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  • 1051.
    Yang, Hai-Tao
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Genetic analysis of autoimmune diseases using animal models: Mapping susceptibility genes for multiple sclerosis and rheumatoid arthritis2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Autoimmune diseases such as rheumatoid arthritis and multiple sclerosis are common human diseasesaffecting 1% and 0.1% of the population respectively. These diseases are characterized by abnormal self-tolerance in the immune system and autoimmune reactions. Epidemiological studies indicate that geneticcomponents together with environmental factors influence these diseases.

    The etiology of autoimmune diseases is poorly understood. Previous studies have found that MHCgenes are important for disease but these studies also indicated that additional genes are involved.

    Studies of complex diseases such as autoimmune diseases are difficult because they are caused by more than one gene or the interactions between several genes along with environmental factors. Directanalysis of complex diseases in human families is often hampered by incomplete penetrance, phenocopies and genetic heterogeneity.

    Analysing complex diseases by using animal models provides a shortcut because environmental factors can be controlled and the populations are more homogenous. This thesis work has analysed several animal models for autoimmune diseases in mice and rats by genome-wide scans and multi-trait quantitative trait loci (QTL) linkage analysis. Experimental allergic encephalomyelitis (EAE) is an animal model for human MS and collagen induced arthritis (CIA) is a model for RA.

    We found a number of susceptiblility loci for EAE and CIA which mapped to different chromosomal regions. We mapped 3 non-MHC loci in the EAE mouse model. Also. 4 loci were mapped in the mouse CIA model and 11 loci in the EAE rat model. Among these susceptibile loci, we found that some of them are shared between EAE and arthritis and therefore may contain common autoimmune disease genes.

  • 1052.
    Yang, Jian
    et al.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia..
    Bakshi, Andrew
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Zhu, Zhihong
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Hemani, Gibran
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Bristol, Sch Social & Community Med, IEU, MRC, Bristol, Avon, England..
    Vinkhuyzen, Anna A. E.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Lee, Sang Hong
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ New England, Sch Environm & Rural Sci, Armidale, NSW, Australia..
    Robinson, Matthew R.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Perry, John R. B.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Boston Childrens Hosp, Div Endocrinol, Cambridge, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Maegi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Soranzo, Nicole
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Dept Haematol, Cambridge, England..
    Keller, Matthew C.
    Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA.;Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA..
    Wray, Naomi R.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Goddard, Michael E.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia.;Jobs Transport & Resources, Dept Econ Dev, Biosci Res Div, Bundoora, Vic, Australia..
    Visscher, Peter M.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia..
    Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index2015Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 10, s. 1114-1120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that similar to 97% and similar to 68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all similar to 17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

  • 1053. Yang, Lei
    et al.
    Zhao, Guang-Hui
    Liu, Huan
    Wang, Xi
    Guo, Xiong
    Lammi, Mikko J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). School of Public Health, Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi’an, People’s Republic of China.
    Field synopsis and meta-analyses of genetic epidemiological evidence for Kashin-Beck disease, an endemic osteoarthropathy in China2016Inngår i: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 291, nr 5, s. 1823-1833, artikkel-id 27256326Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kashin-Beck disease (KBD) is a chronic degenerative osteoarthropathy with unclear etiology. To provide current evidence supporting a genetic predisposition for KBD, we conducted a systematic review and meta-analysis of published literature on the genetic epidemiology of KBD. The PubMed, China National Knowledge Infrastructure and Wan Fang Data were searched up to August 2015 for articles published in English and Chinese. Genome-wide and exome sequencing, linkage, and case-control association studies for any genetic variants associated with KBD were included. Meta-analysis was performed for all single nucleotide polymorphisms (SNPs) that were evaluated in two or more studies. The effect size was summarized as odds ratios (ORs) with 95 % confidence intervals (CIs) by fixed and random effects models. A total of 24 articles were systematically reviewed. Eleven short tandem repeats on chromosomes 2, 11 and 12, 34 SNPs in 12 genes, as well as copy number variant 452 were identified as KBD susceptibility factors in individual studies. The meta-analysis of the GPX1 rs1050450, DIO2 rs225014, TrxR2 rs5748469 and HLA-DRB1 rs7745040 failed to reveal any associations with KBD. However, the meta-analysis of HLA-DRB1 rs9275295 allele A was associated with KBD (OR = 1.737, 95 % CI: 1.002-3.012). In addition, seven haplotypes in GPX1, GPX4, HLA-DRB1 and GDF5 genes also showed significant associations with KBD. In conclusions, our study could identify a number of genetic markers associated with KBD. However, the evidence does not currently support a strong association between the specific variants and KBD because of the limited number of studies, and in the future, more rigorous studies are needed to confirm KBD's links with these variants.

