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1.	Klionsky, Daniel J, et al. (author) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). 2016 In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 12:1, s. 1-222 Journal article (peer-reviewed)
2.	Kanoni, Stavroula, et al. (author) Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. 2022 In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1 Journal article (peer-reviewed)abstract Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
3.	Amare, Azmeraw, et al. (author) Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder. 2023 In: Research square. - : Research Square Platform LLC. Journal article (peer-reviewed)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<��.
4.	Amare, Azmeraw T, et al. (author) Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. 2023 In: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261 Journal article (peer-reviewed)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
5.	Dinnus, Christian, et al. (author) IT-Organisationen wirksam verändern : Innovative KVP-Praxis: Mit kleinen Schritten zu nachhaltigem Erfolg 2013 Book (peer-reviewed)abstract In jedem Unternehmen gibt es Stellen, an denen es nicht rund läuft. In manchen Organisationseinheiten ist Sand im Getriebe, es knirscht und knackt – schon bereits bei der Zusammenarbeit mit anderen Abteilungen. Was kann man tun? Eine Möglichkeit besteht darin, ein großes Veränderungsprojekt aufzusetzen und alle Mitarbeiter und Führungskräfte ins kalte Wasser zu werfen. Doch viele dieser großen Veränderungsprojekte scheitern. Hauptgrund ist, dass Führungskräfte von der Notwendigkeit der Änderungen nicht überzeugt sind. Die Autoren dieses Buchs haben daher einen anderen Ansatz entwickelt: Veränderung ja, aber in kleinen, nachhaltigen Schritten. In einem solchen kontinuierlichen Veränderungsprozess geht es darum, nach und nach stabil laufende Prozesse einzuführen bzw. bestehende Prozesse zu optimieren. Mit dieser Methode wird die Akzeptanz der Mitarbeiter erreicht. Sie bietet Führungskräften die Möglichkeit, Veränderungen und Prozesse mitzugestalten und sich im Rahmen ihrer Linienverantwortung gezielt einzubringen.
6.	Docherty, Anna R, et al. (author) GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors. 2023 In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738 Journal article (peer-reviewed)abstract Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
7.	Kalman, Janos L, et al. (author) Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study. 2019 In: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75 Journal article (peer-reviewed)abstract Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
8.	Mullins, Niamh, et al. (author) Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors 2022 In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327 Journal article (peer-reviewed)abstract BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
9.	Amare, Azmeraw T, et al. (author) Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study. 2018 In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 65-74 Journal article (peer-reviewed)abstract Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P<5×10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
10.	BECKENBAUER, THOMAS, et al. (author) Fahrbahnbelag und Verfahren zur Herstellung desselben 2008 Patent (pop. science, debate, etc.)
11.	Bertl, Kristina, et al. (author) A Wide Mesio-Distal Gap Distance in Sites of Congenitally Missing Maxillary Lateral Incisors Is Related to a Thin Bucco-Palatal Alveolar Ridge Width 2016 In: Clinical Oral Implants Research. - : John Wiley & Sons. - 0905-7161 .- 1600-0501. ; 27:S13 : Abstracts of the EAO Congress, s. 218-219 Journal article (other academic/artistic)abstract Background: In cases of a missing maxillary lateral incisor, an implant-supported crown is often the treatment of choice in order to avoid affecting intact adjacent teeth; however, proper implant placement requires a specific minimum amount of alveolar ridge bone volume. In general, alveolar ridge development is depended on tooth development and eruption; consequently, tooth loss has major impact on alveolar ridge dimensions and tooth agenesis seems to impair proper alveolar ridge development. It seems thus reasonable to consider that the impact of tooth agenesis on alveolar ridge development might depend on the gap width, i.e. the distance between the neighboring – regularly erupted – teeth. In particular, the influence from the adjacent teeth on alveolar ridge development would be diminished with an increasing mesio-distal gap distance, which in turn might result in deficient alveolar ridge dimensions, i.e. reduced height and bucco-palatal width in the center of the edentulous alveolar ridge. Aim/Hypothesis: This study aimed (a) to evaluate whether there is a correlation between the mesio-distal gap size and alveolar ridge dimension in patients missing the maxillary lateral incisor either due to agenesis or loss; (b) to determine the edentulous