• Parental origin of sequence variants associated with complex diseases

      Kong, Augustine; Steinthorsdottir, Valgerdur; Masson, Gisli; Thorleifsson, Gudmar; Sulem, Patrick; Besenbacher, Soren; Jonasdottir, Aslaug; Sigurdsson, Asgeir; Kristinsson, Kari Th; Jonasdottir, Adalbjorg; et al. (Nature Publishing Group, 2009-12)
      Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
    • Polygenic risk scores for schizophrenia and bipolar disorder predict creativity.

      Power, Robert A; Steinberg, Stacy; Bjornsdottir, Gyda; Rietveld, Cornelius A; Abdellaoui, Abdel; Nivard, Michel M; Johannesson, Magnus; Galesloot, Tessel E; Hottenga, Jouke J; Willemsen, Gonneke; et al. (Nature Publishing Group, 2015-07)
      We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 × 10(-6) and 3.8 × 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.
    • Prediction of intracellular metabolic states from extracellular metabolomic data.

      Aurich, Maike K; Paglia, Giuseppe; Rolfsson, Óttar; Hrafnsdóttir, Sigrún; Magnúsdóttir, Manuela; Stefaniak, Magdalena M; Palsson, Bernhard Ø; Fleming, Ronan M T; Thiele, Ines; Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland, Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg, Univ Iceland, Sch Hlth Sci, Fac Food Sci & Nutr, Reykjavik, Iceland, Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA (Springer, 2015-06)
      Metabolic models can provide a mechanistic framework to analyze information-rich omics data sets, and are increasingly being used to investigate metabolic alternations in human diseases. An expression of the altered metabolic pathway utilization is the selection of metabolites consumed and released by cells. However, methods for the inference of intracellular metabolic states from extracellular measurements in the context of metabolic models remain underdeveloped compared to methods for other omics data. Herein, we describe a workflow for such an integrative analysis emphasizing on extracellular metabolomics data. We demonstrate, using the lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM, how our methods can reveal differences in cell metabolism. Our models explain metabolite uptake and secretion by predicting a more glycolytic phenotype for the CCRF-CEM model and a more oxidative phenotype for the Molt-4 model, which was supported by our experimental data. Gene expression analysis revealed altered expression of gene products at key regulatory steps in those central metabolic pathways, and literature query emphasized the role of these genes in cancer metabolism. Moreover, in silico gene knock-outs identified unique control points for each cell line model, e.g., phosphoglycerate dehydrogenase for the Molt-4 model. Thus, our workflow is well-suited to the characterization of cellular metabolic traits based on extracellular metabolomic data, and it allows the integration of multiple omics data sets into a cohesive picture based on a defined model context.
    • Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults.

      Schelbert, Erik B; Cao, Jie J; Sigurdsson, Sigurdur; Aspelund, Thor; Kellman, Peter; Aletras, Anthony H; Dyke, Christopher K; Thorgeirsson, Gudmundur; Eiriksdottir, Gudny; Launer, Lenore J; et al. (2012-09-05)
      Unrecognized myocardial infarction (MI) is prognostically important. Electrocardiography (ECG) has limited sensitivity for detecting unrecognized MI (UMI). Determine prevalence and mortality risk for UMI detected by cardiac magnetic resonance (CMR) imaging or ECG among older individuals. ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling cohort of older individuals in Iceland, data for 936 participants aged 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes. Prevalence and mortality of MI through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI). Of 936 participants, 91 had recognized MI (RMI) (9.7%; 95% CI, 8% to 12%), and 157 had UMI detected by CMR (17%; 95% CI, 14% to 19%), which was more prevalent than the 46 UMI detected by ECG (5%; 95% CI, 4% to 6%; P < .001). Participants with diabetes (n = 337) had more UMI detected by CMR than by ECG (n = 72; 21%; 95% CI, 17% to 26%, vs n = 15; 4%; 95% CI, 2% to 7%; P < .001). Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 30 of 91 participants (33%; 95% CI, 23% to 43%) with RMI died, and 44 of 157 participants (28%; 95% CI, 21% to 35%) with UMI died, both higher rates than the 119 of 688 participants (17%; 95% CI, 15% to 20%) with no MI who died. Unrecognized MI by CMR improved risk stratification for mortality over RMI (NRI, 0.34; 95% CI, 0.16 to 0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (hazard ratio [HR], 1.45; 95% CI, 1.02 to 2.06, absolute risk increase [ARI], 8%) and significantly improved risk stratification for mortality (NRI, 0.16; 95% CI, 0.01 to 0.31), but UMI by ECG did not (HR, 0.88; 95% CI, 0.45 to 1.73; ARI, -2%; NRI, -0.05; 95% CI, -0.17 to 0.05). Compared with those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; 95% CI, 28% to 43%, or 56/157, vs 73%; 95% CI, 63% to 82%, or 66/91; P < .001). In a community-based cohort of older individuals, the prevalence of UMI by CMR was higher than the prevalence of RMI and was associated with increased mortality risk. In contrast, UMI by ECG prevalence was lower than that of RMI and was not associated with increased mortality risk.
    • Processed pseudogenes acquired somatically during cancer development.

