The impact of China's universal two-child policy on total, preterm, and multiple births: a nationwide interrupted time-series analysis.

BACKGROUND: Although years have passed since the implementation of China's universal two-child policy, the effectiveness of this policy remains unclear. To address this knowledge gap, we, here, assessed the impact of the two-child policy on total live births, preterm births, and multiple live births. METHODS: Data identifying pregnancies resulting in at least one live birth between April 1 2013 and December 31 2018 were collected from the Hospital Quality Monitoring System database. Using an interrupted time-series analysis, we estimated immediate level changes and long-term trends in total, preterm (birth before 37 weeks' gestation), and multiple live births that had occurred after July 2016, when the universal two-child policy had taken effect. RESULTS: A total of 8,273,622 live births were reported during the study time frame. The number of live births (p = 0.277), preterm births (p = 0.052), and multiple births (p = 0.856) per month slightly increased immediately after July 2016, but these increases did not meet statistical significance. Further, all three outcomes showed a significant downward trend that lasted until the end of 2018 (p < 0.0001 for all). Among all live births, the percentage of preterm births remained stable (p = 0.101), while the percentage of multiple live births that were preterm significantly increased (trend change = 0.21% per month, 95% CI 0.14 to 0.28, p < 0.0001). The percentage of live multiple births among all live births significantly decreased (p for trend = 0.0039). CONCLUSIONS: Overall, our data reveal a transient baby boom, as well as an increase in the proportion of live multiple births that were preterm, after China's two-child policy took effect. The latter should be noted by healthcare professionals due to the high risk of complications and special medical care required by preterm babies.

Characteristics of gut microbiota of term small gestational age infants within 1 week and their relationship with neurodevelopment at 6 months.

Introduction: Small for gestational age (SGA) infants are at a higher risk of neurodevelopmental delay than infants appropriate for gestational age (AGA). Previous studies have confirmed that gut microbiota in early life influences subsequent neurodevelopment. However, few studies have reported corresponding data in SGA populations. Objective: We aimed to evaluate the characteristics of the gut microbiota of term SGA infants and the associations between the gut microbiota in SGA infants and neurodevelopmental outcomes at 6 months of age. Methods: Fecal samples were collected on days 1, 3, 5, and 7 from term SGA and AGA infants born between June 2020 and June 2021 at the Peking University First Hospital. 16S ribosomal deoxyribonucleic acid amplicon sequencing was used to analyze the fecal microbiota. We followed up for 6 months and used the Ages and Stages Questionnaires-3 (ASQ-3) to evaluate the neurodevelopmental outcomes among SGA infants. Results: A total of 162 neonates were enrolled, with 41 SGA infants (25.3%) in the study group and 121 AGA infants (74.7%) in the control group. The gut microbial diversity in the SGA group was lower than that in the AGA group on days 1, 3, 5, and 7. Non-metric multidimensional scaling and analysis of similarities showed significant differences between the two groups. The SGA group had increased relative abundances of Ralstonia (3, 5, and 7 days) and Clostridium (3 and 7 days). The dominant microorganisms of the SGA group were Ralstonia on day 1, Escherichia_Shigella on days 3 and 7, and Clostridia on day 5. We found that the gut microbial diversity of SGA infants with poor communication scores was higher than that of SGA infants with good communication scores on day 3. Fine motor scores were negatively correlated with the relative abundance of Bacteroides_fragilis on day 1. A negative correlation was observed between gross motor scores and relative abundance of Clostridium_saccharobutylicum on day 7. Bacteroidota, Bacteroidia, Bacteroides, and Bacteroides_fragilis were the dominant microorganisms in the good communication score group on day 7. Communication scores were positively correlated with the relative abundance of Bacteroidota, Bacteroides, and Bacteroides_fragilis on day 7. Conclusion: The gut microbial diversity of term SGA infants was significantly lower in the first week of life than that of term AGA infants. Certain pathogenic and conditional pathogenic bacteria, such as Escherichia_Shigella, Ralstonia and Clostridium increased or formed the dominant microbiota in SGA infants. Alpha diversity, Bacteroidota, Bacteroides, Bacteroides_fragilis, and Clostridium_saccharobutylicum found in SGA infants may be associated with neurodevelopmental outcomes at 6 months of age, indicating possible therapeutic targets for clinical intervention.