alveolar ridge dimension in the region of the missing maxillary lateral incisor and simulate straightforward implant placement; and (c) to assess any effect of tooth agenesis on the alveolar ridge dimension at the adjacent teeth (i.e. central incisor, canine). Material and Methods: Per protocol, 3 groups (n = 40 per group) were planned, including patients (1) with agenesis of one permanent maxillary lateral incisor (TA); (2) with the maxillary permanent lateral incisors regularly erupted but lost >3 months prior to the CT scan (TL); and (3) with the maxillary permanent lateral incisors regularly erupted and in situ (control; C). The following parameters were manually recorded by a single calibrated examiner: (1) mesio-distal gap width between the central incisor and the canine; (2) average bucco-palatal alveolar ridge width in the coronal (1st to 5th mm) and apical (6th to 10th mm) part of the alveolar ridge; (3) alveolar ridge bone area from a level 1 mm below the top of the alveolar ridge and 10 mm apically; (4) alveolar ridge height; and (5) possibility of straightforward implant placement (10 mm long x 3 or 3.5 mm in diameter). Further, clinical data regarding the actual treatment performed, i.e. bone grafting prior to- or in association with implant installation, were retrieved from the dental records of the patients of TA. Differences in alveolar ridge dimensions (i.e., bucco-palatal width, area, height) among groups [TA vs. TL vs. C) groups were assessed by One-way-ANOVA with LSD post-hoc test; correlations between the alveolar ridge dimension and the mesio-distal gap width were tested by the Spearman correlation coefficient. Results: Altogether 104 maxillary CT-scans were evaluated; the intended sample size of 40 was not achieved for TL due to frequently uncertain history of tooth loss. The area and bucco-palatal width of the alveolar ridge at the lateral incisor and at the adjacent teeth was significantly reduced in TA compared to TL and C (Table 1). Further, in TA, but not TL, an increasing mesio-distal distance between the adjacent teeth resulted in a significantly reduced bucco-palatal width of the coronal part of the edentulous alveolar ridge (r = −0.464, P = 0.003). This impeded simulated straightforward implant placement in >50% of the cases in TA, even with a reduced implant diameter of 3 mm. This simulation had good agreement with the actual treatment performed. Based on clinical data from 26 patients of the TA group, straightforward implant placement was not possible in 58% of the cases. Conclusions and Clinical Implications: The present results indicate that the wider the mesio-distal gap is in maxillary lateral incisor agenesis sites, the thinner bucco-palatally should the alveolar ridge be expected to be. In particular, a mesio-distal gap of >6 mm precluded straightforward implant placement in 60–80% of the cases. These results are relevant for treatment planning, since additional hard and/or soft tissue augmentation procedures should be frequently expected for optimal functional and aesthetic outcomes.
12.	Bertl, Kristina, et al. (author) A wide mesio-distal gap in sites of congenitally missing maxillary lateral incisors is related to a thin alveolar ridge 2017 In: Clinical Oral Implants Research. - : John Wiley & Sons. - 0905-7161 .- 1600-0501. ; 28:9, s. 1038-1045 Journal article (peer-reviewed)abstract OBJECTIVES: To evaluate (i) a possible correlation between the mesio-distal gap width and the alveolar ridge (AR) dimensions in patients missing the maxillary lateral incisor (I2) either due to agenesis or loss and (ii) the possibility of straightforward implant placement based on simulation. METHODS: The bucco-palatal width, area, and height of the AR at the position of I2, and the mesio-distal gap width between the central incisor and the canine, were assessed in maxillary CT scans of three groups: Patients with (i) agenesis of I2 (TA ; n = 40); (ii) I2 regularly erupted but extracted (TL ; n = 24); (iii) I2 regularly erupted and in situ (C; n = 40). Further, the possibility of straightforward placement of an implant 3 or 3.5 mm in diameter ×10 mm in length, with 1 mm distance from the buccal and palatal plate of the alveolar ridge was simulated and compared to the actual treatment delivered. RESULTS: Bucco-palatal width and area of the AR at I2 and the adjacent teeth was significantly reduced in TA compared to TL and C. Further, in TA , but not TL , an increasing mesio-distal gap width between the central incisor and canine resulted in a significantly reduced bucco-palatal width of the edentulous AR. This impeded a simulated straightforward implant placement in >50% of the cases in TA , even with a reduced implant diameter. CONCLUSIONS: In patients congenitally missing I2, an increased mesio-distal gap width correlates significantly with reduced edentulous AR dimensions. A mesio-distal gap of >6 mm was associated with thin bucco-palatal alveolar ridges, precluding straightforward implant placement in 60-80% of the cases.
