Preeclampsia, especially preterm preeclampsia and early-onset preeclampsia, is a life-threating pregnancy disorder, and the heterogeneity and complexity of preeclampsia make it difficult to predict ...risk and to develop treatments. Plasma cell-free RNA carries unique information from human tissue and may be useful for noninvasive monitoring of maternal, placental, and fetal dynamics during pregnancy.
This study aimed to investigate various RNA biotypes associated with preeclampsia in plasma and to develop classifiers to predict preterm preeclampsia and early-onset preeclampsia before diagnosis.
We performed a novel, cell-free RNA sequencing method termed polyadenylation ligation-mediated sequencing to investigate the cell-free RNA characteristics of 715 healthy pregnancies and 202 pregnancies affected by preeclampsia before symptom onset. We explored differences in the abundance of different RNA biotypes in plasma between healthy and preeclampsia samples and built preterm preeclampsia and early-onset preeclampsia prediction classifiers using machine learning methods. Furthermore, we validated the performance of the classifiers using the external and internal validation cohorts and assessed the area under the curve and positive predictive value.
We detected 77 genes, including messenger RNA (44%) and microRNA (26%), that were differentially expressed in healthy mothers and mothers with preterm preeclampsia before symptom onset, which could separate participants with preterm preeclampsia from healthy samples and that played critical functional roles in preeclampsia physiology. We developed 2 classifiers for predicting preterm preeclampsia and early-onset preeclampsia before diagnosis based on 13 cell-free RNA signatures and 2 clinical features (in vitro fertilization and mean arterial pressure), respectively. Notably, both classifiers showed enhanced performance when compared with the existing methods. The preterm preeclampsia prediction model achieved 81% area under the curve and 68% positive predictive value in an independent validation cohort (preterm, n=46; control, n=151); the early-onset preeclampsia prediction model had an area under the curve of 88% and a positive predictive value of 73% in an external validation cohort (early-onset preeclampsia, n=28; control, n=234). Furthermore, we demonstrated that downregulation of microRNAs may play vital roles in preeclampsia through the upregulation of preeclampsia-relevant target genes.
In this cohort study, a comprehensive transcriptomic landscape of different RNA biotypes in preeclampsia was presented and 2 advanced classifiers with substantial clinical importance for preterm preeclampsia and early-onset preeclampsia prediction before symptom onset were developed. We demonstrated that messenger RNA, microRNA, and long noncoding RNA can simultaneously serve as potential biomarkers of preeclampsia, holding the promise of prevention of preeclampsia in the future. Abnormal cell-free messenger RNA, microRNA, and long noncoding RNA molecular changes may help to elucidate the pathogenic determinants of preeclampsia and open new therapeutic windows to effectively reduce pregnancy complications and fetal morbidity.
Abstract
Circular RNAs (circRNAs), which are single-stranded RNA molecules that have individually formed into a covalently closed continuous loop, act as sponges of microRNAs to regulate ...transcription and translation. CircRNAs are important molecules in the field of cancer diagnosis, as growing evidence suggests that they are closely related to pathological cancer features. Therefore, they have high potential for clinical use as novel cancer biomarkers. In this article, we present our updates to CircNet (version 2.0), into which circRNAs from circAtlas and MiOncoCirc, and novel circRNAs from The Cancer Genome Atlas database have been integrated. In total, 2732 samples from 37 types of cancers were integrated into CircNet 2.0 and analyzed using several of the most reliable circRNA detection algorithms. Furthermore, target miRNAs were predicted from the full-length circRNA sequence using three reliable tools (PITA, miRanda and TargetScan). Additionally, 384 897 experimentally verified miRNA–target interactions from miRTarBase were integrated into our database to facilitate the construction of high-quality circRNA–miRNA–gene regulatory networks. These improvements, along with the user-friendly interactive web interface for data presentation, search, and visualization, showcase the updated CircNet database as a powerful, experimentally validated resource, for providing strong data support in the biomedical fields. CircNet 2.0 is currently accessible at https://awi.cuhk.edu.cn/∼CircNet.
Down syndrome (DS) is a chromosomal disorder caused by a third copy of all or part of chromosome 21. Clinical observations and preclinical studies both suggest that DS may be associated with ...significant metabolic and bioenergetic alterations. But the metabolic alterations in pregnant women carrying DS fetuses still remains unclear. In this study, we investigated the characteristic metabolomics and lipidomics changes during fetal development of DS.