  • 1054. Yoshida, Kazumasa
    et al.
    Bacal, Julien
    Desmarais, Damien
    Padioleau, Ismaël
    Tsaponina, Olga
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pantesco, Véronique
    Dubois, Emeric
    Parrinello, Hugues
    Skrzypczak, Magdalena
    Ginalski, Krzysztof
    Lengronne, Armelle
    Pasero, Philippe
    The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast2014Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 54, nr 4, s. 691-697Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In S. cerevisiae, replication timing is controlled by epigenetic mechanisms restricting the accessibility of origins to limiting initiation factors. About 30% of these origins are located within repetitive DNA sequences such as the ribosomal DNA (rDNA) array, but their regulation is poorly understood. Here, we have investigated how histone deacetylases (HDACs) control the replication program in budding yeast. This analysis revealed that two HDACs, Rpd3 and Sir2, control replication timing in an opposite manner. Whereas Rpd3 delays initiation at late origins, Sir2 is required for the timely activation of early origins. Moreover, Sir2 represses initiation at rDNA origins, whereas Rpd3 counteracts this effect. Remarkably, deletion of SIR2 restored normal replication in rpd3Δ cells by reactivating rDNA origins. Together, these data indicate that HDACs control the replication timing program in budding yeast by modulating the ability of repeated origins to compete with single-copy origins for limiting initiation factors.

  • 1055.
    Younis, Shady
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala University.
    Functional characterization of the biological significance of the ZBED6/ZC3H11A locus in placental mammals2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The recent advances in molecular and computational biology have made possible the study of complicated transcriptional regulatory networks that control a wide range of biological processes and phenotypic traits. In this thesis, several approaches were combined including next generation sequencing, gene expression profiling, chromatin and RNA immunoprecipitation, bioinformatics and genome editing methods in order to characterize the biological significance of the ZBED6 and ZC3H11A genes.

    A mutation in the binding site of ZBED6, located in an intron of IGF2, disrupts the binding and leads to 3-fold upregulation of IGF2 mRNA in pig muscle tissues. The first part of the thesis presents a detailed functional characterization of ZBED6. Transient silencing of ZBED6 expression in mouse myoblasts led to increased Igf2 expression (~2-fold). ChIP-seq analysis of ZBED6 and histone modifications showed that ZBED6 preferentially binds active promoters and modulates their transcriptional activities (paper I). In the follow-up studies using CRISPR/Cas9 we showed that either the deletion of ZBED6 or its binding site in Igf2 (Igf2ΔGGCT) led to more than 30-fold up-regulation of Igf2 expression in myoblasts. Differentiation of these genetically engineered cells resulted in hypertrophic myotubes. Transcriptome analysis revealed ~30% overlap between the differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with significant enrichment of muscle-specific genes. ZBED6-overexpression in myoblasts led to cell cycle arrest, reduced cell viability, reduced mitochondrial activities and impaired the differentiation of myoblasts (paper II). Further studies on cancer cells showed that ZBED6 influences the growth of colorectal cancer cells with dramatic changes in the transcription of hundreds of cancer-related genes (paper III). The phenotypic characterization of Zbed6-/- and Igf2pA/mG mouse models showed that the ZBED6-Igf2 axis has a major effect on regulating muscle growth and the growth of internal organs. Transcriptome analysis demonstrated a massive up-regulation of Igf2 expression (~30-fold) in adult tissues, but not in fetal tissues, of transgenic mice (paper IV).

    In the second part of the thesis we investigated the cellular function of Zc3h11a, the gene harboring ZBED6 in one of its first introns. The function of the ZC3H11A protein is so far poorly characterized. We show that ZC3H11A is a novel stress-induced protein that is required for efficient mRNA export from the nucleus. The inactivation of ZC3H11A inhibited the growth of multiple viruses including HIV, influenza, HSV and adenoviruses (paper V).

  • 1056.
    Younis, Shady
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Kamel, Wael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wang, Hao
    Department of Biochemistry and Biophysics, Stockholm University.
    Yu, Di
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Daniels, Robert
    Department of Biochemistry and Biophysics, Stockholm University.
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hinkula, Jorma
    Department of Clinical and Experimental Medicine, Linköping University.
    Akusjärvi, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Andersson, Leif
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Multiple viruses rely on the stress-induced protein ZC3H11A for efficient replication2017Manuskript (preprint) (Annet vitenskapelig)
  • 1057. Yousefzadeh, M. J.
    et al.
    Wyatt, D. W.
    Takata, K.
    Mu, Y.
    Hensley, S. C.
    Tomida, J.
    Bylund, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doublie, S.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ramsden, D. A.
    McBride, K. M.
    Wood, R. D.
    Mammalian POLQ, Chromosome Stability and DNA Double-Strand Break Repair2015Inngår i: Environmental and Molecular Mutagenesis, ISSN 0893-6692, E-ISSN 1098-2280, Vol. 56, s. S48-S48Artikkel i tidsskrift (Annet vitenskapelig)
  • 1058. Yousefzadeh, Matthew J
    et al.
    Wyatt, David W
    Takata, Kei-Ichi
    Mu, Yunxiang
    Hensley, Sean C
    Tomida, Junya
    Bylund, Göran O
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doublié, Sylvie
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ramsden, Dale A
    McBride, Kevin M
    Wood, Richard D
    Mechanism of suppression of chromosomal instability by DNA polymerase POLQ2014Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 10, s. e1004654-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.

