| 1. |
- Ablikim, M., et al.
(författare)
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Measurements of (XcJ)-> K+K-K+K- decays
- 2006
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 642:3, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- Using 14M psi(2S) events taken with the BESII detector, chi(cJ) -> 2(K+K-) decays are studied. For the four-kaon final state, the branching fractions are B(chi(c0,1,2) ->.2(K+K-)) = (3.48 +/- 0.23 +/- 0.47) x 10(-3), (0.70 +/- 0.13 +/- 0.10) x 10(-3), and (2.17 +/- 0.20 +/- 0.31) x 10(-3). For the phi K+K- final state, the branching fractions, which are measured for the first time, are B(chi(c0,1,2) -> phi K+K-) = (1.03 +/- 0.22 +/- 0.15) x 10(-3), (0.46 +/- 0.16 +/- 0.06) x 10(-3), and (1.67 +/- 0.26 +/- 0.24) x 10(-4). For the phi phi final state, B(chi(c0,2) -> phi phi) = (0.94 +/- 0.21 +/- 0.13) x 10(-3) and (1.70 +/- 0.30 +/- 0.25) x 10(-3).
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| 2. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 3. |
- Albrechtsen, A., et al.
(författare)
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Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 56:2, s. 298-310
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Tidskriftsartikel (refereegranskat)abstract
- Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
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| 4. |
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| 5. |
- Yang, X. M., et al.
(författare)
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Overexpression of Rac GTPase Activating Protein 1 Contributes to Proliferation of Cancer Cells by Reducing Hippo Signaling to Promote Cytokinesis
- 2018
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085. ; 155:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma (HCC) cells and might be targeted to slow liver tumor growth. METHODS: Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using gene ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that are associated with patient survival times. Candidate genes were overexpressed or knocked down with small hairpin RNAs in SMMC7721, MHCC97H, or HCCLM3 cell lines; we analyzed their proliferation, viability, and clone-formation ability and their growth as subcutaneous or orthotopic xenograft tumors in mice. We performed microarray analyses to identify alterations in signaling pathways and immunoblot and immunofluorescence assays to detect and localize proteins in tissues. Yeast 2-hybrid screens and mass spectrometry combined with co-immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation and proximity ligation assays. Chromatin immunoprecipitation, promoter luciferase activity, and quantitative real-time polymerase chain reaction analyses were used to identify factors that regulate transcription of specific genes. RESULTS: The genes that were most frequently overexpressed in different types of cancer cells were involved in cell division processes. We identified 3 cytokinesis-regulatory proteins among the 10 genes most frequently overexpressed by all cancer cell types. Rac GTPase activating protein 1 (RACGAP1) was the cytokinesis-regulatory protein that was most highly overexpressed in multiple cancers. Increased expression of RACGAP1 in tumor tissues was associated with shorter survival times of patients with cancer. Knockdown of RACGAP1 in HCC cells induced cytokinesis failure and cell apoptosis. In microarray analyses, we found knockdown of RACGAP1 in SMMC7721 cells to reduce expression of genes regulated by yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1 or TAZ). RACGAP1 reduced activation of the Hippo pathway in HCC cells by increasing activity of RhoA and polymerization of filamentous actin. Knockdown of YAP reduced phosphorylation of RACGAP1 and redistribution at the anaphase central spindle. We found transcription of the translocated promoter region, nuclear basket protein (TPR) to be regulated by YAP and coordinately expressed with RACGAP1 to promote proliferation of HCC cells. TPR redistributed upon nuclear envelope breakdown and formed complexes with RACGAP1 during mitosis. Knockdown of TPR in HCC cells reduced phosphorylation of RACGAP1 by aurora kinase B and impaired their redistribution at the central spindle during cytokinesis. STAT3 activated transcription of RACGAP in HCC cells. CONCLUSIONS: In an analysis of gene expression patterns of multiple tumor types, we found RACGAP1 to be frequently overexpressed, which is associated with shorter survival times of patients. RACGAP1 promotes proliferation of HCC cells by reducing activation of the Hippo and YAP pathways and promoting cytokinesis in coordination with TPR.
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| 6. |
- Mishra, A, et al.
(författare)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Tidskriftsartikel (refereegranskat)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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| 7. |
- Nie, M, et al.
(författare)
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PD-1/PD-L Pathway Potentially Involved in ITP Immunopathogenesis
- 2019
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Ingår i: Thrombosis and haemostasis. - : Georg Thieme Verlag KG. - 2567-689X .- 0340-6245. ; 119:5, s. 758-765
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Tidskriftsartikel (refereegranskat)abstract
- The binding of programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2 on antigen-presenting cells turns off autoreactive T cells and induces peripheral tolerance. Aberrant PD-1/PD-L signalling could result in a breakdown of peripheral tolerance and lead to autoimmune diseases. In this study, we detected PD-1 and PD-L expression on T cells and dendritic cells (DCs) in immune thrombocytopenia (ITP) patients with active disease by flow cytometry. The effects of PD-L1-Fc fusion protein (PD-L1-Fc) on T cells and on secretion of interferon-γ (IFN-γ) and interleukin-2 (IL-2) were detected by flow cytometry and enzyme-linked immunosorbent assay, respectively. Compared with healthy controls, PD-1 expression was significantly increased in CD4+ T cells and CD8+ T cells from patients with active ITP. However, PD-L1 expression on monocyte-derived DCs was lower in patients with active ITP than in healthy controls. In vitro assays revealed that PD-L1-Fc increased T cell apoptosis, inhibited activation and proliferation of CD4+ T cells and CD8+ T cells and decreased IFN-γ and IL-2 secretion in patients with active ITP. These results suggest that the aberrant PD-1/PD-L negative co-stimulatory pathway may play a role in ITP. Enhancing PD-1/PD-L signalling might be a promising therapeutic approach for ITP patients by enhancing T cell apoptosis, inhibiting T cell activation and proliferation and reducing secretion of inflammatory factors.
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| 8. |
- Ren, WC, et al.
(författare)
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Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma
- 2018
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 131:24, s. 2670-2681
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.
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| 9. |
- Wang, Y., et al.
(författare)
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Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial
- 2020
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants. Methods: The study was a prospective randomized clinical trial performed among four NICU centers. A total of 1327 preterm infants with gestational age <= 32 weeks were admitted to the centers, and 42 infants were excluded leaving 1285 eligible infants to be randomized to the rhEPO or control group. Infants in the rhEPO group were given 500 IU/kg rhEPO intravenously every other day for 2 weeks, while the control group was given the same volume of saline. The primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age. Results: A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Meanwhile, rhEPO treatment significantly reduced the number of red blood cells transfusion in the confirmed NEC cases (1.2 +/- 0.4 vs. 2.7 +/- 1.0, p = 0.004). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of confirmed NEC at gestational age < 28 weeks (p = 0.019), and the incidence of all stages NEC in preterm infants with hemoglobin < 90 g/l (p = 0.000) and 5 min Apgar score > 5 (p = 0.028). Conclusion: Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants.
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| 10. |
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