Assisted reproductive technology and neurodevelopmental outcomes in offspring: a prospective birth cohort study in East China.

RESEARCH QUESTION: Is ART associated with adverse neurodevelopmental outcome in 12-month-old offspring compared with those conceived through natural conception? DESIGN: In this prospective cohort study, 488 infertile women undergoing ART and 1397 women with natural conception were recruited and followed until their offspring were 12 months old. The primary outcome was the neurodevelopment in the offspring. The association between exposure to ART and Gesell developmental scale scores was investigated using multiple linear regression models after adjusting for confounders. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to verify the results. RESULTS: In total, 18 (3.7%) and 40 (2.9%) children in the ART and natural conception groups, respectively, had been diagnosed with neurodevelopmental delay at 12 months of age. It was found that gross motor, adaptive behaviour, language and total development quotient scores were comparable between the groups. Following multivariate linear regression and IPTW, social behaviour development quotient scores were found to be slightly higher in the ART group than the natural conception group. Higher social behaviour development quotient scores in the ART group were also observed in the male and the singleton subgroups. CONCLUSIONS: At 12 months, offspring born after ART appeared to have similar motor, language and adaptive behaviour skills, and total development quotient scores, to those born after natural conception. However, social behaviour development in 12-month-old infants was slightly higher in those conceived using ART than in naturally conceived offspring, especially in male or singleton infants. These findings may provide new information in evaluating the potential benefits and risks of ART.

Regulating electron transportation by tungsten oxide nanocapacitors for enhanced radiation therapy.

In the process of radiation therapy (RT), the cytotoxic effects of excited electrons generated from water radiolysis tend to be underestimated due to multiple biochemical factors, particularly the recombination between electrons and hydroxyl radicals (·OH). To take better advantage of radiolytic electrons, we constructed WO3 nanocapacitors that reversibly charge and discharge electrons to regulate electron transportation and utilization. During radiolysis, WO3 nanocapacitors could contain the generated electrons that block electron-·OH recombination and contribute to the yield of ·OH at a high level. These contained electrons could be discharged from WO3 nanocapacitors after radiolysis, resulting in the consumption of cytosolic NAD+ and impairment of NAD+-dependent DNA repair. Overall, this strategy of nanocapacitor-based radiosensitization improves the radiotherapeutic effects by increasing the utilization of radiolytic electrons and ·OH, warranting further validation in multiple tumour models and preclinical experiments.

Association of chorioamnionitis with infertility treatment and subsequent neonatal outcomes in the US: a population-based cohort study.

BACKGROUND: Chorioamnionitis (CAM) is a common risk factor for preterm births, resulting in several adverse outcomes. The association between infertility treatment and CAM is unclear. Therefore, this study examined the association between infertility treatment and CAM and described subsequent neonatal outcomes. METHODS: This population-based cohort study used data from the National Vital Statistics System Database. We included women who had a singleton live birth from January 1, 2016 to December 31, 2018. Women-infant pairs were stratified by infertility treatment, and the main outcome was a reported diagnosis of CAM in a checkbox format: clinical CAM or maternal temperature of > 38 °C. Multivariate logistic regression was used to examine the association between infertility treatment and CAM and the effect of infertility treatment on neonatal outcomes in women diagnosed with CAM. RESULTS: The final sample comprised 10,900,495 woman-infant pairs, and 1.4% received infertility treatment. Compared with the natural conception group, women receiving infertility treatment had a significantly higher risk of CAM (adjusted odds ratio [aOR] 1.772 [95% confidence interval {CI}, 1.718-1.827]). Furthermore, newborns exposed to CAM had a higher risk of very low birth weight (VLBW) (aOR, 2.083 [95% CI, 1.664-2.606], P < .001), preterm birth (aOR, 1.497 [95% CI, 1.324-1.693]; P < .001), neonatal intensive care unit admission (aOR, 1.234 [95% CI, 1.156-1.317]; P < .001), and other adverse neonatal outcomes in the infertility treatment group compared with ones conceived naturally. CONCLUSIONS: This study found that women who received infertility treatment had a higher risk of CAM. And CAM deteriorated neonatal outcomes in the infertility treatment group.

Urinary antibiotics concentrations, their related affecting factors and infant growth in the first 6 months of life: A prospective cohort study.

