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- He, YQ, et al.
(författare)
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A polygenic risk score for nasopharyngeal carcinoma shows potential for risk stratification and personalized screening
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 1966-
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Tidskriftsartikel (refereegranskat)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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- Lin, J, et al.
(författare)
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Oncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1, s. 224-
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Tidskriftsartikel (refereegranskat)abstract
- The advantage of oncolytic viruses (OV) in cancer therapy is their dual effect of directly killing tumours while prompting anti-tumour immune response. Oncolytic parapoxvirus ovis (ORFV) and other OVs are thought to induce apoptosis, but apoptosis, being the immunogenically inert compared to other types of cell death, does not explain the highly inflamed microenvironment in OV-challenged tumors. Here we show that ORFV and its recombinant therapeutic derivatives are able to trigger tumor cell pyroptosis via Gasdermin E (GSDME). This effect is especially prominent in GSDME-low tumor cells, in which ORFV-challenge pre-stabilizes GSDME by decreasing its ubiquitination and subsequently initiates pyroptosis. Consistently, GSDME depletion reduces the proportion of intratumoral cytotoxic T lymphocytes, pyroptotic cell death and the success of tumor ORFV virotherapy. In vivo, the OV preferentially accumulates in the tumour upon systemic delivery and elicits pyroptotic tumor killing. Consequentially, ORFV sensitizes immunologically ‘cold’ tumors to checkpoint blockade. This study thus highlights the critical role of GSDME-mediated pyroptosis in oncolytic ORFV-based antitumor immunity and identifies combinatorial cancer therapy strategies.
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- Li, Jian, et al.
(författare)
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A new indicator for a fair comparison on the energy performance of data centers
- 2020
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Ingår i: Applied Energy. - Oxford : Elsevier Ltd. - 0306-2619 .- 1872-9118. ; 276
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Tidskriftsartikel (refereegranskat)abstract
- The power usage effectiveness (PUE) is commonly used as the key performance indicator to evaluate the energy performance of data centers. However, using only PUE cannot enable a fair comparison when data centers are operating in different regions, due to the unneglectable impacts of climatic conditions on the power consumption of cooling systems. To solve this problem, a new indicator, coefficient of PUE (COPUE), is proposed, which is defined as the ratio of the measured PUE of real data centers to the local benchmark PUE. The benchmark PUE is reckoned based on the current most commonly used cooling technology, which consists of water-cooled chillers and water cooling towers. A simplified method for calculating benchmark PUE is also developed. The degree hour of water cooling is introduced to consider the impacts of local climatic conditions. It presents the annual accumulated hours, in which chilled water is needed to satisfy the cooling demand of data centers. Through several case studies, COPUE has been proved to be an effective indicator for comparing the energy performance of data centers. When the same cooling technology is adopted, it can reflect how good the design and operation are; while, when different cooling technologies are adopted, it can be used to demonstrate which one is superior.
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- Li, XB, et al.
(författare)
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Novel TCF21high pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix
- 2023
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 72:4, s. 710-721
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Tidskriftsartikel (refereegranskat)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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- Gao, R, et al.
(författare)
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Resetting histone modifications during human prenatal germline development
- 2023
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Ingår i: Cell discovery. - : Springer Science and Business Media LLC. - 2056-5968. ; 9:1, s. 14-
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Tidskriftsartikel (refereegranskat)abstract
- Histone modifications play critical roles in regulating gene expression and present dynamic changes during early embryo development. However, how they are reprogrammed during human prenatal germline development has not yet been elucidated. Here, we map the genome-wide profiles of three key histone modifications in human primordial germ cells (hPGCs) from weeks 8 to 23 of gestation for the first time by performing ULI-NChIP-seq. Notably, H3K4me3 exhibits a canonical promoter-enriched pattern, though with relatively lower enrichment, and is positively correlated with gene expression in globally hypomethylated hPGCs. In addition, H3K27me3 presents very low enrichment but plays an important role in not only dynamically governing specific bivalent promoters but also impeding complete X chromosome reactivation in female hPGCs. Given the activation effects of both global DNA demethylation and H3K4me3 signals, repressive H3K9me3 and H3K27me3 marks are jointly responsible for the paradoxical regulation of demethylation-resistant regions in hPGCs. Collectively, our results provide a unique roadmap of three core histone modifications during hPGC development, which helps to elucidate the architecture of germ cell reprogramming in an extremely hypomethylated DNA environment.