13.	Botteri, Edoardo, et al. (author) Changes in lifestyle and risk of colorectal cancer in the european prospective investigation into cancer and nutrition 2023 In: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 118:4, s. 702-711 Journal article (peer-reviewed)abstract Introduction: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort.Methods: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI).Results: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile.Discussion: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.
14.	Botteri, Edoardo, et al. (author) Lifestyle changes in middle age and risk of cancer : evidence from the European Prospective Investigation into Cancer and Nutrition 2024 In: European Journal of Epidemiology. - 0393-2990. ; 39:2, s. 147-159 Journal article (peer-reviewed)abstract In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers—including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others—using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95–0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07–1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65–0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.
15.	Castro-Espin, Carlota, et al. (author) Dietary patterns related to biological mechanisms and survival after breast cancer diagnosis : results from a cohort study 2023 In: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 128, s. 1301-1310 Journal article (peer-reviewed)abstract Background: Inflammatory, insulin and oestrogenic pathways have been linked to breast cancer (BC). We aimed to examine the relationship between pre-diagnostic dietary patterns related to these mechanisms and BC survival.Methods: The diabetes risk reduction diet (DRRD), inflammatory score of diet (ISD) and oestrogen-related dietary pattern (ERDP) were calculated using dietary data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to assess associations between dietary patterns and overall mortality and competing risk models for associations with BC-specific mortality.Results: We included 13,270 BC cases with a mean follow-up after diagnosis of 8.6 years, representing 2340 total deaths, including 1475 BC deaths. Higher adherence to the DRRD score was associated with lower overall mortality (HR1–SD 0.92; 95%CI 0.87–0.96). Greater adherence to pro-inflammatory diets was borderline associated with 6% higher mortality HR1–SD 1.06; 95%CI 1.00–1.12. No significant association with the oestrogen-related dietary pattern was observed. None of the dietary patterns were associated with BC-specific mortality.Conclusions: Greater adherence to an anti-diabetic and anti-inflammatory diet prior to diagnosis is associated with lower overall mortality among BC survivors. Long-term adherence to these dietary patterns could be a means to improve the prognosis of BC survivors.
16.	Cearns, Micah, et al. (author) Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach - CORRIGENDUM. 2022 In: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 221:2 Journal article (peer-reviewed)
17.	Christakoudi, Sofia, et al. (author) A body shape index (ABSI) is associated inversely with post-menopausal progesterone-receptor-negative breast cancer risk in a large European cohort 2023 In: BMC Cancer. - 1471-2407. ; 23:1 Journal article (peer-reviewed)abstract Background: Associations of body shape with breast cancer risk, independent of body size, are unclear because waist and hip circumferences are correlated strongly positively with body mass index (BMI). Methods: We evaluated body shape with the allometric “a body shape index” (ABSI) and hip index (HI), which compare waist and hip circumferences, correspondingly, among individuals with the same weight and height. We examined associations of ABSI, HI, and BMI (per one standard deviation increment) with breast cancer overall, and according to menopausal status at baseline, age at diagnosis, and oestrogen and progesterone receptor status (ER+/-PR+/-) in multivariable Cox proportional hazards models using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Results: During a mean follow-up of 14.0 years, 9011 incident breast cancers were diagnosed among 218,276 women. Although there was little evidence for association of ABSI with breast cancer overall (hazard ratio HR = 0.984; 95% confidence interval: 0.961–1.007), we found borderline inverse associations for post-menopausal women (HR = 0.971; 0.942-1.000; n = 5268 cases) and breast cancers diagnosed at age ≥ 55 years (HR = 0.976; 0.951–1.002; n = 7043) and clear inverse associations for ER + PR- subtypes (HR = 0.894; 0.822–0.971; n = 726) and ER-PR- subtypes (HR = 0.906; 0.835–0.983 n = 759). There were no material associations with HI. BMI was associated strongly positively with breast cancer overall (HR = 1.074; 1.049–1.098), for post-menopausal women (HR = 1.117; 1.085–1.150), for cancers diagnosed at age ≥ 55 years (HR = 1.104; 1.076–1.132), and for ER + PR + subtypes (HR = 1.122; 1.080–1.165; n = 3101), but not for PR- subtypes. Conclusions: In the EPIC cohort, abdominal obesity evaluated with ABSI was not associated with breast cancer risk overall but was associated inversely with the risk of post-menopausal PR- breast cancer. Our findings require validation in other cohorts and with a larger number of PR- breast cancer cases.