      Cooke, Susanna L; Shlien, Adam; Marshall, John; Pipinikas, Christodoulos P; Martincorena, Inigo; Tubio, Jose M C; Li, Yilong; Menzies, Andrew; Mudie, Laura; Ramakrishna, Manasa; et al. (Nature, 2014)
      Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
    • A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy.

      Kapur, Rick; Kustiawan, Iwan; Vestrheim, Anne; Koeleman, Carolien A M; Visser, Remco; Einarsdottir, Helga K; Porcelijn, Leendert; Jackson, Dave; Kumpel, Belinda; Deelder, André M; et al. (Amer Soc Hematology, 2014-01-23)
      Immunoglobulin G (IgG) formed during pregnancy against human platelet antigens (HPAs) of the fetus mediates fetal or neonatal alloimmune thrombocytopenia (FNAIT). Because antibody titer or isotype does not strictly correlate with disease severity, we investigated by mass spectrometry variations in the glycosylation at Asn297 in the IgG Fc because the composition of this glycan can be highly variable, affecting binding to phagocyte IgG-Fc receptors (FcγR). We found markedly decreased levels of core fucosylation of anti-HPA-1a-specific IgG1 from FNAIT patients (n = 48), but not in total serum IgG1. Antibodies with a low amount of fucose displayed higher binding affinity to FcγRIIIa and FcγRIIIb, but not to FcγRIIa, compared with antibodies with a high amount of Fc fucose. Consequently, these antibodies with a low amount of Fc fucose showed enhanced phagocytosis of platelets using FcγRIIIb(+) polymorphonuclear cells or FcγRIIIa(+) monocytes as effector cells, but not with FcγRIIIa(-) monocytes. In addition, the degree of anti-HPA-1a fucosylation correlated positively with the neonatal platelet counts in FNAIT, and negatively to the clinical disease severity. In contrast to the FNAIT patients, no changes in core fucosylation were observed for anti-HLA antibodies in refractory thrombocytopenia (post platelet transfusion), indicating that the level of fucosylation may be antigen dependent and/or related to the immune milieu defined by pregnancy.
    • A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.

      Rivas, Manuel A; Graham, Daniel; Sulem, Patrick; Stevens, Christine; Desch, A Nicole; Goyette, Philippe; Gudbjartsson, Daniel; Jonsdottir, Ingileif; Thorsteinsdottir, Unnur; Degenhardt, Frauke; et al. (Nature, 2016)
      Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
    • Quality of care in European home care programs using the second generation interRAI Home Care Quality Indicators (HCQIs).

      Foebel, Andrea D; van Hout, Hein P; van der Roest, Henriëtte G; Topinkova, Eva; Garms-Homolova, Vjenka; Frijters, Dinnus; Finne-Soveri, Harriet; Jónsson, Pálmi V; Hirdes, John P; Bernabei, Roberto; et al. (BioMed Central, 2015)
      Evaluating the quality of care provided to older individuals is a key step to ensure that needs are being met and to target interventions to improve care. To this aim, interRAI's second-generation home care quality indicators (HCQIs) were developed in 2013. This study assesses the quality of home care services in six European countries using these HCQIs as well as the two derived summary scales.
    • Quantitative assignment of reaction directionality in a multicompartmental human metabolic reconstruction.

      Haraldsdóttir, H S; Thiele, I; Fleming, R M T; Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland, Univ Iceland, Fac Med, Reykjavik, Iceland, Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykjavik, Iceland (Cell Press, 2012-04-18)
      Reaction directionality is a key constraint in the modeling of genome-scale metabolic networks. We thermodynamically constrained reaction directionality in a multicompartmental genome-scale model of human metabolism, Recon 1, by calculating, in vivo, standard transformed reaction Gibbs energy as a function of compartment-specific pH, electrical potential, and ionic strength. We show that compartmental pH is an important determinant of thermodynamically determined reaction directionality. The effects of pH on transport reaction thermodynamics are only seen to their full extent when metabolites are represented as pseudoisomer groups of multiple protonated species. We accurately predict the irreversibility of 387 reactions, with detailed propagation of uncertainty in input data, and manually curate the literature to resolve conflicting directionality assignments. In at least half of all cases, a prediction of a reversible reaction directionality is due to the paucity of compartment-specific quantitative metabolomic data, with remaining cases due to uncertainty in estimation of standard reaction Gibbs energy. This study points to the pressing need for 1), quantitative metabolomic data, and 2), experimental measurement of thermochemical properties for human metabolites.
    • Rate of de novo mutations and the importance of father's age to disease risk.