The risk variant rs11836367 contributes to breast cancer onset and metastasis by attenuating Wnt signaling via regulating NTN4 expression.

Most genome-wide association study (GWAS)-identified breast cancer-associated causal variants remain uncharacterized. To provide a framework of understanding GWAS-identified variants to function, we performed a comprehensive study of noncoding regulatory variants at the NTN4 locus (12q22) and NTN4 gene in breast cancer etiology. We find that rs11836367 is the more likely causal variant, disrupting enhancer activity in both enhancer reporter assays and endogenous genome editing experiments. The protective T allele of rs11837367 increases the binding of GATA3 to the distal enhancer and up-regulates NTN4 expression. In addition, we demonstrate that loss of NTN4 gene in mice leads to tumor earlier onset, progression, and metastasis. We discover that NTN4, as a tumor suppressor, can attenuate the Wnt signaling pathway by directly binding to Wnt ligands. Our findings bridge the gaps among breast cancer-associated single-nucleotide polymorphisms, transcriptional regulation of NTN4, and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.

Emotional Prosodies Processing and Its Relationship With Neurodevelopment Outcome at 24 Months in Infants of Diabetic Mothers.

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. Hyperglycemia of pregnancy is a risk not only for later obesity of the offspring but also do harm to their neurodevelopment from fetus. An ERP research has shown that children with autism spectrum disorder (ASD) was characterized by impaired semantic processing. In this study, we used event-related potential (ERP) to assess the procession of different emotional prosodies (happy, fearful, and angry) in neonates of diabetic mothers, compared to the healthy term infants. And to explore whether the ERP measure has potential value for the evaluation of neurodevelopmental outcome in later childhood. A total of 43 full-term neonates were recruited from the neonatology department of Peking University First Hospital from December 1, 2017 to April 30, 2019. They were assigned to infants of diabetic mothers (IDM) group (n = 23) or control group (n = 20) according to their mother's oral glucose tolerance test's (OGTT) result during pregnancy. Using an oddball paradigm, ERP data were recorded while subjects listened to deviation stimulus (20%, happy/fearful/angry prosodies) and standard stimulus (80%, neutral prosody) to evaluate the potential prognostic value of ERP indexes for neurodevelopment at 24 months of age. Results showed that 1) mismatch response (MMR) amplitudes in IDM group were lower than the control; 2) lower MMR amplitude to fearful prosody at frontal lobe was a high risk for increased Modified Checklist for Autism in Toddlers (M-CHAT) scores at 24 months. These findings suggests that hyperglycemia of pregnancy may influence the ability to process emotional prosodies in neonatal brain; it could be reflected by decreased MMR amplitude in response to fearful prosody. Moreover, the decreased MMR amplitude at the frontal lobe may indicated an increased risk of ASD.

Extracellular ATP promotes breast cancer chemoresistance via HIF-1α signaling.

