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| 4. |
- Munn-Chernoff, M. A., et al.
(author)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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In: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Journal article (peer-reviewed)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 5. |
- Abdallah, J., et al.
(author)
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Mechanical construction and installation of the ATLAS tile calorimeter
- 2013
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In: Journal of Instrumentation. - 1748-0221. ; 8, s. T11001-
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Journal article (peer-reviewed)abstract
- This paper summarises the mechanical construction and installation of the Tile Calorimeter for the ATLAS experiment at the Large Hadron Collider in CERN, Switzerland. The Tile Calorimeter is a sampling calorimeter using scintillator as the sensitive detector and steel as the absorber and covers the central region of the ATLAS experiment up to pseudorapidities +/- 1.7. The mechanical construction of the Tile Calorimeter occurred over a period of about 10 years beginning in 1995 with the completion of the Technical Design Report and ending in 2006 with the installation of the final module in the ATLAS cavern. During this period approximately 2600 metric tons of steel were transformed into a laminated structure to form the absorber of the sampling calorimeter. Following instrumentation and testing, which is described elsewhere, the modules were installed in the ATLAS cavern with a remarkable accuracy for a structure of this size and weight.
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| 7. |
- Appeltans, W., et al.
(author)
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The Magnitude of Global Marine Species Diversity
- 2012
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In: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 22:23, s. 2189-2202
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Journal article (peer-reviewed)abstract
- Background: The question of how many marine species exist is important because it provides a metric for how much we do and do not know about life in the oceans. We have compiled the first register of the marine species of the world and used this baseline to estimate how many more species, partitioned among all major eukaryotic groups, may be discovered. Results: There are similar to 226,000 eukaryotic marine species described. More species were described in the past decade (similar to 20,000) than in any previous one. The number of authors describing new species has been increasing at a faster rate than the number of new species described in the past six decades. We report that there are similar to 170,000 synonyms, that 58,000-72,000 species are collected but not yet described, and that 482,000-741,000 more species have yet to be sampled. Molecular methods may add tens of thousands of cryptic species. Thus, there may be 0.7-1.0 million marine species. Past rates of description of new species indicate there may be 0.5 +/- 0.2 million marine species. On average 37% (median 31%) of species in over 100 recent field studies around the world might be new to science. Conclusions: Currently, between one-third and two-thirds of marine species may be undescribed, and previous estimates of there being well over one million marine species appear highly unlikely. More species than ever before are being described annually by an increasing number of authors. If the current trend continues, most species will be discovered this century.
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| 8. |
- van Bragt, JJMH, et al.
(author)
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Characteristics and treatment regimens across ERS SHARP severe asthma registries
- 2020
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 55:1
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Journal article (peer-reviewed)abstract
- Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
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| 11. |
- Ip, H. F., et al.
(author)
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Genetic association study of childhood aggression across raters, instruments, and age
- 2021
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Journal article (peer-reviewed)abstract
- Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGG(overall). The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from r(g)= 0.46 between self- and teacher-assessment to r(g)d= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range r(g): 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r(g)=-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |r(g)| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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| 12. |
- Izadi, Z., et al.
(author)
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Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19
- 2021
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In: Jama Network Open. - : American Medical Association (AMA). - 2574-3805. ; 4:10
-
Journal article (peer-reviewed)abstract
- IMPORTANCE Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. OBJECTIVE To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. DESIGN, SETTING, AND PARTICIPANTS This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age >= 18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. EXPOSURES Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. MAIN OUTCOMES AND MEASURES The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. RESULTS A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P < .001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P = .004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P = .33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. CONCLUSIONS AND RELEVANCE In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs.
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| 15. |
- Clark, Andrew G., et al.
(author)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Journal article (peer-reviewed)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 16. |
- Campbell, Brittany B., et al.
(author)
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Comprehensive Analysis of Hypermutation in Human Cancer
- 2017
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In: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 171:5
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Journal article (peer-reviewed)abstract
- © 2017 Elsevier Inc. We present an extensive assessment of mutation burden through sequencing analysis of > 81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.
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| 17. |
- Düsterer, S., et al.