Antibiotic exposure even in low-dose could have potential adverse health effects, especially during early life. There is a lack of data on antibiotic burdens in early infancy. We aim to assess antibiotic exposure in infants from birth to 6 months of age, their related affecting factors and the association between antibiotic exposure and infancy growth. Urine samples were collected at ages of 3 days, 42 days, 3 months and 6 months from 197 term-born Chinese infants. A total of 33 representative antibiotics were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Urinary antibiotics were detectable in 69.4%, 63.2%, 75.0% and 84.3% of infants at ages of 3 days, 42 days, 3 and 6 months, respectively. The dominant antibiotic categories detected were: Preferred as Veterinary Antibiotics (PVAs), Human Antibiotics (HAs), and Veterinary Antibiotics (VAs). The detectable rates were 30.6%, 45.8%, 58.9%, and 81.4% for PVAs, 34.1%, 20.8%, 28.6%, and 45.1% for HAs, and 36.5%, 12.5%, 6.3%, and 5.9% for VAs, at age 3 days, 42 days, 3 and 6 months, respectively. Urinary concentrations of HAs and preferred as human antibiotics (PHAs) in newborns at age 3 days were not associated with maternal intrapartum antibiotic prophylaxis. Similarly, no associations were observed between urinary antibiotics concentration and antibiotics use in infants at age 42 days or 6 months. The numbers and concentrations of urine detectable antibiotics were similar between infants with exclusive breastfeeding and infants fed with formula or mixed-feeding at all ages of 42 days, 3 and 6 months. At age of 42 days, infants in the low tertile of total antibiotics concentration or with one antibiotic detected had higher weight-for-length Z score and greater head circumference, compared to infants with no antibiotics detected. No associations were found between urinary antibiotics and any of the infant anthropometric measures at age 6 months. In conclusion, urinary antibiotics were detectable in most infants during the first 6 months of life, and PVAs, HAs and VAs were the most commonly detected antibiotics. This suggested the possibility of a foods-originated antibiotics exposure in children. No strong nor consistent associations were found between urinary antibiotic concentration and infant growth at the first six months of life. Still, attention is needed on the adverse health effect of early life exposure to antibiotics in future studies.

Relationship of maternal obesity and vitamin D concentrations with fetal growth in early pregnancy.

PURPOSE: To evaluate the effects of the association between first trimester vitamin D (VitD) concentrations and increased prepregnancy body mass index (BMI) on early fetal growth restriction (FGR). METHODS: This retrospective cohort study included 15,651 women with singleton pregnancy who delivered at the International Peace Maternity and Child Health Hospital between January 2015 and November 2016. Women were classified in two groups based on their serum 25(OH)D vitamin levels status: VitD sufficient (SUFF) group and VitD insufficient or deficient (INSUFF/DEF). The cut-off point for VitD concentration was 50.00 nmol/L. Comparisons were made between women with normal prepregnancy body weight (BMI 18.5-23.9 kg/m2) and overweight and obese (OWO) women (BMI > 24.0 kg/m2). Early FGR was defined as first-trimester gestational age-adjusted crown-rump length (CRL) in the lowest 20th centile of the population. Multivariate logistic regression was used to evaluate the association between maternal serum 25(OH)D levels and prepregnancy BMI with first trimester CRL and early FGR. RESULTS: In VitD INSUFF/DEF group, the first trimester CRL was decreased (P = 0.005), and the risk of early FGR was increased by 13% (95% CI 1.04-1.24, P = 0.004) compared to the VitD SUFF group. In OWO group, the first trimester CRL was also significantly decreased (P < 0.0001), and the risk of early FGR was significantly increased by 58% (95% CI 1.40-1.78, P < 0.001) compared with normal weight group. Furthermore, there was a significant combined effect of maternal VitD concentrations and OWO on CRL (P for interaction = 0.02) and the risk of early FGR (P for interaction = 0.07). CONCLUSION: Sufficient first trimester serum 25(OH)D concentration was a protective factor for early fetal growth, especially among OWO mothers. Chinese Clinical Trial Registry (Registration number: ChiCTR1900027447 with date of registration on November 13, 2019-retrospectively registered).

Relationship between maternal vitamin D status in the first trimester of pregnancy and maternal and neonatal outcomes: a retrospective single center study.