We have previously demonstrated that extracellular adenosine 5'-triphosphate (ATP) promotes breast cancer cell chemoresistance. However, the underlying mechanism remains unclear. Using a cDNA microarray, we demonstrated that extracellular ATP can stimulate hypoxia-inducible factor (HIF) signaling. In this study, we report that hypoxia-inducible factor 1α (HIF-1α) was upregulated after ATP treatment and mediated the ATP-driven chemoresistance process. We aimed to investigate the mechanisms and identify potential clinically relevant targets that are involved. Using mass spectrometry, we found that aldolase A (ALDOA) interacts with HIF-1α and increases HIF-1α expression. We then demonstrated that STAT3-ALDOA mediates ATP-HIF-1α signaling and upregulates the HIF-1 target genes adrenomedullin (ADM) and phosphoinositide-dependent kinase-1 (PDK1). Moreover, we show that PI3K/AKT acts upstream of HIF-1α in ATP signaling and contributes to chemoresistance in breast cancer cells. In addition, HIF-1α-knockdown or treatment with direct HIF inhibitors combined with the ATP hydrolase apyrase in MDA-MB-231 cells induced enhanced drug sensitivity in nude BALB/c mice. We then used in vitro spheroid formation assays to demonstrate the significance of ATP-HIF-1α in mediating chemoresistance. Furthermore, considering that indirect HIF inhibitors are effective in clinical cancer therapy, we treated tumor-bearing BALB/c mice with STAT3 and PI3K/AKT inhibitors and found that the dual-targeting strategy sensitized breast cancer to cisplatin. Finally, using breast cancer tissue microarrays, we found that ATP-HIF-1α signaling is associated with cancer progression, poor prognosis, and resistance to chemotherapy. Taken together, we suggest that HIF-1α signaling is vital in ATP-driven chemoresistance and may serve as a potential target for breast cancer therapies.

Near-Infrared Spectroscopy Monitoring of Cerebral Oxygenation and Influencing Factors in Neonates from High-Altitude Areas.

BACKGROUND: Accurate detection of cerebral oxygen saturation (rSO2) may be useful for neonatal brain injury prevention, and the normal range of rSO2 of neonates at high altitude remained unclear. OBJECTIVE: To compare cerebral rSO2 and cerebral fractional tissue oxygen extraction (cFTOE) at high-altitude and low-altitude areas in healthy neonates and neonates with underlying diseases. METHODS: 515 neonates from low-altitude areas and 151 from Tibet were enrolled. These neonates were assigned into the normal group, hypoxic-ischemic encephalopathy (HIE) group, and other diseases group. Near-infrared spectroscopy was used to measure rSO2 in neonates within 24 h after admission. The differences of rSO2, pulse oxygen saturation (SpO2), and cFTOE levels were compared between neonates from low- and high-altitude areas. RESULTS: (1) The mean rSO2 and cFTOE levels in normal neonates from Tibet were 55.0 ± 6.4% and 32.6 ± 8.5%, significantly lower than those from low-altitude areas (p < 0.05). (2) At high altitude, neonates with HIE, pneumonia (p < 0.05), anemia, and congenital heart disease (p < 0.05) have higher cFTOE than healthy neonates. (3) Compared with HIE neonates from plain areas, neonates with HIE at higher altitude had lower cFTOE (p < 0.05), while neonates with heart disease in plateau areas had higher cFTOE than those in plain areas (p < 0.05). CONCLUSIONS: The rSO2 and cFTOE levels in normal neonates from high-altitude areas are lower than neonates from the low-altitude areas. Lower cFTOE is possibly because of an increase in blood flow to the brain, and this may be adversely affected by disease states which may increase the risk of brain injury.

Significance of the ability to differentiate emotional prosodies for the early diagnosis and prognostic prediction of mild hypoxic-ischemic encephalopathy in neonates.

BACKGROUND: Perinatal brain injury affects around 300,000 neonates in China each year, early diagnosis and active intervention are also crucial for timely treatment and better prognoses. As hearing is the earliest as well as the most sensitive sense to develop in neonates, we propose that the ability to differentiate among different emotional prosodies may differ between neonates with and without brain injuries. METHODS: We enrolled full-term neonates admitted to the neonatology department of Peking University First Hospital from January 2016 to December 2016, conducted functional near-infrared spectroscopy (fNIRS) monitoring within 24 hr of admission, and analyzed changes in oxyhemoglobin (ΔHbO2 ) and deoxyhemoglobin (ΔHb) to study the ability of neonates to differentiate among emotional prosodies. The neonates were followed up to 36 months for neurological outcome evaluation. RESULTS AND CONCLUSIONS: We found that neonates showed the early ability to differentiate among emotional prosodies, responding most sensitively to positive emotions, and this ability may have been impaired following brain injury.