(author)
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Angle resolved photoelectron spectroscopy of two-color XUV-NIR ionization with polarization control
- 2016
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In: Journal of Physics B: Atomic, Molecular and Optical Physics. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 49:16
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Journal article (peer-reviewed)abstract
- Electron emission caused by extreme ultraviolet (XUV) radiation in the presence of a strong near infrared (NIR) field leads to multiphoton interactions that depend on several parameters. Here, a comprehensive study of the influence of the angle between the polarization directions of the NIR and XUV fields on the two-color angle-resolved photoelectron spectra of He and Ne is presented. The resulting photoelectron angular distribution strongly depends on the orientation of the NIR polarization plane with respect to that of the XUV field. The prevailing influence of the intense NIR field over the angular emission characteristics for He(1s) and Ne(2p) ionization lines is shown. The underlying processes are modeled in the frame of the strong field approximation (SFA) which shows very consistent agreement with the experiment reaffirming the power of the SFA for multicolor-multiphoton ionization in this regime.
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| 18. |
- Sparks, JA, et al.
(author)
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Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry
- 2021
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 80:9, s. 1137-1146
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Journal article (peer-reviewed)abstract
- To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA).MethodsWe analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders.ResultsOf 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity.ConclusionsPeople with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.
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| 19. |
- Costello, David M., et al.
(author)
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Global patterns and controls of nutrient immobilization on decomposing cellulose in riverine ecosystems
- 2022
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In: Global Biogeochemical Cycles. - : John Wiley & Sons. - 0886-6236 .- 1944-9224. ; 36:3
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Journal article (peer-reviewed)abstract
- Microbes play a critical role in plant litter decomposition and influence the fate of carbon in rivers and riparian zones. When decomposing low-nutrient plant litter, microbes acquire nitrogen (N) and phosphorus (P) from the environment (i.e., nutrient immobilization), and this process is potentially sensitive to nutrient loading and changing climate. Nonetheless, environmental controls on immobilization are poorly understood because rates are also influenced by plant litter chemistry, which is coupled to the same environmental factors. Here we used a standardized, low-nutrient organic matter substrate (cotton strips) to quantify nutrient immobilization at 100 paired stream and riparian sites representing 11 biomes worldwide. Immobilization rates varied by three orders of magnitude, were greater in rivers than riparian zones, and were strongly correlated to decomposition rates. In rivers, P immobilization rates were controlled by surface water phosphate concentrations, but N immobilization rates were not related to inorganic N. The N:P of immobilized nutrients was tightly constrained to a molar ratio of 10:1 despite wide variation in surface water N:P. Immobilization rates were temperature-dependent in riparian zones but not related to temperature in rivers. However, in rivers nutrient supply ultimately controlled whether microbes could achieve the maximum expected decomposition rate at a given temperature. Collectively, we demonstrated that exogenous nutrient supply and immobilization are critical control points for decomposition of organic matter.
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| 20. |
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| 21. |
- Elander, N. O., et al.
(author)
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Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer
- 2018
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In: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 118:7, s. 947-954
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Journal article (peer-reviewed)abstract
- Background: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy.Methods: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA).Results: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009).Conclusion: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.
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| 22. |
- Elander, N. O., et al.
(author)
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Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy
- 2018
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In: British Journal of Cancer. - : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 118:8, s. 1084-1088
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Journal article (peer-reviewed)abstract
- BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma.METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups.RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group.CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.
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| 24. |
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| 26. |
- Liu, Y., et al.
(author)
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The minimum information required for a glycomics experiment (MIRAGE) project: improving the standards for reporting glycan microarray-based data
- 2017
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In: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 27:4, s. 280-284
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Journal article (peer-reviewed)abstract
- MIRAGE (Minimum Information Required for A Glycomics Experiment) is an initiative that was created by experts in the fields of glycobiology, glycoanalytics and glycoinformatics to produce guidelines for reporting results from the diverse types of experiments and analyses used in structural and functional studies of glycans in the scientific literature. As a sequel to the guidelines for sample preparation (Struwe et al. 2016, Glycobiology, 26: 907-910) and mass spectrometry data (Kolarich et al. 2013, Mol. Cell Proteomics, 12: 991-995), here we present the first version of guidelines intended to improve the standards for reporting data from glycan microarray analyses. For each of eight areas in the workflow of a glycan microarray experiment, we provide guidelines for the minimal information that should be provided in reporting results. We hope that the MIRAGE glycan microarray guidelines proposed here will gain broad acceptance by the community, and will facilitate interpretation and reproducibility of the glycan microarray results with implications in comparison of data from different laboratories and eventual deposition of glycan microarray data in international databases.