The AF and random urine specimens were selected from 20 pregnant women carrying DS fetuses and 20 pregnant women carrying healthy fetuses. The diagnosis of DS was screened according to chromosome karyotype analysis, and untargeted metabolomic and lipidomic analyses were performed.
Through the analyses of AF, 308 differential metabolites were selected between DS and controls. The metabolites with significant changes mainly involved lipid molecules, organic acids, nucleotides and carbon. Further analysis of lipidomics showed 64 differential metabolites, mainly involving glycerides, sphingolipids and glycerolipids. As for urine metabolomic and lipidomic analyses, there existed consistent metabolites with AF, but the number was much less.
Compared with the controls, carbon metabolism, amino acid metabolism, glyceride metabolism, sphingolipid metabolism and glycerophospholipid metabolism were significantly changed in DS cases. In addition, characterized biomarkers in AF and urine were screened for DS diagnosis, and these metabolites were mainly involved in energy metabolism and liver dysfunction. This finding may help improve the efficiency of prenatal screening for DS.
Background: Breast cancer patients report high levels of psychosocial maladjustment after hospital discharge. Peer support may play an important role in improving anxiety and quality of life in ...breast cancer patients. This study aimed to assess the effect of peer support on quality of life and anxiety in breast cancer patients. Method: A systematic review and meta-analysis of randomized controlled studies were conducted, using data sourced from PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SinoMed, China Science and Technology Periodical Database, China National Knowledge Infrastructure, and Wanfang Data for randomized controlled trials (RCTs) from inception to October 15, 2021. The RCTs reporting the effect of peer support intervention on quality of life and anxiety in breast cancer patients were included. The quality of evidence was assessed using the Cochrane risk of bias tool, that is, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated for the pooled effect size. Results: A total of 14 studies were included in the systematic review and 11 in the meta-analysis. The pooled results revealed that peer support significantly improved quality of life (SMD = 0.69, 95% CI = 0.28–1.11) and anxiety (SMD = −0.45, 95% CI = −0.88 to −0.02) in breast cancer patients. The quality of evidence was low as all studies showed the risk of bias and inconsistency. Conclusion: Peer support intervention has the potential to effectively improve psychosocial adaptations in breast cancer patients. Future studies with a robust design and larger sample size are needed to investigate the potential factors associated with the beneficial effects of peer support.
Autosomal dominant de novo mutations in SYNGAP1 are a cause of intellectual disability (ID) and autism spectrum disorder (ASD), including autosomal dominant mental retardation 5 (MRD5).
By performing ...exome sequencing, we discovered a novel heterozygous variant in SYNGAP1 (c.509 + 1G > A) in a 4-year-old ethnic Chinese boy with ID and ASD but without seizures or malformation.
The c.509 + 1G > A mutation in the SYNGAP1 gene was present in a patient with MRD5.
α-Thalassemia (α-thal) is one of the most common genetic diseases in Southern China. Although more than 300 α-thal mutations have been reported in the world, the mutation spectrum is still not ...comprehensive. In this study, a novel mutation (HBA1: c.349G>T) in a newborn (proband) was first found by next-generation sequencing (NGS). Subsequently, hematological analysis and thalassemia genetic testing were performed for the family members. The results showed that both the proband and her mother were heterozygotes for this novel mutation and presented abnormal hematological indices. Based on the features observed in clinical practice, this novel mutation was considered as a type of α-thal variation.