Extracellular ATP promotes breast cancer invasion and chemoresistance via SOX9 signaling.

Our previous research demonstrated that extracellular adenosine 5'-triphosphate (ATP) could promote breast cancer cell invasion. However, the impact of extracellular ATP on chemoresistance and the mechanisms behind ATP pro-invasion and pro-chemoresistance remain unclear. Here we aimed to determine the molecules or signaling pathways involved. cDNA microarray was performed to identify the differentially expressed genes before and after ATP treatment. As a result, Sex-determining region Y-box 9 (SOX9) was up-regulated after ATP treatment in breast cancer cells. In vitro invasion and migration assays demonstrated that knocking down SOX9 attenuated ATP-driven invasive capability. Mass spectrometry and co-IP revealed that SOX9 interacted with Janus kinase 1 (JAK1). Afterward, IL-6-JAK1-STAT3 signaling was demonstrated to promote SOX9 expression and invasion following ATP treatment. Notably, ATP-IL-6-SOX9 signaling was shown to stimulate chemoresistance in breast cancer cells. ChIP assays identified some potential SOX9 target genes, among which carcinoembryonic antigen-related cell adhesion molecule 5/6 (CEACAM5/6) was demonstrated to mediate ATP pro-invasive function, while ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) mediated ATP-driven chemoresistance. In addition, SOX9-knockdown and apyrase (an ATP hydrolase)-treated MDA-MB-231 cells illustrated decreased tumor growth and enhanced drug sensitivity in nude mice. In vitro spheroid formation assays also proved the significance of ATP-SOX9 in mediating chemoresistance. Moreover, molecules involved in ATP-SOX9 signaling were up-regulated in human breast carcinoma specimens and were associated with poor prognosis. Altogether, SOX9 signaling is vital in ATP-driven invasion and chemoresistance, which may serve as a potential target for breast cancer therapies.

KCNQ2-Neonatal Epileptic Encephalopathy Complicated by Ventricular Tachycardia: A Case Report.

Introduction: Mutations in KCNQ2 are related to a spectrum of neonatal epileptic phenotypes. Here we report a case of KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) that is complicated by an incidentally found ventricular tachycardia. Case Presentation: An infant boy presented with very early onset refractory focal tonic seizures and developmental delay, and was diagnosed with epilepsy. Trio-whole exome sequencing identified a previously reported de novo mutation in KCNQ2 [c.794C>T; p. (Ala265Val)], a known pathogenic variant for KCNQ2-NEE. Interestingly, ventricular tachycardia was incidentally found on electrocardiography. Conclusions: We here suggest the possibility of a potential electrophysiologic link between the two phenotypes and that they may be attributable to the same de novo mutation.

Extracellular ATP promotes breast cancer invasion and epithelial-mesenchymal transition via hypoxia-inducible factor 2α signaling.

Extracellular ATP has been shown to play an important role in invasion and the epithelial-mesenchymal transition (EMT) process in breast cancer; however, the mechanism is unclear. Here, by using a cDNA microarray, we demonstrated that extracellular ATP could stimulate hypoxia-inducible factor (HIF) signaling and upregulate hypoxia-inducible factor 1/2α (HIF-1/2α) expression. After knocking down HIF-1/2α using siRNA, we found that ATP-driven invasion and EMT were significantly attenuated via HIF2A-siRNA in breast cancer cells. By using ChIP assays, we revealed that the biological function of extracellular ATP in invasion and EMT process depended on HIF-2α direct targets, among which lysyl oxidase-like 2 (LOXL2) and matrix metalloproteinase-9 (MMP-9) mediated ATP-driven invasion, and E-cadherin and Snail mediated ATP-driven EMT, respectively. In addition, using silver staining and mass spectrometry, we found that phosphoglycerate kinase 1 (PGK1) could interact with HIF-2α and mediate ATP-driven HIF-2α upregulation. Furthermore, we demonstrated that expressions of HIF-2α and its target proteins could be regulated via ATP by AKT-PGK1 pathway. Using a Balb/c mice model, we illustrated the function of HIF-2α in promoting tumor growth and metastasis in vivo. Moreover, by exploring online databases, we found that molecules involved in ATP-HIF-2α signaling were highly expressed in human breast carcinoma tissues and were associated with poor prognosis. Altogether, these findings suggest that extracellular ATP could promote breast carcinoma invasion and EMT via HIF-2α signaling, which may be a potential target for future anti-metastasis therapy.