  • 1059.
    Yu, N
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Fu, YX
    Sambuughin, N
    Ramsay, M
    Jenkins, T
    Leskinen, E
    Patthy, L
    Jorde, LB
    Kuromori, T
    Li, WH
    Global patterns of human DNA sequence variation in a 10-kb region on chromosome 12001Inngår i: MOLECULAR BIOLOGY AND EVOLUTION, Vol. 18, nr 2, s. 214-222Artikkel i tidsskrift (Fagfellevurdert)
  • 1060.
    Zaghlool, Ammar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Genome-wide Characterization of RNA Expression and Processing2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The production of fully mature protein-coding transcripts is an intricate process that involves numerous regulation steps. The complexity of these steps provides the means for multilayered control of gene expression. Comprehensive understanding of gene expression regulation is essential for interpreting the role of gene expression programs in tissue specificity, development and disease. In this thesis, we aim to provide a better global view of the human transcriptome, focusing on its content, synthesis, processing and regulation using next-generation sequencing as a read-out.

    In Paper I, we show that sequencing of total RNA provides unique insights into RNA processing. Our results revealed that co-transcriptional splicing is a widespread mechanism in human and chimpanzee brain tissues. We also found a correlation between slowly removed introns and alternative splicing. In Paper II, we explore the benefits of exome capture approaches in combination with RNA-sequencing to detect transcripts expressed at low-levels. Based on our results, we demonstrate that this approach increases the sensitivity for detecting low level transcripts and leads to the identification of novel exons and splice isoforms. In Paper III, we highlight the advantages of performing RNA-sequencing on separate cytoplasmic and nuclear RNA fractions. In comparison with conventional poly(A) RNA, cytoplasmic RNA contained a significantly higher fraction of exonic sequence, providing increased sensitivity for splice junction detection and for improved de novo assembly. Conversely, the nuclear fraction showed an enrichment of unprocessed RNA compared to when sequencing total RNA, making it suitable for analysis of RNA processing dynamics. In Paper IV, we used exome sequencing to sequence the DNA of a patient with unexplained intellectual disability and identified a de novo mutation in BAZ1A, which encodes the chromatin-remodeling factor ACF1. Functional studies indicated that the mutation influences the expression of genes involved in extracellular matrix organization, synaptic function and vitamin D3 metabolism. The differential expression of CYP24A, SYNGAP1 and COL1A2 correlated with the patient’s clinical diagnosis.

    The findings presented in this thesis contribute towards an improved understanding of the human transcriptome in health and disease, and highlight the advantages of developing novel methods to obtain global and comprehensive views of the transcriptome.

  • 1061.
    Zaghlool, Ammar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Splicing in the Human Brain2014Inngår i: Brain Transcriptome, Elsevier, 2014, s. 95-125Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    It has become increasingly clear over the past decade that RNA has important functions in human cells beyond its role as an intermediate translator of DNA to protein. It is now known that RNA plays highly specific roles in pathways involved in regulatory, structural, and catalytic functions. The complexity of RNA production and regulation has become evident with the advent of high-throughput methods to study the transcriptome. Deep sequencing has revealed an enormous diversity of RNA types and transcript isoforms in human cells. The transcriptome of the human brain is particularly interesting as it contains more expressed genes than other tissues and also displays an extreme diversity of transcript isoforms, indicating that highly complex regulatory pathways are present in the brain. Several of these regulatory proteins are now identified, including RNA-binding proteins that are neuron specific. RNA-binding proteins also play important roles in regulating the splicing process and the temporal and spatial isoform production. While significant progress has been made in understanding the human transcriptome, many questions still remain regarding the basic mechanisms of splicing and subcellular localization of RNA. A long-standing question is to what extent the splicing of pre-mRNA is cotranscriptional and posttranscriptional, respectively. Recent data, including studies of the human brain, indicate that splicing is primarily cotranscriptional in human cells. This chapter describes the current understanding of splicing and splicing regulation in the human brain and discusses the recent global sequence-based analyses of transcription and splicing.