18.	Coombes, Brandon J, et al. (author) Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study. 2021 In: Complex psychiatry. - : S. Karger AG. - 2673-3005 .- 2673-298X. ; 7:3-4, s. 80-89 Journal article (peer-reviewed)abstract Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
19.	Dam, Veerle, et al. (author) Genetically Determined Reproductive Aging and Coronary Heart Disease : A Bidirectional 2-sample Mendelian Randomization 2022 In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:7, s. E2952-E2961 Journal article (peer-reviewed)abstract Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.
20.	Feldwisch-Drentrup, Hinnerk, et al. (author) Identification of preseizure states in epilepsy: a data-driven approach for multichannel EEG recordings 2011 In: Frontiers in Computational Neuroscience. - : Frontiers Research Foundation. - 1662-5188. ; 5:32 Journal article (peer-reviewed)abstract The retrospective identification of preseizure states usually bases on a time-resolved characterization of dynamical aspects of multichannel neurophysiologic recordings that can be assessed with measures from linear or non-linear time series analysis. This approach renders time profiles of a characterizing measure - so-called measure profiles - for different recording sites or combinations thereof. Various downstream evaluation techniques have been proposed to single out measure profiles that carry potential information about preseizure states. These techniques, however, rely on assumptions about seizure precursor dynamics that might not be generally valid or face the statistical problem of multiple testing. Addressing these issues, we have developed a method to preselect measure profiles that carry potential information about preseizure states, and to identify brain regions associated with seizure precursor dynamics. Our data-driven method is based on the ratio S of the global to local temporal variance of measure profiles. We evaluated its suitability by retrospectively analyzing long-lasting multichannel intracranial EEG recordings from 18 patients that included 133 focal onset seizures, using a bivariate measure for the strength of interactions. In 17/18 patients, we observed S to be significantly correlated with the predictive performance of measure profiles assessed retrospectively by means of receiver-operating-characteristic statistics. Predictive performance was higher for measure profiles preselected with S than for a manual selection using information about onset and spread of seizures. Across patients, highest predictive performance was not restricted to recordings from focal areas, thus supporting the notion of an extended epileptic network in which even distant brain regions contribute to seizure generation. We expect our method to provide further insight into the complex spatial and temporal aspects of the seizure generating process.
21.	Frkatović-Hodžić, Azra, et al. (author) Mapping of the gene network that regulates glycan clock of ageing 2023 In: Aging. - 1945-4589. ; 15:24, s. 14509-14552 Journal article (peer-reviewed)abstract Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.
22.	Gasser, T. Christian, et al. (author) A three-dimensional finite element model for arterial clamping 2002 In: Journal of Biomechanical Engineering. - : ASME International. - 0148-0731 .- 1528-8951. ; 124:4, s. 355-363 Journal article (peer-reviewed)abstract Clamp induced injuries of the arterial wall may determine the outcome of surgical procedures. Thus, it is important to investigate the underlying mechanical effects. We present a three-dimensional finite element model, which allows the study of the mechanical response of an artery-treated as a two-layer tube-during arterial clamping. The important residual stresses, which are associated with the load free configuration of the artery, are also considered. In particular, the finite element analysis of the deformation process of a clamped artery and the associated stress distribution is presented. Within the clamping area a zone of axial tensile peak-stresses was identified, which (may) cause intimal and medial injury. This is an additional injury mechanism, which clearly differs from the commonly assumed wall damage occurring due to compression between the jaws of the clamp. The proposed numerical model provides essential insights into the mechanics of the clamping procedure and the associated injury mechanisms. It allows detailed parameter studies on a virtual clamped artery, which can not be performed with other methodologies. This approach has the potential to identify the most appropriate clamps for certain types of arteries and to guide optimal clamp design.
