with either placebo or no intervention. In the L-arginine treatment groups of the L-arginine trials, there was a significant increase in fetal birth weight (SMD 0.41, 95 % CI [0.24,0.58]), gestational age (SMD 0.30, 95 % CI [0.07,0.54]); L-arginine treatment group have a significant reduction in the ratio of neonatal respiratory distress syndrome (P = 0.009), intracranial hemorrhage of fetuses (P = 0.002), but the number of included studies and people on these outcomes are small. As only one trial (41 patients) compared sildenafil citrate with placebo, it was too small for reliable conclusions about possible differential effects could be drawn. CONCLUSIONS: The results of this meta-analysis showed that L-arginine increased birth weight and prolonged gestational age at labor of IUGR fetuses. However, further large-scale RCTs are needed to adequately assess the effect of L-arginine and Sildenafil citrate on clinical outcomes, because the number of study may be small.

Cognitive and Behavioral Outcomes of Intrauterine Growth Restriction School-Age Children.

CONTEXT: Children who experienced intrauterine growth restriction (IUGR) may be at increased risk for adverse neurologic developmental outcomes during the school-age years of life. OBJECTIVE: To estimate the effect of IUGR on cognition and behavior in school-aged children. DATA SOURCES: Medline, Embase, and PsycINFO were searched for English-language articles published after 1980. DATA SELECTION: We included case-control studies reporting cognitive and/or behavioral data of children who had IUGR and were evaluated afterfifth birthday. DATA EXTRACTION: Cognitive data from 15 studies and behavioral data from 6 studies were selected with a total of 1559 cases and 1630 controls. The cognitive scores and behavioral outcomes were extracted. RESULTS: The controls had significantly higher cognitive scores than the children with IUGR (standardized mean difference [SMD] -0.38, 95% confidence interval [CI] -0.51 to -0.25, P < .00001). The IQ scores of the IUGR group were not significantly correlated with mean birth weight and gestational age (P > .05). Five trials were included in the behavioral outcomes trial, the behavior scores were significantly different between the groups with and without IUGR (SMD 0.31, 95% CI 0.13 to 0.48, P = .001). The incidence of attention-deficit/hyperactivity disorder (ADHD) was not significantly different between 2 groups (P = .11). LIMITATIONS: The number of studies that assessed behavioral and ADHD outcome is small. CONCLUSIONS: The findings demonstrate that IUGR is associated with lower cognitive scores in school-age children. However, further large-scale trials are needed to assess the effects of IUGR on the outcome of behavioral disorder and ADHD.

The AAA ATPase Vps4 Plays Important Roles in Candida albicans Hyphal Formation and is Inhibited by DBeQ.

Candida albicans is an opportunistic human pathogen, and its pathogenicity is associated with hyphal formation. Previous studies have shown that at neutral-to-alkaline pH, hyphal growth is dependent on the Rim101 pathway whose activation requires Snf7, a member of the ESCRT system. In this work, we described the purification and characterization of the C. albicans Vps4, an AAA ATPase required for recycling of the ESCRTs. Its role on hyphal growth has been investigated. Our data suggest deletion of Vps4 decreases overall hyphal growth at pH 7 and increases the growth of multiple hyphae induced by serum, which indicates that the ESCRTs may make a Rim101-independent contribution to hyphal growth. Furthermore, DBeQ, an inhibitor of the AAA ATPase p97, was shown to inhibit the ATPase activity of Vps4 with an IC50 of about 11.5 µM. To a less degree, it also inhibits hyphal growth. Our work may provide a new strategy to control C. albicans infection.

[Relationship between serum adiponectin and bone mineral density in preterm infants].

