In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery ...remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.
Preeclampsia is a common pregnancy-specific disorder characterized by elevated blood pressure and proteinuria. Activation of the maternal immune system and impaired placental angiogenesis are thought ...to contribute to the pathogenesis of preeclampsia. TLR9 (Toll-like receptor 9) plays a role in innate immunity, defending the organism against infection. The purpose of this study was to determine whether TLR9 inhibits angiogenesis at the fetomaternal interface under conditions of preeclampsia. We confirmed the downregulation of VEGFA (vascular endothelial growth factor A) and upregulation of TLR9 and sFLT1 (soluble vascular endothelial growth factor receptor 1) in placentas from preeclamptic women. Then, we established a mouse model with preeclampsia-like symptoms using the synthetic TLR9 agonist CpG (cytidine-phosphate-guanosine)-ODN (oligodeoxynucleotide; ODN1826). We observed the downregulation of VEGFA and the upregulation of sFLT1 in placentas from the preeclampsia-like animal model and in trophoblasts treated with CpG-ODN (ODN2006). In addition, silencing TLR9 promoted the migration and invasion of HTR8/SVneo cells. In conclusion, TLR9 is capable of robustly suppressing angiogenesis by differentially regulating the expression of VEGFA and sFLT1 at the fetomaternal interface, potentially contributing to the development of preeclampsia.
Functional oligosaccharides, known as prebiotics, and ordinary dietary fiber have important roles in modulating the structure of intestinal microbiota. To investigate their effects on the intestinal ...microecosystem, three kinds of diets containing different prebiotics were used to feed mice for 3 weeks, as follows: GI (galacto-oligosaccharides and inulin), PF (polydextrose and insoluble dietary fiber from bran), and a GI/PF mixture (GI and PF, 1:1), 16S rRNA gene sequencing and metabolic analysis of mice feces were then conducted. Compared to the control group, the different prebiotics diets had varying effects on the structure and diversity of intestinal microbiota. GI and PF supplementation led to significant changes in intestinal microbiota, including an increase of
and a decrease of
in the GI-fed, but those changes were opposite in PF fed group. Intriguing, in the GI/PF mixture-fed group, intestinal microbiota had the similar structure as the control groups, and flora diversity was upregulated. Fecal metabolic profiling showed that the diversity of intestinal microbiota was helpful in maintaining the stability of fecal metabolites. Our results showed that a single type of oligosaccharides or dietary fiber caused the reduction of bacteria species, and selectively promoted the growth of
or
bacteria, resulting in an increase in diamine oxidase (DAO) and/or trimethylamine N-oxide (TMAO) values which was detrimental to health. However, the flora diversity was improved and the DAO values was significantly decreased when the addition of nutritionally balanced GI/PF mixture. Thus, we suggested that maintaining microbiota diversity and the abundance of dominant bacteria in the intestine is extremely important for the health, and that the addition of a combination of oligosaccharides and dietary fiber helps maintain the health of the intestinal microecosystem.
We identified differentiated thyroid cancer (DTC) survivors from SEER registries and performed Poisson regression to calculate the relative risks (RRs) of subsequent malignancies (SMs) by different ...sites associated with radioactive iodine (RAI) treatment, and the attributable risk proportion of RAI for developing different SMs.
We identified 4628 of 104,026 DTC patients developing a SM after two years of their DTC diagnosis, with a medium follow-up time of 113 months. The adjusted RRs of developing SM associated with RAI varied from 0.98 (0.58-1.65) for neurologic SMs to 1.37 (1.13-1.66) for hematologic SMs. The RRs of developing all cancer combined SMs generally increased with age at DTC diagnosis and decreased with the latency time. We estimated that the attributable risk proportion of RAI treatment is only 0.9% for all cancer combined SMs and 20% for hematologic SMs, which is the highest among all SMs. The tumor features and mortalities in patients treated with and without RAI are generally comparable.
With the large population based analyses, we concluded that a low percentage of DTC survivors would develop SMs during their follow-up. Although the adjusted RR of SMs development increased slightly in patients receiving RAI, the attributable risk proportion associated with RAI was low, suggesting the absolute number of SMs induced by RAI in DTC survivors would be low. The attributable risk proportion of RAI treatment is the highest in hematological SMs, but when in consideration of its low incidence among all DTC survivors, the absolute number of hematological SMs was low.