Genetic polymorphisms in CDH1 are associated with endometrial carcinoma susceptibility among Chinese Han women.

The cadherin 1 (CDH1) gene plays critical roles in the epithelial-mesenchymal transition process, potentially offering us a glimpse into the development of endometrial carcinoma (EC). The present study aimed to identify whether genetic variants in CDH1 affect EC susceptibility in Chinese Han women, using a strategy combining haplotype-tagging single nucleotide polymorphisms (htSNPs) association analysis with fine-scale mapping. A total of 9 htSNPs in CDH1 were genotyped among 516 cases and 706 age-matched cancer-free controls. Logistic regression analyses revealed 3 htSNPs (rs17715799, rs6499199 and rs13689) to be associated with increased EC risk and 3 htSNPs (rs12185157, rs10431923 and rs4783689) with decreased EC risk. Furthermore, 14 newly imputed SNPs of CDH1 were identified to be associated with EC risk (P<0.05) using genotype imputation analysis. Notably, multivariate logistic analysis demonstrated that rs13689, rs10431923 and rs10431924 could affect EC susceptibility independently (P≤0.001). Subsequent Generalized Multifactor Dimensionality Reduction analysis revealed several best fitting models for predicting EC risk, including SNP-SNP interactions among rs7100190, rs12185157, rs10431923, rs7186053, rs6499199, rs4783689, rs13689, rs6499197 and rs10431924, and SNP-environment interactions between related SNPs and number of childbirth. Moreover, functional annotations suggest that the majority of these susceptible variants may carry potential biological functions that affect certain gene regulatory elements. In summary, this study suggested that the genetic polymorphisms of CDH1 were indeed associated with EC susceptibility on several levels. If further additional functional studies could verify these findings, these genetic variants may serve as future personalized markers for the early prediction of endometrial cancer in Chinese Han women.

Associations of gene­wide SNPs in SNAI1 and TWIST1 with breast cancer and ovarian cancer susceptibility among Chinese Han women.

Extensive evidence suggests that the genetic etiologies of breast cancer (BC) and ovarian cancer (OC) show a certain degree of similarity. This study aimed to find out whether the single nucleotide polymorphisms (SNPs) of genes SNAI1 and TWIST1 may affect BC and OC susceptibility. A total of 7 tagging­SNPs (tSNPs) were directly genotyped in 1,161 BC cases, 286 OC cases and 1,273 cancer­free controls among Chinese Han women. Twenty­eight variants in these 2 genes were genotyped by 'in silico' genotype imputation. Logistic regression (LR) revealed that tSNPs SNAI1 rs6125849, TWIST1 rs4721746 and TWIST1 rs4721745 were protective genetic variants for BC/OC. Allelic association tests of gene­wide SNPs demonstrated that the minor alleles of SNAI1 rs6125849, TWIST1 rs4721745 and TWIST1 rs11973396 were strongly associated with BC/OC susceptibility. Multivariate LR presented that SNAI1 rs6125849, TWIST1 rs4721745, rs4721746 and rs11973396 affected BC/OC susceptibility independently, and women harboring all four protective genoytpes had the lowest risk. Multifactor dimensionality reduction analysis further showed that SNAI1 rs6125849 and TWIST1 rs4721745 had the strongest synergistic interaction. Functional annotation predicted that the minor alleles of SNAI1 rs6125849 and TWIST1 rs4721745 altered their binding affinities with transcription factors E2F6 and TCF11­MafG respectively. These results indicate that genetic variants in SNAI1 and TWIST1, most probably SNAI1 rs6125849 and TWIST1 rs4721745, may modulate BC and OC susceptibility.