23.	Gosalawit-Utke, Rapee, et al. (author) Ca(BH4)(2)-MgF2 Reversible Hydrogen Storage: Reaction Mechanisms and Kinetic Properties 2011 In: Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 115:9, s. 3762-3768 Journal article (peer-reviewed)abstract A composite of Ca(BH4)(2)-MgF2 is proposed as a reversible hydrogen storage system. The dehydrogenation and rehydrogenation reaction mechanisms are investigated by in situ time-resolved synchrotron radiation powder X-ray diffraction (SR-PXD) and Raman spectroscopy. The formation of an intermediate phase (CaF2-xHx) is observed during rehydrogenation. The hydrogen content of 4.3 wt % is obtained within 4 h during the first dehydrogenation at isothermal and isobaric conditions of 330 degrees C and 0.5 bar H-2, respectively. The cycling efficiency is evaluated by three release and uptake cycles together with absorbed hydrogen content in the range 5.1-5.8 wt % after 2.5 h (T = 330 degrees C and p(H-2) = 130 bar). The kinetic properties on the basis of hydrogen absorption are comparable for all cycles. As compared to pure Ca(BH4)(2) and Ca(BH4)(2)-MgH2 composite, Ca(BH4)(2)-MgF2 composite reveals the kinetic destabilization and the reproducibility of hydrogen storage capacities during cycling, respectively.
24.	Herrera-Rivero, Marisol, et al. (author) Exploring the genetics of lithium response in bipolar disorders. 2023 In: Research square. Other publication (other academic/artistic)abstract Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
25.	Herrera-Rivero, Marisol, et al. (author) Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder. 2023 In: Research square. Other publication (other academic/artistic)abstract The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
26.	Hochmal, Ana Karina, et al. (author) Calredoxin represents a novel type of calcium-dependent sensor-responder connected to redox regulation in the chloroplast 2016 In: Nature Communications. - : Springer Nature. - 2041-1723. ; 7 Journal article (peer-reviewed)abstract Calcium (Ca2+) and redox signalling play important roles in acclimation processes from archaea to eukaryotic organisms. Herein we characterized a unique protein from Chlamydomonas reinhardtii that has the competence to integrate Ca2+- and redox-related signalling. This protein, designated as calredoxin (CRX), combines four Ca2+-binding EF-hands and a thioredoxin (TRX) domain. A crystal structure of CRX, at 1.6 Å resolution, revealed an unusual calmodulin-fold of the Ca2+-binding EF-hands, which is functionally linked via an inter-domain communication path with the enzymatically active TRX domain. CRX is chloroplast-localized and interacted with a chloroplast 2-Cys peroxiredoxin (PRX1). Ca2+-binding to CRX is critical for its TRX activity and for efficient binding and reduction of PRX1. Thereby, CRX represents a new class of Ca2+-dependent ‘sensor-responder’ proteins. Genetically engineered Chlamydomonas strains with strongly diminished amounts of CRX revealed altered photosynthetic electron transfer and were affected in oxidative stress response underpinning a function of CRX in stress acclimation.
27.	Hombach-Klonisch, Sabine, et al. (author) Cancer stem cells as targets for cancer therapy : selected cancers as examples 2008 In: Archivum Immunologiae et Therapiae Experimentalis. - : Springer Science and Business Media LLC. - 0004-069X .- 1661-4917. ; 56:3, s. 165-180 Research review (peer-reviewed)abstract It is becoming increasingly evident that cancer constitutes a group of diseases involving altered stem-cell maturation/differentiation and the disturbance of regenerative processes. The observed malignant transformation is merely a symptom of normal differentiation processes gone astray rather than the primary event. This review focuses on the role of cancer stem cells (CSCs) in three common but also relatively under-investigated cancers: head and neck, ovarian, and testicular cancer. For didactic purpose, the physiology of stem cells is first introduced using hematopoietic and mesenchymal stem cells as examples. This is followed by a discussion of the (possible) role of CSCs in head and neck, ovarian, and testicular cancer. Aside from basic information about the pathophysiology of these cancers, current research results focused on the discovery of molecular markers specific to these cancers are also discussed. The last part of the review is largely dedicated to signaling pathways active within various normal and CSC types (e.g. Nanog, Nestin, Notch1, Notch2, Oct3 and 4, Wnt). Different elements of these pathways are also discussed in the context of therapeutic opportunities for the development of targeted therapies aimed at CSCs. Finally, alternative targeted anticancer therapies arising from recently identified molecules with cancer-(semi-)selective capabilities (e.g. apoptin, Brevinin-2R) are considered.
28.	Hou, Liping, et al. (author) Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. 2016 In: Lancet (London, England). - 1474-547X. ; 387:10023, s. 1085-1093 Journal article (peer-reviewed)abstract Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.