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| 27. |
- Rachakonda, P. Sivaramakrishna, et al.
(author)
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Somatic Mutations in Exocrine Pancreatic Tumors: Association with Patient Survival
- 2013
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Journal article (peer-reviewed)abstract
- KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95% CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95% CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95% CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application.
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| 28. |
- Saba, Luca, et al.
(author)
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Carotid plaque-RADS : a novel stroke risk classification system
- 2024
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In: JACC Cardiovascular Imaging. - : Elsevier. - 1936-878X .- 1876-7591. ; 17:1, s. 62-75
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Journal article (peer-reviewed)abstract
- Background: Carotid artery atherosclerosis is highly prevalent in the general population and is a well-established risk factor for acute ischemic stroke. Although the morphological characteristics of vulnerable plaques are well recognized, there is a lack of consensus in reporting and interpreting carotid plaque features.Objectives: The aim of this document is to establish a consistent and comprehensive approach for imaging and reporting carotid plaque by introducing the Plaque–Reporting and Data System (RADS) score.Methods: A panel of experts recognized the necessity to develop a classification system for carotid plaque and its defining characteristics. Using a multimodality analysis approach, the Plaque-RADS categories were established through consensus, drawing on existing published reports.Results: The authors present a universal classification that is applicable to both researchers and clinicians. The Plaque-RADS score offers a morphological assessment in addition to the prevailing quantitative parameter of “stenosis.” The Plaque-RADS score spans from grade 1 (indicating complete absence of plaque) to grade 4 (representing complicated plaque). Accompanying visual examples are included to facilitate a clear understanding of the Plaque-RADS categories.Conclusions: Plaque-RADS is a standardized and reliable system of reporting carotid plaque composition and morphology via different imaging modalities, such as ultrasound, computed tomography, and magnetic resonance imaging. This scoring system has the potential to help in the precise identification of patients who may benefit from exclusive medical intervention and those who require alternative treatments, thereby enhancing patient care. A standardized lexicon and structured reporting promise to enhance communication between radiologists, referring clinicians, and scientists.
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| 29. |
- York, W. S., et al.
(author)
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MIRAGE: The minimum information required for a glycomics experiment
- 2014
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In: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 24:5, s. 402-406
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Journal article (peer-reviewed)abstract
- The MIRAGE (minimum information required for a glycomics experiment) initiative was founded in Seattle, WA, in November 2011 in order to develop guidelines for reporting the qualitative and quantitative results obtained by diverse types of glycomics analyses, including the conditions and techniques that were applied to prepare the glycans for analysis and generate the primary data along with the tools and parameters that were used to process and annotate this data. These guidelines must address a broad range of issues, as glycomics data are inherently complex and are generated using diverse methods, including mass spectrometry (MS), chromatography, glycan array-binding assays, nuclear magnetic resonance (NMR) and other rapidly developing technologies. The acceptance of these guidelines by scientists conducting research on biological systems in which glycans have a significant role will facilitate the evaluation and reproduction of glycomics experiments and data that is reported in scientific journals and uploaded to glycomics databases. As a first step, MIRAGE guidelines for glycan analysis by MS have been recently published (Kolarich D, Rapp E, Struwe WB, Haslam SM, Zaia J., et al. 2013. The minimum information required for a glycomics experiment (MIRAGE) project - Improving the standards for reporting mass spectrometry-based glycoanalytic data. Mol. Cell Proteomics. 12:991-995), allowing them to be implemented and evaluated in the context of real-world glycobiology research. In this paper, we set out the historical context, organization structure and overarching objectives of the MIRAGE initiative.
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| 30. |
- Aebersold, Ruedi, et al.
(author)
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How many human proteoforms are there?
- 2018
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In: Nature Chemical Biology. - : NATURE PUBLISHING GROUP. - 1552-4450 .- 1552-4469. ; 14:3, s. 206-214
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Journal article (peer-reviewed)abstract
- Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA-and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.