BACKGROUND: This study aimed to investigate the relationship between maternal serum vitamin D status in the first trimester of pregnancy and maternal as well as neonatal outcomes, considered the prevalence of vitamin D deficiency (serum 25(OH)D < 50 nmol/L) around the world, especially in the pregnant women. METHODS: From January 2015 to December 2016, in this cross-sectional retrospective study, we enrolled women receiving regular prenatal examinations and giving birth in the International Peace Maternity and Child Health Hospital. Cases confirmed as multiple pregnancy, incomplete medical records, and vitamin D level recorded after 13 weeks of gestation were excluded. A total of 23,394 mother-infant pairs were included ultimately. Obstetric and neonatal information were extracted from the database. Maternal serum vitamin D concentration was measured by chemiluminescence microparticle immunoassay. Logistic regression analysis (unadjusted and adjusted models) was used to analyze the association between vitamin D and maternal and neonatal outcomes. RESULTS: The average 25(OH) D concentration was 43.20 ± 0.10 nmol/L; 67.09% of patients were vitamin D deficient(25(OH) D < 50.00 nmol/L), 29.84% were vitamin D insufficient (50 nmol/L ≤ 25(OH)D < 75 nmol/L), 3.07% were sufficient (25(OH)D ≥ 75 nmol/L). The maternal 25(OH)D levels varied with age, pre-pregnancy BMI, season when blood sample was collected, number of previous-pregnancy. Notably, newborns delivered by women with deficient vitamin D status had a higher incidence rate of admission to NICU (Deficiency: 12.20% vs Insufficiency: 10.90% vs Sufficiency: 11.70%, Pbonferroni = .002) and a longer stay (deficiency: 6.2 ± 4.1 days vs insufficiency: 5.9 ± 3.1 days vs sufficiency: 5.1 ± 2.1 days, Pbonferroni = .010). Moreover, maternal vitamin D deficiency was a dependent risk factor for admission to NICU (unadjusted OR = 1.35, 95% CI,1.05-1.74 Pbonferroni = .022; adjusted OR = 1.31, 95% CI,1.010-1.687 Pbonferroni = .042). CONCLUSIONS: Maternal vitamin D deficiency (25(OH) D < 50 nmol/L) was prevalent in eastern coastal China. The incidence rate of GDM as well as preeclampsia was higher in vitamin D insufficient group while vitamin D deficiency group was liable to intrauterine infection when compared with the other two groups. Most importantly, low vitamin D status in the first trimester of pregnancy was a dependent risk factor for admission to NICU. More well-designed perspective researches are necessary to clarify the role of vitamin D in the early stage of pregnancy.

Histological chorioamnionitis is associated with an increased risk of wheezing in preterm children less than 34 gestational weeks.

BACKGROUND: Chorioamnionitis is associated with various neonatal short- and long-term morbidities. The effect of chorioamnionitis on premature children's outcomes remains controversial. The aim of this study is to investigate the relationship between histological chorioamnionitis (HCA) and physiological development, wheezing, and atopic diseases in preterm children. METHODS: Singleton, preterm children (< 34 weeks), whose mother underwent pathological placental examinations, were retrospectively enrolled and the outcomes were assessed at 24-40 months during follow-up. Wheezing and atopic diseases including eczema, food allergies, and allergic rhinitis were screened by a questionnaire along with medical diagnosis. Anthropometric indexes and blood pressure were measured. Cognitive and behavioural developments were assessed by the Gesell Development and Diagnosis Scale. Blood IgE and routine examination were analyzed with venous blood and serum metabolomic profiling was assessed via liquid chromatography-mass spectrometry (LC-MS). A multivariate logistic regression model was used to estimate the association between HCA and the current outcomes. RESULTS: Among the 115 enrolled children, 47 were exposed to HCA. The incidence of wheezing was significantly higher in children exposed to HCA, as 38.30% of children who were exposed to HCA and 16.18% of children who were not had been diagnosed with wheezing. After adjusting for related confounders in the multivariate logistic regression model, there remained a 2.72-fold increased risk of wheezing in children with HCA (adjusted odds ratio, aOR, 2.72; 95% confidence interval, 1.02-7.23). Moreover, 163 differential metabolites, such as butanoic acid, annotemoyin 1 and charine, were identified in the HCA exposed children's serum. Enrichment analysis revealed that these compounds participated in diverse key metabolomic pathways relating to physical and neuro- developments, including glycerophospholipid, alpha-linolenic acid and choline metabolisms. There were no significant differences in atopic diseases, serum IgE, eosinophils' level, anthropometric indexes, blood pressure, or cognitive or behavioural developments between the two groups. CONCLUSION: HCA exposure is associated with an increased risk of wheezing in preterm children less than 34 gestational weeks.