OBJECTIVE: To examine serum adiponectin level in preterm infants and to evaluate the relationship between serum adiponectin and bone mineral density in preterm infants. METHODS: Seventy-two appropriate-for-gestational-age neonates were classified into three groups according to their gestational ages: early preterm (31-33(+6) weeks, 13 cases), late preterm (34-36(+6) weeks, 16 cases), and full-term (37-42 weeks, 43 cases). Venous blood was collected at one week of their life to measure serum adiponectin concentration. During the period, omnisense ultrasound bone sonometer was applied to measure speed of sound (SOS) of the left tibia. RESULTS: The median of tibia SOS in the early preterm group was significantly lower than in the late preterm and full term groups (P<0.05), and the median of tibia SOS in the late preterm group was lower than in the full-term group (P<0.05). Serum adiponectin level was lowest in the early preterm group, and the full-term group had the highest serum adiponectin level. Serum adiponectin level was positively correlated with tibia SOS in preterm infants (r=0.664, P<0.05). According to the result of multivariate linear stepwise regression analysis, serum adiponectin and birth weight were independent predictor of tibia SOS in preterm infants. CONCLUSIONS: Serum adiponectin level is lower in preterm infants than that in full-term infants. There is a positive correlation between serum adiponectin and bone mineral density in preterm infants.

[Effect of intrauterine growth retardation on gluconeogenic enzymes in rat liver].

OBJECTIVE: To investigate the expression of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and G-6-Pase mRNA of hepatic tissue in rats with intrauterine growth retardation (IUGR) and to explore the molecular mechanism of insulin resistance in IUGR rats. METHODS: Pregnant rats were randomly divided into 2 groups: a normal group and a model group. The normal group were fed with 21% protein forage and the model group with 10% low protein forage to obtain IUGR pup rats. The pup rats were introduced to the normal group and the IUGR group prospectively. At 1, 3 and 8 weeks, the body weight, blood glucose, insulin concentration and insulin resistance index of the pup rats were measured. Expression of PEPCK and G-6-Pase mRNA were detected by RT-PCR. RESULTS: The birth weight of the IUGR group was significantly lower than that of the normal group (P<0.001). The weight of the IUGR group was still lower than that of the normal group at 1, 3 and 8 weeks. There was no significant difference in the blood glucose, insulin level and insulin resistance index between the 2 groups (P>0.05). The hepatic expression of PEPCK and G-6-Pase mRNA in the IUGR group was significantly higher than that of the normal group at 1, 3 and 8 weeks (P<0.01). CONCLUSION: The significantly increased expression of PEPCK and G-6-Pase mRNA of hepatic tissue in IUGR rats may increase gluconeogenesis, which is probably one of the molecular mechanisms of insulin resistance and diabetes in IUGR.

[Effects of L-Arg on expression of PI3K and PKB in liver among low-birth-weight newborn rats].

OBJECTIVE: To measure the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) in liver tissue among low-birth-weight newborn rats treated with L-arginine (L-Arg) in early life, and to investigate the effect of L-Arg on insulin resistance. METHODS: Eighteen pregnant rats were randomly divided into three groups: control, model and intervention (n=6 each). The control group was fed with normal protein feed (protein content=21%) during pregnancy to establish a normal-birth-weight newborn rat model, and the model and intervention groups were fed with low-protein feed (protein content=10%) during pregnancy to establish a low-birth-weight newborn rat model. Newborn rats from the three pregnant rat groups were also assigned to control, model and intervention groups. During 21 days of lactation, maternal rats in the control and model groups were fed with normal protein feed and normal drinking water, while maternal rats in the intervention group were fed with normal protein feed and drinking water rich in L-Arg (200 mg/kg·d). After ablactation, the three groups of newborn rats were fed with normal protein feed and normal drinking water. Liver tissue samples were collected from these newborn rats at 1, 3 and 8 weeks after birth. Protein expression of PI3K and PKB in liver tissue was measured by Western blot. RESULTS: At 1 week after birth, the newborn rats in the intervention group had significantly higher protein expression of PI3K than in the model group (P=0.045), but there was no significant difference when compared with the control group (P=0.503). At 8 weeks after birth, the newborn rats in the intervention group had significantly higher protein expression of PKB than the model group (P=0.039), but there was no significant difference when compared with the control group (P>0.05). CONCLUSIONS: A supplement of L-Arg in early life can boost protein synthesis, increase protein expression of PI3K and PKB in liver tissue, promote insulin signaling and reduce insulin resistance.