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| 31. |
- Aughton, Karen, et al.
(author)
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hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA
- 2021
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In: Cancers. - : MDPI. - 2072-6694. ; 13:22
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Journal article (peer-reviewed)abstract
- Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.Simple Summary:Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Colin, S. P., et al.
(author)
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Stealth predation and the predatory success of the invasive ctenophore Mnemiopsis leidyi
- 2010
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 107:40, s. 17223-17227
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Journal article (peer-reviewed)abstract
- In contrast to higher metazoans such as copepods and fish, ctenophores are a basal metazoan lineage possessing a relatively narrow set of sensory-motor capabilities. Yet lobate ctenophores can capture prey at rates comparable to sophisticated predatory copepods and fish, and they are capable of altering the composition of coastal planktonic communities. Here, we demonstrate that the predatory success of the lobate ctenophore Mnemiopsis leidyi lies in its use of cilia to generate a feeding current that continuously entrains large volumes of fluid, yet is virtually undetectable to its prey. This form of stealth predation enables M. leidyi to feed as a generalist predator capturing prey, including microplankton (approximately 50 mu m), copepods (approximately 1 mm), and fish larvae (> 3 mm). The efficacy and versatility of this stealth feeding mechanism has enabled M. leidyi to be notoriously destructive as a predator and successful as an invasive species.
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| 37. |
- De Bustos, Cecilia, 1977-
(author)
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Genetic and Epigenetic Variation in the Human Genome : Analysis of Phenotypically Normal Individuals and Patients Affected with Brain Tumors
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Genetic and epigenetic variation is a key determinant of human diversity and has an impact on disease predisposition. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) are the main forms of genetic variation. The challenge is to distinguish normal variations from disease-associated changes. Combination of genetic and epigenetic alterations, often together with an environmental component, can cause cancer. In paper I, we investigated possible alterations affecting the transcriptional regulation of PDGFRα in patients affected with central nervous system tumors by characterizing the haplotype combinations in the PDGFRA gene promoter. A specific over-representation of one haplotype (H2δ) in primitive neuroectodermal tumors and ependymomas was observed, suggesting a functional role for the ZNF148/PDGFRα pathway in the tumor pathogenesis. In paper II, 50 glioblastomas were analyzed for DNA copy number variation with a chromosome 22 tiling genomic array. While 20% of tumors displayed monosomy 22, copy number variations affecting a portion of chromosome 22 were found in 14% of cases. This implies the presence of genes involved in glioblastoma development on 22q. Paper III described the analysis of copy number variation of 37 ependymomas using the same array. We detected monosomy in 51.5% of the samples. In addition, we identified two overlapping germline deletions of 2.2 Mb and 320 kb (the latter designated as Ep CNP). In order to investigate whether Ep CNP was a common polymorphism in the normal population or had an association with ependymoma development, we constructed a high-resolution PCR product-based microarray covering this locus (paper IV). For this purpose, we developed a program called Sequence Allocator, which automates the process of array design. This approach allowed assessment of copy number variation within regions of segmental duplications. Our results revealed that gains or deletions were identical in size and encompassed 290 kb. Therefore, papers I-IV suggest that some SNPs and CNPs can be regarded as tumor-associated polymorphisms. Finally, paper V describes variation of DNA methylation among fully differentiated tissues by using an array covering ~9% of the human genome. Major changes in the overall methylation were also found in colorectal cancer cell lines lacking one or two DNA methyltransferases.
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| 38. |
- Düsterer, S, et al.
(author)
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Two-color XUV+NIR femtosecond photoionization of neon in the near-threshold region
- 2019
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In: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 21
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Journal article (peer-reviewed)abstract
- Results of angle-resolved electron spectroscopy of near-threshold photoionization of Ne atoms by combined femtosecond extreme ultraviolet and near infrared fields are presented. The dressed-electron spectra show an energetic distribution into so-called sidebands, being separated by the photon energy of the dressing laser. Surprisingly, for the low kinetic energy (few eV) sidebands, the photoelectron energy varies as a function of the emission angle. Such behavior has not yet been observed in sideband creation and has not been predicted in commonly used theoretical descriptions such as strong field approximation and soft photon approach. Describing the photoionization with a time-dependent Schrödinger equation allows a qualitative description of the observed effect, as well as the prediction of fine structure in the sideband distribution.