Abstract Acute myeloid leukemia (AML) is a heterogeneous hematological tumor with poor immunotherapy effect. This study was to develop a monocyte/macrophage-related prognostic risk score (MMrisk) and ...identify new therapeutic biomarkers for AML. We utilized differentially expressed genes (DEGs) in combination with single-cell RNA sequencing to identify monocyte/macrophage-related genes (MMGs). Eight genes were selected for the construction of a MMrisk model using univariate Cox regression analysis and LASSO regression analysis. We then validated the MMrisk on two GEO datasets. Lastly, we investigated the immunologic characteristics and advantages of immunotherapy and potential targeted drugs for MMrisk groups. Our study identified that the MMrisk is composed of eight MMGs, including HOPX, CSTB, MAP3K1, LGALS1, CFD, MXD1, CASP1 and BCL2A1. The low MMrisk group survived longer than high MMrisk group (P < 0.001). The high MMrisk group was positively correlated with B cells, plasma cells, CD4 memory cells, Mast cells, CAFs, monocytes, M2 macrophages, Endothelial, tumor mutation, and most immune checkpoints (PD1, Tim-3, CTLA4, LAG3). Furthermore, drug sensitivity analysis showed that AZD.2281, Axitinib, AUY922, ABT.888, and ATRA were effective in high-risk MM patients. Our research shows that MMrisk is a potential biomarker which is helpful to identify the molecular characteristics of AML immunology.
Context:
There is uncertainty over the dose of 131I required for thyroid remnant ablation. Most previous studies have been inadequately powered to establish the best fixed dose of 131I for effective ...ablation.
Objective:
The aim of the study was to assess the effects of low- vs high-dose regimens of radioiodine in thyroid remnant ablation for patients with differentiated thyroid carcinoma.
Data Sources:
Sources included the Cochrane Library, MEDLINE, EMBASE, and SCOPUS (all until September 2012).
Study Selection:
Randomized controlled trials that assess the efficacy of low- or high-dose of radioiodine ablation of thyroid remnants were collected.
Data Extraction:
Two authors performed the data extraction independently.
Data Synthesis:
Nine randomized controlled trials involving 2569 patients were included. The 1100-MBq vs the 3700-MBq radioiodine showed no statistically significant difference in successful thyroid remnant ablation (risk ratio RR, 0.91 0.79 to 1.04; P = .15), both the 1100 vs the 1850 MBq (RR, 0.95 0.83 to 1.10; P = .52) and the 1850 vs the 3700 MBq (RR, 1.00 0.85 to 1.17; P = .98) also showed no significant differences (95% confidence intervals were calculated for each estimate). Also, no significant differences existed in quality-of-life scores on the SF-36 between different 131I-dose groups both on the day of ablation (RR, 0.15 −0.65 to 0.96, P = .71; I2 = 29%, P = .24) and 3 months after ablation (RR, −1.1 −2.37 to 0.17, P = .09; I2 = 22%, P = .26). A low dose of 1100 MBq radioiodine showed significant benefits in reducing adverse effects (total RR, 0.65 0.55 to 0.77, P < .1; I2 = 31%, P =.14) and shorter hospital isolation (RR, 0.4 0.32 to 0.50; P < .05).
Conclusions:
The low dose of 1100 MBq radioiodine activity is sufficient for thyroid remnant ablation as compared to 3700 MBq radioiodine activity with similar quality of life, less common adverse effects, and a shorter hospital stay.
Qingfei oral liquid (QF) is a traditional Chinese medicine that has been used to treat patients with viral pneumonia and asthma for decades. Our previous study revealed that QF prevents airway ...inflammation and reduces airway hyperresponsiveness (AHR) in respiratory syncytial virus (RSV)-infected asthmatic mice. RSV infection can exacerbate asthma in pediatric patients and induce autophagy, which leads to the promotion of inflammatory cytokine production in the pathology of this disease. The effect of QF on regulating autophagy in RSV-infected asthma patients has not been fully elucidated. In this study, we identified compounds of QF by HPLC–DAD-Q-TOF-MS/MS. The RSV infected OVA challenged mice, we evaluated the RSV-infected asthma model. We found that treatment with QF alleviated airway inflammation and mitigated airway AHR in RSV-infected asthmatic mice. In addition, we found that QF inhibited autophagosome formation and the expression of LC3 protein by using electron and laser confocal microscopy, respectively, to assess RSV-infected asthmatic mice lung tissues. Furthermore, QF was found to reduce the quantity of autophagy and its related proteins LC3B (light chain 3B), Beclin-1, p62 and Atg5 (autophagy-related gene 5) and downstream inflammatory cytokines TNF-α, IL-4, IL-6, and IL-13 via an action in mTOR-dependent signaling in vivo and in vitro. These findings suggest that QF can alleviate the inflammation caused by RSV infection in asthmatic mice, and its mechanism may be involved in the regulation of autophagy via the mTOR signaling pathway.
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•Respiratory syncytial virus (RSV) infection exacerbates asthma airway inflammation.•Autophagy is important role to induce airway inflammation in the RSV-infection asthma.•QF can inhibit Autophagy to alleviate airway inflammation in RSV-infected asthma.