PTEN is post-translationally modified by ubiquitin via association with multiple E3 ubiquitin ligases, including NEDD4-1, XIAP, and WWP2. Despite the rapid progress made in researching the impact of ...ubiquitination on PTEN function, our understanding remains fragmented. Building on the previously observed interaction between SIPL1 and PTEN, we report here that SIPL1 promotes PTEN polyubiquitination via lysine 48 (K48)-independent polyubiquitin chains. Substitution of the K48 residue of ubiquitin with arginine (R) enhanced SIPL1-mediated PTEN polyubiquitination. In contrast, the K63R substitution significantly reduced it. The ubiquitin-like (UBL) domain is required for SIPL1-induced PTEN polyubiquitination. This post-translational modification promoted the association of SIPL1 with PTEN. Elevated amounts of the SIPL1/PTEN complex were precipitated in 293T cells co-transfected with PTEN, SIPL1, and ubiquitin compared to cells co-transfected with SIPL1 and PTEN only. Additionally, formation of the SIPL1/PTEN complex was inhibited when either lysine-less (K0) ubiquitin or K63R ubiquitin was co-transfected together with SIPL1+PTEN. The PTEN component in the SIPL1/PTEN complex contained polyubiquitin chains. The ubiquitination reaction may play a structural role, stabilizing the SIPL1/PTEN complex, as a ubiquitin binding-defective SIPL1 mutant (TFLV) is proficient in PTEN association. Collectively, we demonstrate that SIPL1 binds PTEN and enhances PTEN polyubiquitination which in turn promotes the interaction between SIPL1 and PTEN.
•SIPL1 induces PTEN polyubiquitination.•Lysine 63 (K63) but not K48 of ubiquitin is critical for PTEN polyubiquitination.•SIPL1 induces PTEN polyubiquitination via binding both PTEN and ubiquitin.•Polyubiquitination of PTEN does not cause PTEN degradation.•PTEN polyubiquitination promotes its association with SIPL1.
Cerebral palsy (CP) is a unique neurological disorder which adversely affects motion. Cytokines and gut microbial composition contribute to CP and other diseases, such as reproductive tract ...inflammation and bone loss. Importantly,
(
) reduces the degree of inflammation and improves overall health status. As our previous study showed that
(
) OF44, a selected strain of gut bacteria originally used to treat reproductive tract inflammation and bone loss, has effects similar to that of
, we decided to use
OF44 on CP rats. Validation of the effects of
OF44 on CP adds to its confirmed effects in treating osteoporosis and reproductive tract microbiota disorders, increasing its potential as a probiotic. The purpose of this was to ascertain whether
OF44 can alleviate the symptoms of CP.
CP rat models were created through left carotid artery ligation. Following this, 100-day old CP rats were exposed to
OF44,
, or normal saline gastric gavage daily for 28 days. Grouping of the rats is determined randomly. Before and after the gavage, behavioral experiments were conducted and the inflammation levels assessed via measurements of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) inflammatory markers. The efficacy of the outcome is measured by performing statistical analysis like the
-test on the data to see its significance. Additionally, variations inside gut microbiome were evaluated via 16S ribosomal RNA sequencing.
Before intervention, CP rats failed to exhibit depression-like behavior (P=0.6).
OF44 treatment significantly reduced the level of IL-6 (P=4.8e-05),
treatment significantly reduced the level of TNF-α (P=0.04). In addition, both treatments altered the composition and complexity of the gut microbiome.
Our results indicated that
OF44 has potential in alleviating inflammation and altering the gut microbial composition in CP, and that it has the potential to clinically treat CP. There are some limitations of this study. For example, dietary differences and their effects on gastrointestinal dysfunction are not considered in this study, and only two behavioral experiments were used.
Prostate cancer metastasis is the main cause of disease-related mortality. Elucidating the mechanisms underlying prostate cancer metastasis is critical for effective therapeutic intervention. In this ...study, we performed gene-expression profiling of prostate cancer stem-like cells (PCSC) derived from DU145 human prostate cancer cells to identify factors involved in metastatic progression. Our studies revealed contactin 1 (CNTN1), a neural cell adhesion protein, to be a prostate cancer-promoting factor. CNTN1 knockdown reduced PCSC-mediated tumor initiation, whereas CNTN1 overexpression enhanced prostate cancer cell invasion in vitro and promoted xenograft tumor formation and lung metastasis in vivo. In addition, CNTN1 overexpression in DU145 cells and corresponding xenograft tumors resulted in elevated AKT activation and reduced E-cadherin (CDH1) expression. CNTN1 expression was not readily detected in normal prostate glands, but was clearly evident on prostate cancer cells in primary tumors and lymph node and bone metastases. Tumors from 637 patients expressing CNTN1 were associated with prostate cancer progression and worse biochemical recurrence-free survival following radical prostatectomy (P < 0.05). Collectively, our findings demonstrate that CNTN1 promotes prostate cancer progression and metastasis, prompting further investigation into the mechanisms that enable neural proteins to become aberrantly expressed in non-neural malignancies.
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