Synthesis and Properties of Salicylaldehydes Fine-Tuned by Modular Assembly using "Plug-and-Socket"-Type Extendibility.

A salicylaldehyde derivative bearing four pyridine arms, 3,5-bis(N,N-bis(2-pyridylmethyl)aminomethyl)-2,4-dihydroxybenzaldehyde (Hbpsal) as a "socket", was prepared and used to derive a series of zinc complexes with various extra anions "plugged" into their vacant site. The crystal structure and 1 H NMR spectra were noticeably influenced by the extra anions, allowing fine-tuning of the properties by "plug-and-socket"-type modification. Similar to unsubstituted salicylaldehyde, the zinc complexes reacted with primary amines to afford Schiff-base compounds. Because of the potential chirality around the coordination sphere, reaction with a chiral amine resulted in an equilibrium system between diastereomers, the potential of which as chiral sources tunable by the extra anions is discussed. Some of the complexes were further converted into zinc- or nickel-salphen (=N,N-bis(salicylidene)-1,2-phenylenediamine) complexes. The electrochemical properties of the nickel complex were slightly modified by the extra anions, whereas the photophysical properties of the zinc complex appeared unchanged.

Identification of m6A-associated LncRNAs as predict factors for the immune infiltration and prognosis of thyroid cancer.

OBJECTIVE: This study aims to evaluate the prognostic value of m6A-associated long noncoding RNAs (lncRNAs) and their interaction with tumour microenvironment in thyroid cancer (THCA). METHODS: The clinical and gene expression data of tumours from 502 patients with THCA and 58 adjacent normal tissues were retrieved from The Cancer Genome Atlas (TCGA)-THCA dataset. The Pearson test was utilized to identify potential m6A-associated lncRNAs (p < 0.001 and Pearson correlation coefficient > 0.4). Quantitative real-time polymerase chain reaction was performed to verify the expression levels of lncRNAs in tissues. MTT, EdU, colony formation and wound-healing assays were performed to determine the functions of m6A-associated lncRNAs in THCA cell proliferation and metastasis. RESULTS: M6A-associated lncRNAs were identified in three cluster groups. A significant survival difference was found among them, with cluster 1 patients showing worse survival. Moreover, lower immune and estimate scores were correlated to poorer prognosis, and CD8+ T cell and memory CD4+ T cell levels were increased in cluster 1. Cluster 2, with better overall survival, had high expression of PD-L1 and CTLA-4. Eleven of the m6A-associated lncRNAs were screened to establish the risk model, including AC007365.1, AC008555.1, AC040160.1, AC064807.1, AC126773.4, AL023583.1, AL512306.2, EIF2AK3-DT, LINC00667, LYPLAL1-DT and MIR181A2HG. Based on the median risk score, THCA patients were stratified into low-risk and high-risk groups. Overall survival analysis showed a dramatic difference between the two groups. qRCR was performed to verify the expression levels of lncRNA (LYPLAL1-DT, EIF2AK3-DT and MIR181A2HG) in THCA and adjacent normal tissues. Furthermore, functional experiments showed that knockdown of MIR181A2HG obviously inhibited the proliferation and migration of papillary thyroid cancer (PTC) cells in vitro, whereas LYPLAL1-DT overexpression promoted PTC cell proliferation and migration. CONCLUSIONS: Eleven of the m6A-associated lncRNAs were identified as a risk model to predict clinical outcomes and provide a novel and efficient immunotherapeutic strategy for THCA patients.Key messagesm6A-associated lncRNAs can be used to predict the clinical outcomes of thyroid cancer patients.An m6A-associated lncRNAs risk model, which can accurately evaluate the immune status and risk stratification in individual thyroid cancer patients, was established.Knockdown/overexpression of representative lncRNAs in the risk model significantly affected the proliferation and migration of papillary thyroid cancer cells.

Relationship Between Birth Weight and Asthma Diagnosis: A Cross-Sectional Survey Study Based on the National Survey of Children's Health in the U.S.