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| 39. |
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| 40. |
- Greenhalf, William, et al.
(author)
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Pancreatic Cancer hENT1 Expression and Survival From Gemcitabine in Patients From the ESPAC-3 Trial
- 2014
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 106:1, s. djt347-
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Journal article (peer-reviewed)abstract
- Background Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. Methods Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. Results Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (chi(2)(1)=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (chi(2)(1)=9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (chi(2)(1) = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (chi(2)(1) = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald chi(2)(1) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald chi(2)(1) = 1.22; P = .27) patients. Conclusions Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.
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| 41. |
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| 42. |
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| 43. |
- Liu, Fan, et al.
(author)
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Directed evolution of rRNA improves translation kinetics and recombinant protein yield
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- In bacteria, ribosome kinetics are considered rate-limiting for protein synthesis and cell growth. Enhanced ribosome kinetics may augment bacterial growth and biomanufacturing through improvements to overall protein yield, but whether this can be achieved by ribosome-specific modifications remains unknown. Here, we evolve 16S ribosomal RNAs (rRNAs) from Escherichia coli, Pseudomonas aeruginosa, and Vibrio cholerae towards enhanced protein synthesis rates. We find that rRNA sequence origin significantly impacted evolutionary trajectory and generated rRNA mutants with augmented protein synthesis rates in both natural and engineered contexts, including the incorporation of noncanonical amino acids. Moreover, discovered consensus mutations can be ported onto phylogenetically divergent rRNAs, imparting improved translational activities. Finally, we show that increased translation rates in vivo coincide with only moderately reduced translational fidelity, but do not enhance bacterial population growth. Together, these findings provide a versatile platform for development of unnatural ribosomal functions in vivo.
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| 44. |
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| 45. |
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| 46. |
- Molina-Montes, E, et al.
(author)
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Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses
- 2021
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 70:2, s. 319-329
-
Journal article (peer-reviewed)abstract
- To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).DesignInformation about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.ResultsT2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55).ConclusionFindings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
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| 47. |
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| 48. |
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| 49. |
- Olive, M., et al.
(author)
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New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations
- 2015
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:13, s. 3638-3650
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Journal article (peer-reviewed)abstract
- Protein aggregate myopathies (PAMs) define muscle disorders characterized by protein accumulation in muscle fibres. We describe a new PAM in a patient with proximal muscle weakness and hypertrophic cardiomyopathy, whose muscle fibres contained inclusions containing myosin and myosin-associated proteins, and aberrant distribution of microtubules. These lesions appear as intact A- and M-bands lacking thin filaments and Z-discs. These features differ from inclusions in myosin storage myopathy (MSM), but are highly similar to those in mice deficient for the muscle-specific RING finger proteins MuRF1 and MuRF3. Sanger sequencing excluded mutations in the MSM-associated gene MYH7 but identified mutations in TRIM63 and TRIM54, encoding MuRF1 and MuRF3, respectively. No mutations in other potentially disease-causing genes were identified by Sanger and whole exome sequencing. Analysis of seven family members revealed that both mutations segregated in the family but only the homozygous TRIM63 null mutation in combination with the heterozygous TRIM54 mutation found in the proband caused the disease phenotype. Both MuRFs are microtubule-associated proteins localizing to sarcomeric M-bands and Z-discs. They are E3 ubiquitin ligases that play a role in degradation of sarcomeric proteins, stabilization of microtubules and myogenesis. Lack of ubiquitin and the 20S proteasome subunit in the inclusions found in the patient suggested impaired turnover of thick filament proteins. Disruption of microtubules in cultured myotubes was rescued by transient expression of wild-type MuRF1. The unique features of this novel myopathy point to defects in homeostasis of A-band proteins in combination with instability of microtubules as cause of the disease.
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| 50. |
- Petzold, Axel, et al.
(author)
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Diagnosis and classification of optic neuritis
- 2022
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In: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 21:12, s. 1120-1134
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Research review (peer-reviewed)abstract
- There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.
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