29.	Hou, Liping, et al. (author) Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. 2016 In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94 Journal article (peer-reviewed)abstract Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
30.	Kelsoe, John, et al. (author) Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study. 2023 In: Research square. Other publication (other academic/artistic)abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
31.	Landi, MT, et al. (author) Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility 2020 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:5, s. 494- Journal article (peer-reviewed)
32.	Langenberg, Svenja, et al. (author) Physical activity is unrelated to cognitive performance in pre-bariatric surgery patients 2015 In: Journal of Psychosomatic Research. - : Elsevier BV. - 0022-3999 .- 1879-1360. ; 79:2, s. 165-170 Journal article (peer-reviewed)abstract ObjectiveTo investigate the relationship between physical activity (PA) and cognitive performance in extreme obesity.MethodsSeventy-one bariatric surgery candidates (77.5% women) with a mean body mass index (BMI) of 46.9 kg/m2 (SD = 6.0) and a mean age of 41.4 (SD = 11.9) years completed SenseWear Pro2 activity monitoring for seven days. Cognitive functioning was assessed by a computerized test battery including tasks of executive function (Iowa Gambling Task), visuospatial short-term memory (Corsi Block Tapping Test) and verbal short-term memory (Auditory-Verbal Learning Test). Questionnaires assessing eating disturbances and depressive symptoms were administered. Somatic comorbidities were assessed by medical chart review.ResultsThe level of PA was low with mean steps per day within wear time being 7140 (SD = 3422). Most patients were categorized as sedentary (31.0%) or low active (26.8%). No significant association between PA estimates and cognitive performance was found. Lower PA was modestly correlated with higher BMI but not with age, somatic comorbidity or depressive symptoms. Moderated regression analyses suggested a significant interaction effect between depression and PA in predicting performance on the Corsi Block Tapping Test. Patients with (29.6%) and without (70.4%) regular binge eating did not differ with respect to PA or cognitive function.ConclusionThe findings indicate no association between daily PA and cognitive performance in morbidly obese patients. Future studies should explore the relationship between the variables with regard to dose–response-questions, a broader BMI range and with respect to potential changes after substantial weight loss due to bariatric surgery.
33.	Law, MH, et al. (author) Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma 2015 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:9, s. 987- Journal article (peer-reviewed)
34.	Mahamat-Saleh, Yahya, et al. (author) Baseline and lifetime alcohol consumption and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) 2023 In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 152:3, s. 348-362 Journal article (peer-reviewed)abstract Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend =.001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend =.04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend =.17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend =.13; BCC: HR = 1.08, 95% CI = 1.00-1.17, Ptrend =.03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend =.13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend =.0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; Ptrend =.14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer.
35.	Mayén, Ana Lucia, et al. (author) A longitudinal evaluation of alcohol intake throughout adulthood and colorectal cancer risk 2022 In: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 37:9, s. 915-929 Journal article (peer-reviewed)abstract Background: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk. Objective: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk. Methods: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50 years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases. Results: Mean age at baseline was 50.2 years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite. Conclusions: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk.
36.	Mueller, Birgit, et al. (author) Describing human decisions in agent-based models - ODD plus D, an extension of the ODD protocol 2013 In: Environmental Modelling & Software. - : Elsevier BV. - 1364-8152 .- 1873-6726. ; 48, s. 37-48 Journal article (peer-reviewed)abstract Representing human decisions is of fundamental importance in agent-based models. However, the rationale for choosing a particular human decision model is often not sufficiently empirically or theoretically substantiated in the model documentation. Furthermore, it is difficult to compare models because the model descriptions are often incomplete, not transparent and difficult to understand. Therefore, we expand and refine the 'ODD' (Overview, Design Concepts and Details) protocol to establish a standard for describing ABMs that includes human decision-making (ODD + D). Because the ODD protocol originates mainly from an ecological perspective, some adaptations are necessary to better capture human decision-making. We extended and rearranged the design concepts and related guiding questions to differentiate and describe decision-making, adaptation and learning of the agents in a comprehensive and clearly structured way. The ODD + D protocol also incorporates a section on 'Theoretical and Empirical Background' to encourage model designs and model assumptions that are more closely related to theory. The application of the ODD + D protocol is illustrated with a description of a social ecological ABM on water use. Although the ODD + D protocol was developed on the basis of example implementations within the socio-ecological scientific community, we believe that the ODD + D protocol may prove helpful for describing ABMs in general when human decisions are included.
