| 1. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)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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| 2. |
- Munk, P., et al.
(author)
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Genomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Antimicrobial resistance (AMR) is a major threat to global health. Understanding the emergence, evolution, and transmission of individual antibiotic resistance genes (ARGs) is essential to develop sustainable strategies combatting this threat. Here, we use metagenomic sequencing to analyse ARGs in 757 sewage samples from 243 cities in 101 countries, collected from 2016 to 2019. We find regional patterns in resistomes, and these differ between subsets corresponding to drug classes and are partly driven by taxonomic variation. The genetic environments of 49 common ARGs are highly diverse, with most common ARGs carried by multiple distinct genomic contexts globally and sometimes on plasmids. Analysis of flanking sequence revealed ARG-specific patterns of dispersal limitation and global transmission. Our data furthermore suggest certain geographies are more prone to transmission events and should receive additional attention.
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| 3. |
- Tang, Ting-Ting, et al.
(author)
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Impaired thymic export and apoptosis contribute to regulatory T-cell defects in patients with chronic heart failure.
- 2011
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 6:9, s. e24272-
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Journal article (peer-reviewed)abstract
- Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients.
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| 4. |
- Ao, Hong, et al.
(author)
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Orbital climate variability on the northeastern Tibetan Plateau across the Eocene-Oligocene transition
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- The first major build-up of Antarctic glaciation occurred in two consecutive stages across the Eocene-Oligocene transition (EOT): the EOT-1 cooling event at similar to 34.1-33.9Ma and the Oi-1 glaciation event at similar to 33.8-33.6Ma. Detailed orbital-scale terrestrial environmental responses to these events remain poorly known. Here we present magnetic and geochemical climate records from the northeastern Tibetan Plateau margin that are dated precisely from similar to 35.5 to 31Ma by combined magneto- and astro-chronology. These records suggest a hydroclimate transition at similar to 33.7Ma from eccentricity dominated cycles to oscillations paced by a combination of eccentricity, obliquity, and precession, and confirm that major Asian aridification and cooling occurred at Oi-1. We conclude that this terrestrial orbital response transition coincided with a similar transition in the marine benthic delta O-18 record for global ice volume and deep-sea temperature variations. The dramatic reorganization of the Asian climate system coincident with Oi-1 was, thus, a response to coeval atmospheric CO2 decline and continental-scale Antarctic glaciation. Marine records indicate a greenhouse to icehouse climate transition at similar to 34 million years ago, but how the climate changed within continental interiors at this time is less well known. Here, the authors show an orbital climate response shift with aridification on the northeastern Tibetan Plateau during this time.
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| 5. |
- Bar, N., et al.
(author)
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A reference map of potential determinants for the human serum metabolome
- 2020
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In: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Journal article (peer-reviewed)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 6. |
- Bettegowda, Chetan, et al.
(author)
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Detection of circulating tumor DNA in early- and late-stage human malignancies
- 2014
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:224, s. 224ra24-
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Journal article (peer-reviewed)abstract
- The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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| 7. |
- Grauers, Anna, et al.
(author)
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Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis
- 2015
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In: The Spine Journal. - Stockholm : Karolinska Institutet, Dept of Clinical Science, Intervention and Technology. - 1529-9430 .- 1878-1632.
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Journal article (peer-reviewed)abstract
- Background: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. Purpose: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. Study design: This was a case control study. Patient sample: A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. Outcome measure: The outcome measure was idiopathic scoliosis. Methods: The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5′UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. Results: Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10−18). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5′UTR, noncoding exon and promoter regions of LBX1. Conclusions: Here, we confirm LBX1 as a susceptibility gene for idiopathic scoliosis in a Scandinavian population and report that we are unable to find evidence of other genes of similar or stronger effect.
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| 8. |
- Jiao, Guan-Sheng, et al.
(author)
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Syntheses and spectroscopic properties of energy transfer systems based on squaraines
- 2003
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In: Tetrahedron. ; 59:17, s. 3109-16
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Journal article (peer-reviewed)abstract
- The purpose of this project was to prepare fluorescent dyes that could absorb energy at relatively short wavelengths, and fluoresce in the near-IR region. To achieve this, copper- and palladium-mediated C–N couplings were used to prepare the ‘cassettes’, i.e the carbazole derivative 3b and the carbazole-, phenothiazine-, and phenoazine-squaraines 4b–d. These compounds have carbazole, phenothiazine, and phenoazine donor-components that absorb around about 300–320 nm, and squaraine acceptor-parts that fluoresce in the range 650–700 nm. The efficiencies of energy transfer from the donor to the acceptor, and the overall quantum yields of the cassettes were determined.
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| 9. |
- Jiao, Hong, et al.