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- Park, J, et al.
(författare)
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Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
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- Zhang, L, et al.
(författare)
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Using human genetics to understand the epidemiological association between obesity, serum urate, and gout
- 2023
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 62:10, s. 3280-3290
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesWe aimed to clarify the genetic overlaps underlying obesity-related traits, serum urate, and gout.MethodsWe conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci, and causal relationships between obesity (the exposure variable), gout (the primary outcome) and serum urate (the secondary outcome). Summary statistics were collected from the hitherto largest genome-wide association studies conducted for BMI (N = 806 834), waist-to-hip ratio (WHR; N = 697 734), WHR adjusted for BMI (WHRadjBMI; N = 694 649), serum urate (N = 288 649), and gout (Ncases = 13 179 and Ncontrols = 750 634).ResultsPositive overall genetic correlations were observed for BMI (rg = 0.27, P = 6.62 × 10−7), WHR (rg = 0.22, P = 6.26 × 10−7) and WHRadjBMI (rg = 0.07, P = 6.08 × 10−3) with gout. Partitioning the whole genome into 1703 LD (linkage disequilibrium)-independent regions, a significant local signal at 4q22 was identified for BMI and gout. The global and local shared genetic basis was further strengthened by the multiple pleiotropic loci identified in the cross-phenotype association study, multiple shared gene–tissue pairs observed by Transcriptome-wide association studies, as well as causal relationships demonstrated by Mendelian randomization [BMI–gout: OR (odds ratio) = 1.66, 95% CI = 1.45, 1.88; WHR–gout: OR = 1.57, 95% CI = 1.37, 1.81]. Replacing the binary disease status of gout with its latent pathological measure, serum urate, a similar pattern of correlation, pleiotropy and causality was observed with even more pronounced magnitude and significance.ConclusionOur comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis and pleiotropic loci, as well as a causal relationship between obesity, serum urate, and gout, highlighting an intrinsic link underlying these complex traits.
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- Zhang, XQ, et al.
(författare)
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Serum Lysyl Oxidase Is a Potential Diagnostic Biomarker for Kidney Fibrosis
- 2020
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 51:11, s. 907-918
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Kidney fibrosis is the ultimate consequence of advanced stages of chronic kidney disease (CKD); however, there are currently no reliable biomarkers or noninvasive diagnostic tests available for the detection of kidney fibrosis. Lysyl oxidase (LOX) promotes collagen cross-linking, and serum LOX levels have been shown to be elevated in patients with fibrosis of the heart, lungs, and liver. However, serum LOX levels have not been reported in patients with kidney fibrosis. We explored whether serum LOX levels are associated with kidney fibrosis. <b><i>Method:</i></b> Overall, 202 patients with kidney disease underwent renal biopsy, scoring of kidney fibrosis, and determination of the area of kidney fibrosis. LOX levels were measured in serum and in kidney tissues. We analyzed the association of circulating LOX and tissue LOX levels with the scores and areas of kidney fibrosis. LOX expression was also investigated with in vitro and in vivo kidney fibrosis models. <b><i>Results:</i></b> Serum LOX levels were higher in patients with kidney fibrosis than in those without kidney fibrosis (<i>p</i> < 0.001) and higher in patients with moderate-severe kidney fibrosis than in patients with mild kidney fibrosis (<i>p</i> < 0.001). Both serum LOX and renal tissue LOX levels correlated with the area of kidney fibrosis (<i>r</i> = 0.748, <i>p</i> < 0.001; <i>r</i> = 0.899, <i>p</i> < 0.001, respectively). Receiver operating characteristic curve analysis of serum LOX levels showed an area under the curve of 0.80 (95% CI: 0.74–0.86). The optimal serum LOX level cutoff point was 253.34 pg/mL for the prediction of kidney fibrosis and 306.56 pg/mL for the prediction of moderate-severe kidney fibrosis. LOX expression levels were significantly upregulated (2.3–2.6 and 6-fold, respectively) in in vitro and in vivo interstitial fibrosis models. <b><i>Conclusions:</i></b> Both serum LOX and tissue LOX levels correlated with the presence and degree of kidney fibrosis in patients with CKD. These results suggest that serum LOX levels could potentially serve as a noninvasive diagnostic biomarker for kidney fibrosis and may further potentially serve as a stratified biomarker for the identification of mild and moderate-severe kidney fibrosis.
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