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- Deng, CF, et al.
(author)
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Association between maternal smoke exposure and congenital heart defects from a case-control study in China
- 2022
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 14973-
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Journal article (peer-reviewed)abstract
- There is a gap in knowledge how maternal exposure to environmental tobacco smoke (ETS) is associated with offspring congenital heart defects (CHDs). In this case–control study, we collected data on 749 fetuses with CHDs and 880 fetuses without any congenital anomalies to examine the association of maternal ETS with fetal CHDs and the potentially moderating effect by maternal hazardous and noxious substances (HNS), periconceptional folate intake and paternal smoking. Maternal exposure to ETS in first trimester was associated with increased risk of CHDs in a dose–response gradient, with the AORs (95% CI) were1.38 (1.00–1.92), 1.60 (1.07–2.41), and 4.94 (2.43–10.05) for ETS < 1 h/day, 1–2 h/day, and ≥ 2 h/day, respectively. With the doubly unexposed group as reference categories, AORs for maternal ETS exposure ≥ 2 h/day in the absence of folate intake, in the presence of HNS exposure or paternal smoking, were 7.21, 11.43, and 8.83, respectively. Significant additive interaction between ETS exposure and maternal folate intake on CHDs was detected. Maternal ETS exposure during first trimester may increase the risk of offspring CHDs in a dose–response shape, and such effect may be modified by maternal folate intake or other potential factors.
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- He, YQ, et al.
(author)
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A polygenic risk score for nasopharyngeal carcinoma shows potential for risk stratification and personalized screening
- 2022
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 1966-
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Journal article (peer-reviewed)abstract
- Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10−7 to 4.79 × 10−44). By incorporating the PRS into EBV-serology-based NPC screening, the test’s positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.
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- Li, XB, et al.
(author)
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Novel TCF21high pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix
- 2023
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 72:4, s. 710-721
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Journal article (peer-reviewed)abstract
- Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis.DesignTPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 onTCF21DNA hypermethylation. Pericyte-conditionalTcf21-knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling.ResultsThirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21highTPCs, termed ‘matrix–pericytes’, was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM).Tcf21depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21highTPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impairTCF21DNA hypermethylation in TCF21highTPCs.ConclusionThis study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.
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- Lu, WS, et al.
(author)
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PDGFD switches on stem cell endothelial commitment
- 2022
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In: Angiogenesis. - : Springer Science and Business Media LLC. - 1573-7209 .- 0969-6970. ; 25:4, s. 517-533
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Journal article (peer-reviewed)abstract
- The critical factors regulating stem cell endothelial commitment and renewal remain not well understood. Here, using loss- and gain-of-function assays together with bioinformatic analysis and multiple model systems, we show that PDGFD is an essential factor that switches on endothelial commitment of embryonic stem cells (ESCs). PDGFD genetic deletion or knockdown inhibits ESC differentiation into EC lineage and increases ESC self-renewal, and PDGFD overexpression activates ESC differentiation towards ECs. RNA sequencing reveals a critical requirement of PDGFD for the expression of vascular-differentiation related genes in ESCs. Importantly, PDGFD genetic deletion or knockdown increases ESC self-renewal and decreases blood vessel densities in both embryonic and neonatal mice and in teratomas. Mechanistically, we reveal that PDGFD fulfills this function via the MAPK/ERK pathway. Our findings provide new insight of PDGFD as a novel regulator of ESC fate determination, and suggest therapeutic implications of modulating PDGFD activity in stem cell therapy.
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