Extracellular ATP drives breast cancer cell migration and metastasis via S100A4 production by cancer cells and fibroblasts.

Our previous work has demonstrated that extracellular ATP is an important pro-invasive factor, and in this study, we tapped into a possible mechanism involved. We discovered that ATP could upregulate both the intracellular expression and secretion of S100A4 in breast cancer cells and fibroblasts. Apart from stimulating breast cancer cell motility via intracellular S100A4, ATP enhanced the ability of breast cancer cells to transform fibroblasts into cancer-associated fibroblast (CAF)-like cells, which in turn secreted S100A4 to further promote cancer cell motility. Both apyrase and niclosamide treatments could inhibit metastasis of inoculated tumors to lung, liver and kidney in mice model, and CAFs from these treated tumors exhibited weakened migration-stimulating capacity for breast cancer cells. Collectively, our data indicate that extracellular ATP promotes the interactions between breast cancer cells and fibroblasts, which work collaboratively via production of S100A4 to exacerbate breast cancer metastasis.

Diagnosis and Differential Diagnosis of Desmoplastic Fibroblastoma by Clinical, Radiological, and Histopathological Analyses.

BACKGROUND: Desmoplastic fibroblastoma (collagenous fibroma) is an uncommon benign soft-tissue tumor, rarely involving bone. It shares some overlapping features with other infiltrate tumors, such as desmoid-type fibromatosis, neurofibroma, and low-grade fibromyxoid sarcoma. The misdiagnosis may cause unnecessary surgical overtreatment, especially for those involving bone. In order to deepen the understanding of the diagnosis and differential diagnosis of desmoplastic fibroblastoma, we planned to analyze the clinical, radiological, and histopathological features and the outcome of desmoplastic fibroblastoma on the basis of case analysis and literature review. METHODS: Sixteen cases were retrieved from the surgical pathology records from May 2011 to April 2016 in the Department of Pathology in Beijing Jishuitan Hospital. Formalin-fixed, paraffin-embedded specimens of 16 cases of desmoplastic fibroblastoma were collected. Hematoxylin and eosin stain and immunohistochemistry were used to observe the histological features of desmoplastic fibroblastoma of soft tissue and bone. The images for diagnosis obtained from the ultrasonic examination, X-ray, magnetic resonance imaging, and computed tomography were used to observe the radiological features. Related literatures were retrieved from the PubMed and CNKI databases. RESULTS: Sixteen cases of desmoplastic fibroblastoma of soft tissue were located in the hand (n = 7), foot (n = 4), upper arm (n = 1), shoulder (n = 1), forearm (n = 2), and one case occurred in the proximal femur. Age ranged from 32 to 82 years (median age: 58 years). There were six females and ten males. Histologically, the lesions of soft tissue appeared as well-circumscribed masses with abundant collagenous matrix and low vascularity. Tumor cells were stellate- or spindle-shaped and uniformly distributed within the extracellular matrix. In five cases, the desmoplastic fibroblastoma were found to have infiltrated into the skeletal muscle tissue. In one case of desmoplastic fibroblastoma of bone, radiographs revealed osteolytically well-defined lesion. Immunohistochemistry stain showed that vimentin and smooth muscle actin were positive in all cases of desmoplastic fibroblastoma. CONCLUSIONS: Desmoplastic fibroblastoma (collagenous fibroma) has prominent clinical, histopathological, and radiological features. Before the differential diagnosis from other tumors is obtained by thorough analysis and comparison of the similar and different characteristics, the appropriate surgical management and accurate prognosis evaluation could not be delivered to the patient.