Elevated maternal serum uric acid (UA) levels were associated with adverse perinatal outcomes. This study aimed to examine the association between UA and the risk of low birth weight (LBW) / small ...for gestational age (SGA).
A cohort study of women delivered in Shanghai maternity hospital was included between 2017 and 2021. Electronic medical records were utilized to extract information and antenatal care records. The cut-off value of UA was 360 μmol/L. The outcome was LBW/SGA, with LBW defined as birth weight below 2500 g and SGA indicating birth weight below the 10th percentile of average weight for gestational age. The assessment of SGA was based on the Chinese standard curve for birth weight at various gestational ages. Univariate, multivariate logistic regression models, restricted cubic spline were used in this study, with adjustments made for confounding factors.
Sixty-nine thousand six hundred seventy-four live births and singleton pregnancies were included. The ratio of LBW/SGA was 3.3%/9%. Maternal UA levels were significantly negatively correlated with birth weight. High UA levels were associated with high risk of LBW/SGA, especially in third trimester. In BMI < 25 group, the risk of LBW increased to 2.35-fold (95%CI, 1.66-3.31) in hyperuricemic group (UA > 360 μmol/L). The SGA risk was 1.66-fold (95%CI, 1.37-2.00). Gestational hypertension (GH) with hyperuricemica increased the risk of LBW (aOR = 4.00, 95%CI, 2.01-7.93) and SGA (aOR = 2.63, 95%CI, 1.83-3.78). Preeclampsia (PE) with hyperuricemia increased the risk of LBW (aOR = 1.38, 95%CI, 0.63-3.03) and SGA (aOR = 1.81, 95%CI, 1.18-2.78). In delivery gestational week (DGW) ≥ 37 group, if UA > 360 μmol/L, the incidence of LBW increased to 2.46-fold (95%CI, 1.62, 3.73) and the incidence of SGA increased to 1.52-fold (95%CI, 1.24, 1.87). In DGW < 37 group, if UA > 360 μmol/L, the incidence of LBW increased to 2.70-fold (95%CI, 1.92, 3.80) and the incidence of SGA increased to 2.13-fold(95%CI, 1.50, 3.02).
The study found an inverse correlation between UA levels and birth weight. High UA levels were associated with increased risk of LBW/SGA, particularly in third trimester. GH or PE complicated by hyperuricemia were found to have significantly higher risk of developing LBW/SGA. This relationship also existed in pregnant women with BMI < 25.
Objective This study aimed to investigate the genetic etiologies of fetuses with single atria and/or ventricle (SA or/and SV) using different genetic detection methods in a Chinese prenatal cohort. ...Methods In this retrospective study, the various genetic results of 44 fetuses with SA and/or SV were analyzed. All 44 cases were tested by chromosomal microarray analysis (CMA) and karyotyping simultaneously, and 8 underwent whole exome sequencing (WES). Data on the pregnancy outcomes and neonatal prognoses were collected from medical records and postnatal follow-up. Results The whole cohort of 44 fetuses included 14 SA cases (31.8%), 12 SV cases (27.3%), and 18 SA and SV cases (40.9%). A total of 9 pathogenic genetic results were detected by conventional karyotyping, CMA and trio-WES, indicating an overall detection rate of 20.5% (9/44). Six pathogenic chromosomal abnormalities were identified by CMA among the 44 cases, showing a detection rate of 13.6% (6/44). Two microdeletions being missed by karyotyping were diagnosed by CMA, showing an additional diagnostic yield of 4.5% for CMA in present cohort(2/44). Three pathogenic variants in two fetuses were identified by WES, indicating an incremental diagnostic yield of 4.5%(2/44) for WES in fetuses with SA or/and SV. Conclusion In this study, WES achieved an additional diagnostic yield of 4.5% in fetuses with SA or/and SV. WES is valuable for fetal prognosis assessment and could add diagnostic value for fetuses with SA and/or SV when CMA is negative. It would be a valuable technique for the identification of underlying pathogenic variants in prenatal cohorts. Keywords: Congenital heart disease, Chromosomal microarray analysis, Whole exome sequencing
We introduce a novel approach to preference-based reinforcement learning, namely a preference-based variant of a direct policy search method based on evolutionary optimization. The core of our ...approach is a preference-based racing algorithm that selects the best among a given set of candidate policies with high probability. To this end, the algorithm operates on a suitable ordinal preference structure and only uses pairwise comparisons between sample rollouts of the policies. Embedding the racing algorithm in a rank-based evolutionary search procedure, we show that approximations of the so-called Smith set of optimal policies can be produced with certain theoretical guarantees. Apart from a formal performance and complexity analysis, we present first experimental studies showing that our approach performs well in practice.
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