OBJECTIVE: To assess the association between birth weight and childhood asthma risk using data from the 2019-2020 National Survey of Children's Health database. DESIGN: Cross-sectional study. SETTING: The USA. PATIENTS: A representative cohort of American children. EXPOSURE: The exposure of this study was birth weight regardless of gestational age. Birth weight was divided into three groups: <1500 g, 1500-2500 g and >2500 g. MAIN OUTCOME MEASURES: Primary outcomes were parent-reported diagnosis of asthma. METHOD: The Rao-Scott χ2 test was used to compare the groups. The main analyses examined the association between birth weight and parent-report asthma in children using univariable and multivariable logistic models adjusting for preterm birth, age, sex, race, family poverty, health insurance, smoking, maternal age. Subgroup analysis was performed based on interaction test. RESULTS: A total of 60 172 children aged 3-17 years were enrolled in this study; of these, 5202 (~8.6%) had asthma. Children with asthma were more likely to be born preterm, with low birth weight (LBW) or very LBW (VLBW). The incidence of asthma was the highest in VLBW children at 20.9% and showed a downward trend with an increase in birth weight class, with rates of 10.7% and 8.1% in the LBW and normal birthweight groups, respectively. Children with VLBW (OR 1.97; 95% CI 1.29 to 3.01) had higher odds of developing asthma in the adjusted analysis model. However, VLBW was only shown to be a risk factor for asthma among Hispanics, black/African-Americans and children between the ages of 6 and 12 years, demonstrating racial and age disparities. CONCLUSIONS: VLBW increases the risk of childhood asthma; however, racial and age disparities are evident.

Examining the relationship between birth weight and attention-deficit hyperactivity disorder diagnosis.

Background: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition that is prevalent in children worldwide. We evaluated the potential relationship between birth weight and ADHD using newly released data from the National Survey of Children's Health 2019-2020. Methods: This population-based survey study used parent recollection data that were collected and submitted by 50 states and the District of Columbia to the National Survey of Children's Health database from the National Survey of Children's Health database. Those aged < 3 years and without birth weight or ADHD records were excluded. Children were stratified according to ADHD diagnosis and birth weight: very low birth weight (VLBW, < 1,500 g), low birth weight (LBW, 1,500-2,500 g), and normal birth weight (NBW, ≥ 2,500 g). Multivariable logistic regression was applied to examine the causal association between birth weight and ADHD while controlling for child and household characteristics. Results: The final sample consisted of 60,358 children, of whom 6,314 (9.0%) were reported to have an ADHD diagnosis. The prevalence of ADHD was 8.7% in NBW children, 11.5% in LBW, and 14.4% in VLBW. Compared with NBW children, LBW children [adjusted odds ratio (aOR), 1.32 (95% CI, 1.03-1.68)], and VLBW children [aOR, 1.51 (95% CI, 1.06-2.15)] had a significantly higher risk of ADHD after adjusting all variables. These associations persisted in the male subgroups. Conclusion and relevance: This study found that LBW and VLBW children were at a higher risk of ADHD.

Vitamin D3 reverses the transcriptional profile of offspring CD4+ T lymphocytes exposed to intrauterine inflammation.

Chorioamnionitis profoundly influences multiple fetal organs as well as the immune system. Maternal vitamin D (VitD) supplementation may modulate the immune function of offspring. Here, we sought to uncover the immunomodulatory potential of intrauterine inflammation and VitD in offspring CD4+ T cells. Pregnant C57BL/6 mice were treated with intrauterine lipopolysaccharide (LPS) injections, with or without VitD. Splenic CD4+ T cells were negatively selected using anti-biotin microbeads at 28 days after birth. Differentially expressed genes (DEGs) in the offspring CD4+ T cells were identified via RNA sequencing. In total, 181 DEGs induced by LPS exposure were identified in offspring CD4+ T cells. Furthermore, 2461 DEGs were detected after VitD supplementation in addition to LPS exposure. VitD supplementation showed an unexpected ability to counteract the LPS-induced transcriptional responses. VitD supplementation downregulated lymphocyte differentiation (GO: 0030098) and lymphocyte activation (GO: 0046649), and upregulated the responses to viruses (GO: 0009615) and bacteria (GO:0009617) in offspring CD4+ T cells with intrauterine LPS exposure. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that several pathways, including the T cell receptor signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, Th17 cell differentiation, and autophagy, were downregulated by intrauterine VitD intervention following LPS exposure. Subsequently, we confirmed the counteracting effect of VitD against LPS on the expression of several genes (Insr, Foxo1, and Peli1) using qRT-PCR and western blot analyses. We also demonstrated that intrauterine VitD supplementation interferes with offspring Th17 cell differentiation induced by intrauterine LPS exposure. Our study revealed that VitD reverses the transcriptional and Th17 differential profiles of offspring CD4+ T lymphocytes induced by intrauterine LPS, and indicated the contribution of maternal VitD supplementation to immune protection in offspring affected by intrauterine inflammation.

LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma.

Previous research found that LIM domain kinase 2 (LIMK2) expression correlated with a poor prognosis in many cancers. However, its role in lung squamous cell carcinoma (LUSC) has not yet been clarified. Our study aimed to clarify the role of LIMK2 in LUSC prognosis prediction and explore the relationship between LIMK2 and immune infiltration in LUSC. In this study, we first analyzed the expression level and prognostic value of LIMK2 across cancers. Subsequently, we explored the association of LIMK2 expression with immune infiltrating cells and immune checkpoints. our study found that LIMK2 was highly expressed and positively associated with the overall survival of LUSC. Moreover, our study further indicated that LIMK2 expression was significantly negatively correlated with immune cell infiltration and immune checkpoints in LUSC. Finally, we confirmed upstream regulatory noncoding RNAs (ncRNAs) of LIMK2, and the PVT1 and DHRS4-AS1/miR-423-5p/LIMK2 regulatory axes were successfully constructed in LUSC. Put together, LIMK2 is a novel prognostic biomarker and correlates with tumor immune cell infiltration in LUSC, and the expression of LIMK2 is regulated by the PVT1 and DHRS4-AS1/miR-423-5p axes.

Prenatal inflammation causes obesity and abnormal lipid metabolism via impaired energy expenditure in male offspring.

INTRODUCTION: Obesity has becoming a global health issue. Fetus exposed to adversity in the uterine are susceptible to unhealth stimulus in adulthood. Prenatal inflammation is related to poor neonatal outcomes like neurodevelopmental impairments and respiratory complications. Recent studies suggested prenatal lipopolysaccharide (LPS) exposure could result in metabolic disorders. Thus, we hypothesized that offspring exposed to prenatal inflammation could develop into metabolic disorder. METHODS: The pregnant C57BL/6J mice were intraperitoneally injected with 50 µg/kg LPS or saline only once at GD15. The male offspring were weighted weekly until sacrificed. Indirect calorimetry and body composition were both performed at 9 and 18 weeks old. At 20 weeks old, mice were fasted overnight before collecting blood samples and liver for metabolomics analysis and RNA sequencing, respectively. Differentially expressed genes were further verified by RT-qPCR and western blotting. RESULTS: Prenatal inflammation resulted in obesity with increased fat percentage and decreased energy expenditure in middle-age male offspring. Abnormal lipid accumulation, changes of gene expression profile and upregulation of multi-component mechanistic target of rapamycin complex 1 (mTOR)/Peroxisome proliferator-activated receptor-γ pathway was observed in liver, accompanied with decreased bile acids level, unsaturated fatty acids androgens and prostaglandins in serum. Indirect calorimetry showed increased respiratory exchange rate and deceased spontaneous activity at 9 weeks in LPS group. Impaired energy expenditure was also observed at 18 weeks in LPS group. CONCLUSION: Prenatal LPS exposure led to obesity and abnormal lipid metabolism through impaired energy expenditure.

Aberrant methylation of Serpine1 mediates lung injury in neonatal mice prenatally exposed to intrauterine inflammation.

BACKGROUND: Intrauterine inflammation (IUI) alters epigenetic modifications in offspring, leading to lung injury. However, the epigenetic mechanism underlying IUI-induced lung injury remains uncertain. In the present study, we aim to investigate the effect of IUI on lung development, and to identify the key molecule involved in this process and its epigenetic regulatory mechanism. RESULTS: Serpine1 was upregulated in the lung tissue of neonatal mice with IUI. Intranasal delivery of Serpine1 siRNA markedly reversed IUI-induced lung injury. Serpine1 overexpression substantially promoted cell senescence of both human and murine lung epithelial cells, reflected by decreased cell proliferation and increased senescence-associated ß-galactosidase activity, G0/G1 cell fraction, senescence marker, and oxidative and DNA damage marker expression. IUI decreased the methylation level of the Serpine1 promoter, and methylation of the promoter led to transcriptional repression of Serpine1. Furthermore, IUI promoted the expression of Tet1 potentially through TNF-α, while Tet1 facilitated the demethylation of Serpine1 promoter. DNA pull-down and ChIP assays revealed that the Serpine1 promoter was regulated by Rela and Hdac2. DNA demethylation increased the recruitment of Rela to the Serpine1 promoter and induced the release of Hdac2. CONCLUSION: Increased Serpine1 expression mediated by DNA demethylation causes lung injury in neonatal mice with IUI. Therefore, therapeutic interventions targeting Serpine1 may effectively prevent IUI-induced lung injury.

miR-1301-3p promotes the proliferation and migration of lung cancer cells via direct repression of polymerase I and transcript release factor.