37.	Müller, Birgit, et al. (author) Standardised and transparent model descriptions for agent-based models : Current status and prospects 2014 In: Environmental Modelling & Software. - : Elsevier BV. - 1364-8152 .- 1873-6726. ; 55, s. 156-163 Journal article (peer-reviewed)abstract Agent-based models are helpful to investigate complex dynamics in coupled human natural systems. However, model assessment, model comparison and replication are hampered to a large extent by a lack of transparency and comprehensibility in model descriptions. In this article we address the question of whether an ideal standard for describing models exists. We first suggest a classification for structuring types of model descriptions. Secondly, we differentiate purposes for which model descriptions are important. Thirdly, we review the types of model descriptions and evaluate each on their utility for the purposes. Our evaluation finds that the choice of the appropriate model description type is purpose-dependent and that no single description type alone can fulfil all requirements simultaneously. However, we suggest a minimum standard of model description for good modelling practice, namely the provision of source code and an accessible natural language description, and argue for the development of a common standard.
38.	Ou, Anna H., et al. (author) Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study 2024 In: TRANSLATIONAL PSYCHIATRY. - 2158-3188. ; 14:1 Journal article (peer-reviewed)abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
39.	Parikh, Hemang, et al. (author) TXNIP regulates peripheral glucose metabolism in humans 2007 In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 4:5, s. 868-879 Journal article (peer-reviewed)abstract Background Type 2 diabetes mellitus ( T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. Methods and Findings We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein ( TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. Conclusions TXNIP regulates both insulin-dependent and insulin- independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.
40.	Sarin, Nikhil, et al. (author) Redback : a Bayesian inference software package for electromagnetic transients 2024 In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 531:1, s. 1203-1227 Journal article (peer-reviewed)abstract Fulfilling the rich promise of rapid advances in time-domain astronomy is only possible through confronting our observations with physical models and extracting the parameters that best describe what we see. Here, we introduce redback; a Bayesian inference software package for electromagnetic transients. redback provides an object-orientated python interface to over 12 different samplers and over 100 different models for kilonovae, supernovae, gamma-ray burst afterglows, tidal disruption events, engine-driven transients among other explosive transients. The models range in complexity from simple analytical and semi-analytical models to surrogates built upon numerical simulations accelerated via machine learning. redback also provides a simple interface for downloading and processing data from various catalogues such as Swift and FINK. The software can also serve as an engine to simulate transients for telescopes such as the Zwicky Transient Facility and Vera Rubin with realistic cadences, limiting magnitudes, and sky coverage or a hypothetical user-constructed survey or a generic transient for target-of-opportunity observations with different telescopes. As a demonstration of its capabilities, we show how redback can be used to jointly fit the spectrum and photometry of a kilonova, enabling a more powerful, holistic probe into the properties of a transient. We also showcase general examples of how redback can be used as a tool to simulate transients for realistic surveys, fit models to real, simulated, or private data, multimessenger inference with gravitational waves, and serve as an end-to-end software toolkit for parameter estimation and interpreting the nature of electromagnetic transients.
41.	Sawcer, Stephen, et al. (author) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis 2011 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219 Journal article (peer-reviewed)abstract Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
42.	Schymanski, Emma L, et al. (author) Non-target screening with high-resolution mass spectrometry : critical review using a collaborative trial on water analysis 2015 In: Analytical and Bioanalytical Chemistry. - : Springer Berlin/Heidelberg. - 1618-2642 .- 1618-2650. ; 407:21, s. 6237-6255 Research review (peer-reviewed)abstract In this article, a dataset from a collaborative non-target screening trial organised by the NORMAN Association is used to review the state-of-the-art and discuss future perspectives of non-target screening using high-resolution mass spectrometry in water analysis. A total of 18 institutes from 12 European countries analysed an extract of the same water sample collected from the River Danube with either one or both of liquid and gas chromatography coupled with mass spectrometry detection. This article focuses mainly on the use of high resolution screening techniques with target, suspect, and non-target workflows to identify substances in environmental samples. Specific examples are given to emphasise major challenges including isobaric and co-eluting substances, dependence on target and suspect lists, formula assignment, the use of retention information, and the confidence of identification. Approaches and methods applicable to unit resolution data are also discussed. Although most substances were identified using high resolution data with target and suspect-screening approaches, some participants proposed tentative non-target identifications. This comprehensive dataset revealed that non-target analytical techniques are already substantially harmonised between the participants, but the data processing remains time-consuming. Although the objective of a "fully-automated identification workflow" remains elusive in the short term, important steps in this direction have been taken, exemplified by the growing popularity of suspect screening approaches. Major recommendations to improve non-target screening include better integration and connection of desired features into software packages, the exchange of target and suspect lists, and the contribution of more spectra from standard substances into (openly accessible) databases.