      Kong, Augustine; Frigge, Michael L; Masson, Gisli; Besenbacher, Soren; Sulem, Patrick; Magnusson, Gisli; Gudjonsson, Sigurjon A; Sigurdsson, Asgeir; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; et al. (Nature Publishing Group, 2012-08-23)
      Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.
    • A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

      Kiemeney, Lambertus A; Sulem, Patrick; Besenbacher, Soren; Vermeulen, Sita H; Sigurdsson, Asgeir; Thorleifsson, Gudmar; Gudbjartsson, Daniel F; Stacey, Simon N; Gudmundsson, Julius; Zanon, Carlo; et al. (Nature Pub. Co., 2010-05-01)
      Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
    • Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31.

      Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Helgadottir, Hafdis T; Bomer, Nils; Metrustry, Sarah; Bierma-Zeinstra, S; Strijbosch, Annelieke M; Evangelou, Evangelos; Hart, Deborah; Beekman, Marian; et al. (Nature, 2014-05)
      Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10(-10)) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10(-10)). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10(-11) (rs3204689).
    • Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

      Dichgans, Martin; Malik, Rainer; König, Inke R; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D; Assimes, Themistocles L; Levi, Christopher; et al. (Lippincott Williams & Wilkins, 2014-01)
      Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
    • Socioeconomic inequalities in stillbirth rates in Europe: measuring the gap using routine data from the Euro-Peristat Project.

      Zeitlin, Jennifer; Mortensen, Laust; Prunet, Caroline; Macfarlane, Alison; Hindori-Mohangoo, Ashna D; Gissler, Mika; Szamotulska, Katarzyna; van der Pal, Karin; Bolumar, Francisco; Andersen, Anne-Marie Nybo; et al. (BioMed Central Ltd, 2016)
      Previous studies have shown that socioeconomic position is inversely associated with stillbirth risk, but the impact on national rates in Europe is not known. We aimed to assess the magnitude of social inequalities in stillbirth rates in European countries using indicators generated from routine monitoring systems.
    • Substantial between-country differences in organising community care for older people in Europe-a review.

      Van Eenoo, Liza; Declercq, Anja; Onder, Graziano; Finne-Soveri, Harriet; Garms-Homolová, Vjenka; Jónsson, Pálmi V; Dix, Olivia H M; Smit, Johannes H; van Hout, Hein P J; van der Roest, Henriëtte G; et al. (Oxford Univ Press, 2016-04)
      The European population is aging. The main drivers of public spending on health care for people of 65 years and older are hospital admission and admission to long-term care facilities. High quality community care can be a cost-effective and quality solution to respond to the impact of ageing populations on health-care systems. It is unclear how well countries are equipped to provide affordable and quality community care. The aim of this article is to describe and compare community care delivery with care-dependent older people in Europe. 
    • A systems biology approach to drug targets in Pseudomonas aeruginosa biofilm.

      Sigurdsson, Gunnar; Fleming, Ronan M T; Heinken, Almut; Thiele, Ines; [ 1 ] Univ Iceland, Ctr Syst Biol, Reykajavik, Iceland [ 2 ] Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykajavik, Iceland (Public Library Science, 2012)
      Antibiotic resistance is an increasing problem in the health care system and we are in a constant race with evolving bacteria. Biofilm-associated growth is thought to play a key role in bacterial adaptability and antibiotic resistance. We employed a systems biology approach to identify candidate drug targets for biofilm-associated bacteria by imitating specific microenvironments found in microbial communities associated with biofilm formation. A previously reconstructed metabolic model of Pseudomonas aeruginosa (PA) was used to study the effect of gene deletion on bacterial growth in planktonic and biofilm-like environmental conditions. A set of 26 genes essential in both conditions was identified. Moreover, these genes have no homology with any human gene. While none of these genes were essential in only one of the conditions, we found condition-dependent genes, which could be used to slow growth specifically in biofilm-associated PA. Furthermore, we performed a double gene deletion study and obtained 17 combinations consisting of 21 different genes, which were conditionally essential. While most of the difference in double essential gene sets could be explained by different medium composition found in biofilm-like and planktonic conditions, we observed a clear effect of changes in oxygen availability on the growth performance. Eight gene pairs were found to be synthetic lethal in oxygen-limited conditions. These gene sets may serve as novel metabolic drug targets to combat particularly biofilm-associated PA. Taken together, this study demonstrates that metabolic modeling of human pathogens can be used to identify oxygen-sensitive drug targets and thus, that this systems biology approach represents a powerful tool to identify novel candidate antibiotic targets.
    • A systems biology approach to studying the role of microbes in human health.