Aberrant expression of microRNAs (miRNAs or miRs) is associated with a number of human diseases, including lung cancer. Although numerous differentially expressed miRNAs have been identified in lung cancer via microarray and sequencing methods, to the best of our knowledge, only a small portion of these miRNAs have been experimentally verified. In the present study, miR-1301-3p expression levels in lung tumor tissues and lung cancer cells were measured by reverse transcription-quantitative PCR (RT-qPCR) and by analyzing previously published data. Cell Counting Kit-8 and Transwell assays were used to analyze the function of miR-1301-3p in lung cancer tissues and cells. Bioinformatics analysis, RT-qPCR, western blotting and a dual-luciferase reporter assay were performed to investigate the mechanism of miR-1301-3p in lung cancer cells. It was identified that miR-1301-3p is an upregulated miRNA in lung cancer via analyzing previously published microarray and The Cancer Genome Atlas-lung squamous cell carcinoma project data, and the upregulation of miR-1301-3p was confirmed in collected clinical samples and cells. Inhibition of miR-1301-3p suppressed lung cancer cell proliferation and migration. In addition, miR-1301-3p inhibition upregulated E-cadherin, an epithelial cell maker, and downregulated vimentin, a mesenchymal cell marker. Using bioinformatics analysis, it was revealed that polymerase I and transcript release factor (PTRF) is a target of miR-1301-3p. RT-qPCR, western blotting and dual-luciferase reporter assays demonstrated that PTRF is targeted by miR-1301-3p in lung cancer cells. The rescue experiments indicated that silencing PTRF could attenuate the inhibition of cell proliferation and migration induced by miR-1301-3p inhibitor in lung cancer cells. Furthermore, a strong negative correlation between miR-1301-3p and PTRF mRNA was identified in clinical samples. In summary, the present data highlight the involvement of miR-1301-3p in the proliferation and migration of lung cancer cells, indicating that miR-1301-3p may be a promising biomarker for lung cancer.

Association Between Maternal Perceived Stress in All Trimesters of Pregnancy and Infant Atopic Dermatitis: A Prospective Birth Cohort Study.

Background: Currently, most studies indicate that there is a potential link between maternal psychologic stress and the risk of atopic dermatitis (AD) in offspring. However, it is unknown which trimester of pregnancy is most sensitive to maternal stress in terms of risk of infant AD and whether the changes of maternal stress level in different trimesters of pregnancy may be associated with infant AD. In this study, we aimed to investigate the association between maternal perceived stress across three trimesters of pregnancy and AD in infants at 6 months. Methods: A total of 1,638 pregnant women participated in the population-based birth cohort study. Maternal prenatal stress was assessed by self-report questionnaires during each trimester. Infant AD was diagnosed at age 6 months, according to the UK Working Party diagnostic criteria. Univariate and multivariate logistic regression models were used to analyze the association between maternal prenatal stress in each trimester of pregnancy and infant AD. Results: Maternal perceived stress in the 2nd trimester was associated with AD in infants at 6 months (aOR 1.56; 95% CI 1.08-2.25, P = 0.019). Furthermore, increased level of perceived stress from the 1st to the 2nd trimester (aOR 2.05, 95% CI 1.33-3.15, P = 0.001) and from the 1st to the 3rd trimester (aOR 1.92, 95% CI 1.22-3.00, P = 0.004) were also associated with the risk of infant AD at 6 months. Conclusion: A high level of maternal perceived stress in the 2nd trimester and increased level of perceived stress from the 1st to the 2nd and 3rd trimesters of pregnancy may increase the risk of offspring developing AD at 6 months.

Clinical characteristics, treatment patterns and outcomes of patients older than 80 years diagnosed with DLBCL in China over a 10-year period.