(author)
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Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity
- 2011
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 96:6, s. E962-E966
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Journal article (peer-reviewed)abstract
- Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. Setting: General community and referral centers for specialized care was the setting for the study. Participants: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. Main Outcome Measures: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. Results: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 x 10(-6), which was P = 7.0 x 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). Conclusions: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.
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| 10. |
- Jiao, Hong
(author)
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Genetic dissection of multifactorial disease models in the rat
- 2002
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Doctoral thesis (other academic/artistic)abstract
- Type 2 diabetes (T2D) is characterized by two apparently distinct pathophysiologic defects - insulin resistance and a failure of the pancreatic Beta-cells to compensate for this resistance by appropriately increasing insulin secretion. There is strong evidence for an important role of genetics in both of these components. However identifying the genes responsible for the development of the disease has proven problematic because of complex background. Linkage analysis using the Goto-Kakizaki (GK) rat, a well-established genetic model for T2D, provides an ideal tool for understanding the pathogenesis of the disease by highlighting the chromosomal regions, which might harbor candidate diabetogenes. Furthermore by creating reciprocal crosses or changing environmental conditions, the effects of parent-of-origin or environmental factors on the manifestation of a quantitative trait locus (QTL) can be elucidated at the genome-wide level. We have successively created three cohorts of F2 intercrosses of GK and F344 rats, founded by either GK grandmothers (F2GK) or grandfathers (F2F344). Parental, F 1, and F2 rats underwent a number of phenotypic assays i.e. intraperitoneal glucose tolerance test (IPGTT) with measurement of glucose, insulin and body weight. The first genome-wide scan with 253 markers revealed three glucose-related loci, Niddm I (LOD 11), Niddm2 (LOD 4.5) and Niddm3 (LOD 4.6), and one locus, Weight1 (LOD 6.2), for body weight on chromosomes 1, 2, 10, and 7 respectively, supporting the polygenic inheritance pattern of T2D in the GK rat. Furthermore clearly different models of inheritance for hyperglycemia at baseline vs. during the IPGTT were demonstrated, implicating different regulatory mechanisms at these two states. In this study paternal inheritance of diabetes of the GK rat was observed, in that GK fathers conferred significantly higher glucose and insulin levels in the IPGTT than GK mothers in the F I progeny. By comparison of linkage analyses between two reciprocal crosses, four major parent-of-origin-specific QTLs were uncovered, implicating potential importance of mitochondrial and/or epigenetic effects in the GK rat. Niddm4, a major locus on chromosome 9 affected fasting insulin paternally (LOD 6.9 in F2F344 rats vs. 0.66 in F2GK rats). The locus also exerted a significant maternal-specific effect on glucose-induced insulin levels at 120 min, thus showing dual characteristics. In this study we exhibited a distinct distribution pattern of QTLs in two reciprocal crosses, which indicated that genetic susceptibility genes to T2D might be fixed in the GK rat, but their effects were expressed in a manner that depends on the parent-of-origin. We also elucidated the additive and epistatic effects of QTLs. Mitochondrial genomes of the GK and F344 rats have been sequenced and the resulting sequences were checked against the published rat mtDNA sequence. In total 31 sequence variants were found in the GK rat as compared to the sequence of the F344 rat. We uncovered seven gender-influenced QTLs giving strong evidence for linkage on chromosomes 1, 2, 5, 7, 10, and 18 in GK and F344 crosses. By analyzing the gene-gene interaction conditionally on gender effect, eleven locus-pairs showing epistatic interaction (p-value less than 0.0001) were identified to contribute to diabetic susceptibility in the F2 progeny. Using the same approach in the study of experimental autoimmune neuritis (EAN) in rats, a model of GuillainBarré syndrome (GBS), a new region showing linkage to EAN phenotypes was found on chromosome 17. This locus showed strong evidence for linkage in affected rats vs. weak linkage in unaffected rats. Moreover the linkage to serum levels of anti-peripheral nerve myelin (anti-PNM) IgG2b and IgGI was much stronger in the cross with a Dark Agouti (DA) female founder and among male rats respectively. A good linkage map with high accuracy and resolution is essential for a successful QTL mapping. Therefore we completed a linkage map of GK and F344 crosses based on a large number of meiosis (564 rats). The map consists of 530 markers and spans the entire rat genome in a total length of 1826.9 cM with an average interval of 3.4 cM. Subsequently based on the linkage map an integration of 7 linkage and 2 radiation hybrid maps of the rat was created. The integration provides reference to 8627 rat genetic markers. Among them there are more than 550 genes with homology information in human and mouse indicated. In conclusion, by using the GK rat as a diabetic model we have demonstrated the complex genetics of T2D even in an inbred strain. In additional to the polygenic inheritance, effects of susceptibility genes were found to manifest conditionally, e.g. to depend on gender or parental origin, to respond to environment, or to interact with other genes. Our results provide an annotation on the genetics of TEND with detailed information and a platform to a further molecular and cellular analysis.
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