      Thiele, Ines; Heinken, Almut; Fleming, Ronan M T; [ 1 ] Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland [ 2 ] Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykjavik, Iceland [ 3 ] Univ Iceland, Fac Med, Dept Biochem & Mol Biol, Reykjavik, Iceland (Current Biology, 2013-02)
      Host-microbe interactions play a crucial role in human health and disease. Of the various systems biology approaches, reconstruction of genome-scale metabolic networks combined with constraint-based modeling has been particularly successful at in silico predicting the phenotypic characteristics of single organisms. Here, we summarize recent studies, which have applied this approach to investigate microbe-microbe and host-microbe metabolic interactions. This approach can be also expanded to investigate the properties of an entire microbial community, as well as single organisms within the community. We illustrate that the constraint-based modeling approach is suitable to model host-microbe interactions at molecular resolution and will enable systematic investigation of metabolic links between the human host and its microbes. Such host-microbe models, combined with experimental data, will ultimately further our understanding of how microbes influence human health.
    • Systems biology of stored blood cells: can it help to extend the expiration date?

      Paglia, Giuseppe; Palsson, Bernhard Ø; Sigurjonsson, Olafur E; Center for Systems Biology, University of Iceland (Elsevier Science B.V., 2012)
      With increasingly stringent regulations regarding deferral and elimination of blood donors it will become increasingly important to extend the expiration date of blood components beyond the current allowed storage periods. One reason for the storage time limit for blood components is that platelets and red blood cells develop a condition called storage lesions during their storage in plastic blood containers. Systems biology provides comprehensive bio-chemical descriptions of organisms through quantitative measurements and data integration in mathematical models. The biological knowledge for a target organism can be translated in a mathematical format and used to compute physiological properties. The use of systems biology represents a concrete solution in the study of blood cell storage lesions, and it may open up new avenues towards developing better storage methods and better storage media, thereby extending the storage period of blood components. This article is part of a Special Issue entitled: Integrated omics.
    • Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia.

      Bottos, Alessia; Martini, Miriam; Di Nicolantonio, Federica; Comunanza, Valentina; Maione, Federica; Minassi, Alberto; Appendino, Giovanni; Bussolino, Federico; Bardelli, Alberto; Inst Canc Res & Treatment, Lab Vasc Oncol, I-10060 Turin, Italy, Univ Torino, Dept Oncol Sci, I-10060 Turin, Italy, Inst Canc Res & Treatment, Lab Mol Genet, I-10060 Turin, Italy, Fdn Italiana Ric Cancro, Inst Mol Oncol, I-20139 Milan, Italy, Inst Canc Res & Treatment, Lab Transgen Mouse Models, I-10060 Turin, Italy, Univ Piemonte Orientale, Dipartimento Sci Chim Alimentari Farmaceut & Farm, I-28100 Novara, Italy (Natl Acad Sciences, 2012-02-07)
      Carcinomas are comprised of transformed epithelial cells that are supported in their growth by a dedicated neovasculature. How the genetic milieu of the epithelial compartment influences tumor angiogenesis is largely unexplored. Drugs targeted to mutant cancer genes may act not only on tumor cells but also, directly or indirectly, on the surrounding stroma. We investigated the role of the BRAF(V600E) oncogene in tumor/vessel crosstalk and analyzed the effect of the BRAF inhibitor PLX4720 on tumor angiogenesis. Knock-in of the BRAF(V600E) allele into the genome of human epithelial cells triggered their angiogenic response. In cancer cells harboring oncogenic BRAF, the inhibitor PLX4720 switches off the ERK pathway and inhibits the expression of proangiogenic molecules. In tumor xenografts harboring the BRAF(V600E), PLX4720 extensively modifies the vascular network causing abrogation of hypoxia. Overall, our results provide a functional link between oncogenic BRAF and angiogenesis. Furthermore, they indicate how the tumor vasculature can be "indirectly" besieged through targeting of a genetic lesion to which the cancer cells are addicted.
    • Temporal changes and regional differences in treatment uptake of hepatitis C therapy in EuroSIDA.

      Grint, D; Peters, L; Schwarze-Zander, C; Beniowski, M; Pradier, C; Battegay, M; Jevtovic, D; Soriano, V; Lundgren, J D; Rockstroh, J K; et al. (Wiley-Blackwell, 2013-11)
      All HIV/hepatitis C virus (HCV)-coinfected patients with chronic HCV infection and ≥ F2 fibrosis should be considered for HCV therapy. This study aimed to determine the rate of HCV treatment uptake among coinfected patients in Europe.