PURPOSE: The treatment strategy for elderly patients older than 80 years with DLBCL has not been defined yet because of poor treatment tolerability and lack of data. The aim of this trial was to retrospectively investigate clinical characteristics, treatment patterns and outcomes of patients older than 80 years diagnosed with DLBCL in China over a 10-year period. METHODS: This trial comprised 57 patients, aged ≥ 80 years, who were initial diagnosed as diffuse large B-cell lymphoma from 2007 to 2017. They received at least four cycles of reduced-dose R-CHOP21 (Rituximab 375 mg/m2 day 0, Cyclophosphamide 400 mg/m2 day1, Epirubicin 35 mg/m2 day 1, Vincristine 1 mg day 1, and Prednisone 50 mg/m2 days 1-5). An observational population-based, cohort study was performed. RESULTS: The median age was 82.5 years (range 80-90 years ) and the overall response rate was 73.7%. With a median 36.4-month follow-up, 2-year overall survival (OS) and 2-year progression-free survival were 74.3% and 70.9%, respectively. Using rigorous multivariate analysis, we concluded that NCCN-IPI ≥ 5 was the only predictive poor prognostic factor. CONCLUSIONS: High response rate was concluded on very elderly DLBCL patients (≥ 80 years old) with reduced-dose R-CHOP. However, the very elderly patients with NCCN-IPI score ≥ 5 would lead to poor outcome.

Rituximab plus reduced-dose cyclophosphamide, doxorubicin, vincristine and prednisone (RD R-CHOP) chemotherapy is feasible for very elderly patients (≥80 years) with B-cell lymphoma: analysis of treatment outcome.

OBJECTIVE: The aim of this trial was to evaluate the treatment outcome of reduced-dose (RD)R-CHOP treatment in very elderly patients with B-cell lymphoma. METHODS: This trial comprised 40 patients, aged ≥80 years, who were diagnosed with B-cell lymphoma and recruited at a single centre from 2007 to 2013. They received four to eight cycles of reduced-dose R-CHOP (rituximab 375 mg/m2 Day 0, cyclophosphamide 400 mg/m2 Day 1, epirubicin 35 mg/m2 Day 1, vincristine 1 mg Day 1 and prednisone 50 mg/m2 Days 1-5). The data of treatment responses and survival were collected and analysed comprehensively. RESULTS: The median age was 83 years old (range, 80-93 years old) and the median follow-up duration was 40.86 months. The overall response rate (ORR) was 87.5%. With a 40.9-month follow-up, 3-year overall survival (OS), 3-year progression free survival (PFS) and 3-year event-free survival (EFS) were 17.2, 46.5 and 39.1%, respectively. Using multivariate analysis, we concluded that age ≥85 years; LVEF ≤70%; M-CIRS score ≥6 and ECOG-PS ≥2 were predictive poor prognostic factors. CONCLUSIONS: High response rate was concluded on very elderly B-cell lymphoma patients (≥80 years old) with reduced-dose R-CHOP. However, the very elderly patients with poor performance status and more complications benefit less from treatment.

Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for stage I-II natural killer/T-cell lymphoma nasal type: dosimetric and clinical results.

BACKGROUND: This study was to compare radiotherapy treatment planning and treatment outcomes following three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) in stage I-II natural killer (NK)/T-cell lymphoma. METHODS: The cases of 94 patients with stage I-II NK/T-cell lymphoma, nasal type in the upper aerodigestive tract who treated between May 2005 and Dec 2008 were reviewed. These patients received radiotherapy with or without induction chemotherapy. Definitive radiotherapy was conducted using 3DCRT in 47 patients and IMRT in the other 47 patients with a regional field and a total dose of 50 Gy. Dosimetric pmeters of radiation treatment plans, local control probability (LCP), overall survival (OS), and toxicities were analyzed and compared between 3DCRT and IMRT. RESULTS: From the dosimetric analysis, IMRT demonstrated significantly better dose coverage and homogeneity than 3DCRT. However, after a median follow-up of 46 months, IMRT was not associated with improvements in 4y-OS (80.9% for 3DCRT vs. 82.7% for IMRT, p=0.87) or 4y-LCP (86.3% for 3DCRT vs. 88.9% for IMR p=0.85). Of the 18 patients who received cervical lymph node irradiation, those in the IMRT group received a lower mean parotid dose. Furthermore, at-risk organs were strictly kept within the safe dose range in both groups, and no severe late toxicity was observed. CONCLUSIONS: IMRT provided better dose coverage than 3DCRT, although it failed to provide LCP and OS benefits. Definitive radiotherapy with a regional field and a total dose of 50 Gy is efficient and safe for NK/T-cell lymphoma using either IMRT or 3DCRT. However, IMRT may have the potential to reduce parotid gland hypofunction following cervical irradiation.