43.	Thurner, Martin, et al. (author) Sapwood biomass carbon in northern boreal and temperate forests 2019 In: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 28:5, s. 640-660 Journal article (peer-reviewed)abstract Aim Information on the amount of carbon stored in the living tissue of tree stems (sapwood) is crucial for carbon and water cycle applications. Here, we aim to investigate sapwood-to-stem proportions and differences therein between tree genera and derive a sapwood biomass map. Location Northern Hemisphere boreal and temperate forests. Time period 2010. Major taxa studied Twenty-five common tree genera. Methods First, we develop a theoretical framework to estimate sapwood biomass for a given stem biomass by applying relationships between sapwood cross-sectional area (CSA) and stem CSA and between stem CSA and stem biomass. These measurements are extracted from a biomass and allometry database (BAAD), an extensive literature review and our own studies. The established allometric relationships are applied to a remote sensing-based stem biomass product in order to derive a spatially continuous sapwood biomass map. The application of new products on the distribution of stand density and tree genera facilitates the synergy of satellite and forest inventory data. Results Sapwood-to-stem CSA relationships can be modelled with moderate to very high modelling efficiency for different genera. The total estimated sapwood biomass equals 12.87 +/- 6.56 petagrams of carbon (PgC) in boreal (mean carbon density: 1.13 +/- 0.58 kgC m(-2)) and 15.80 +/- 9.10 PgC in temperate (2.03 +/- 1.17 kgC m(-2)) forests. Spatial patterns of sapwood-to-stem biomass proportions are crucially driven by the distribution of genera (spanning from 20-30% in Larix to > 70% in Pinus and Betula forests). Main conclusions The presented sapwood biomass map will be the basis for large-scale estimates of plant respiration and transpiration. The enormous spatial differences in sapwood biomass proportions reveal the need to consider the functionally more important sapwood instead of the entire stem biomass in global carbon and water cycle studies. Alterations in tree species distribution, induced by forest management or climate change, can strongly affect the available sapwood biomass even if stem biomass remains unchanged.
44.	Tsuchiya, Takafumi, et al. (author) Association of the calpain-10 gene with type 2 diabetes in Europeans: Results of pooled and meta-analyses 2006 In: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 89:1-2, s. 174-184 Journal article (peer-reviewed)abstract We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR) = 1.11 (95% confidence interval (0), 1.02-1.20), P = 0.01). Two haplotype combinations were associated with increased risk of T2D) (1-2-1/1-2-1, OR = 1.20 (1.03-1.41), P = 0.02; and 1-1-2/1-2-1, OR = 1.26 (1.01-1.59), P = 0.04) and one with decreased risk (1-1-1/2-2-1, OR = 0.86 (0.75-0.99), P = 0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR = 1.25 (1.05-1.50), P = 0.01). However, there was evidence for heterogeneity with respect to this effect (P = 0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P = 0.89) and strengthened the evidence for association with T2D) in both the pooled (SNP-43G, OR = 1.19 (1.07-1.32), P = 0.001; 1-2-1/1-2-1 haplogenotype, OR = 1.46 (1.19-1.78), P = 0.0003; 1-1-2/1-2-1 haplogenotype, OR = 1.52 (1.12-2.06), P = 0.007; and 1-1-1/2-2-1 haplogenotype, OR = 0.83 (0.70-0.99), P = 0.03) and the meta-analysis (SNP-43*G, OR = 1.18 (1.05-1.32), P = 0.005; 1-2-1/1-2-1 haplogenotype, OR = 1.68 (1.33-2.11), P = 0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans. (c) 2006 Elsevier Inc. All rights reserved.
45.	Turcot, Valerie, et al. (author) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity 2018 In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41 Journal article (peer-reviewed)abstract Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
46.	Walsh, Roddy, et al. (author) Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls 2021 In: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58 Journal article (peer-reviewed)abstract Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

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