  • 1062.
    Zainuddin, Norafiza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Molecular Genetic Analysis in B-cell Lymphomas: A Focus on the p53 Pathway and p16INK4a2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The presence of TP53 mutations has been associated with inferior outcome in diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In DLBCL, the impact of the TP53 codon 72 polymorphism and MDM2 SNP309 has not been clearly elucidated, whereas MDM2 SNP309 was suggested as a poor-prognostic marker in CLL. In addition, p16INK4a promoter hypermethylation has been implicated as a negative prognostic factor in DLBCL. The aim of this thesis was to further evaluate these molecular markers in well-characterised materials of DLBCL and CLL.

    In paper I, we investigated the prognostic role of TP53 mutation, codon 72 polymorphism and MDM2 SNP309 in DLBCL (n=102). The presence of TP53 mutations (12.7%) correlated with a poor lymphoma-specific and progression-free survival, and a particularly pronounced effect was observed in the germinal center subtype. Neither the MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. In paper II, we applied pyrosequencing to measure the level of p16INK4a methylation in DLBCL (n=113). Thirty-seven percent of cases displayed p16INK4a methylation; however, no clear association could be observed between degree of methylation and clinical characteristics or lymphoma-specific survival.

    In papers III–IV, we investigated the prognostic role of MDM2 SNP309 (n=418) and TP53 mutation (n=268) in CLL. No correlation was observed between any particular MDM2 SNP309 genotype and time to treatment and overall survival. Furthermore, no association was found between the different MDM2 SNP309 genotypes and established CLL prognostic markers. TP53 mutations were detected in 3.7% of CLL patients; where the majority showed a concomitant 17p-deletion and only three carried TP53 mutations without 17p-deletion. We confirmed a significantly shorter overall survival and time to treatment in patients with both TP53 mutation and 17p-deletion.

    Altogether, our studies could confirm the negative prognostic impact of TP53 mutations in DLBCL, whereas MDM2 SNP309 and TP53 codon 72 polymorphisms appear to lack clinical relevance. We also question the role of p16INKa methylation as a poor-prognostic factor in DLBCL. Finally, the presence of TP53 mutation in CLL appears to be rare at disease onset and instead arise during disease progression.

  • 1063. Zambrano, Regina M.
    et al.
    Wohler, Elizabeth
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Thuresson, Ann-Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Cutting, Garry R.
    Batista, Denise A.
    Unbalanced translocation 9;16 in two children with dysmorphic features, and severe developmental delay: Evidence of cross-over within derivative chromosome 9 in patient #12011Inngår i: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 54, nr 2, s. 189-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe 2 children with dysmorphic features, and severe developmental delay presenting with overlapping unbalanced translocations of 9q34.3 and 16p13. Patient #1: A 4 year old African-American female with normal karyotype with a pericentric inversion on one chromosome 9 known to be a benign variant. Low resolution array CGH revealed a single BAC clone loss at 9q34.3 and a single BAC clone gain at 16p13.3, confirmed by FISH. Whole genome SNP array analysis refined these findings, identifying a terminal 1.28 Mb deletion (138,879,862-140,164,310) of 9q34.3 and a terminal 1.62 Mb duplication (45,320-1,621,753) of 16p13.3. Sub-telomeric FISH showed an unbalanced cryptic translocation involving the inverted chromosome 9 and chromosome 16. FISH of the father showed a balanced t(9;16) (q34.3;p13.3) involving the non-inverted chromosome 9, and a pericentric inversion on the normal 9 homologous chromosome. The presence of two rearrangements on chromosome 9, both an unbalanced translocation and a pericentric inversion, indicates recombination between the inverted and derivative 9 homologues from her father. Patient #2: A 1 year old Iraqi-Moroccan female with normal karyotype. Array-CGH identified a 0.56 Mb deletion of 9q34.3 (139,586,637-140,147,760) and an 11.31 Mb duplication of 16p13.3p13.13 (31,010-11,313,519). Maternal FISH showed a balanced t(9;16)(q34.3;p13.13). Both patients present with similar clinical phenotype.

  • 1064.
    Zander, Cecilia Soussi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Beckwith-Wiedemann Syndrome Revisited.2015Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 9Artikkel i tidsskrift (Fagfellevurdert)
  • 1065.
    Zander, Cecilia Soussi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Soussi, Thierry
    Breast-cancer stromal cells with TP53 mutations.2008Inngår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, nr 15Artikkel i tidsskrift (Fagfellevurdert)
  • 1066. Zeisel, Amit
    et al.
    Munoz-Manchado, Ana B.
    Codeluppi, Simone
    Lonnerberg, Peter
    La Manno, Gioele
    Jureus, Anna
    Marques, Sueli
    Munguba, Hermany
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Rolny, Charlotte
    Castelo-Branco, Goncalo
    Hjerling-Leffler, Jens
    Linnarsson, Sten
    Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq2015Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, nr 6226, s. 1138-1142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Here, we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in the mouse somatosensory cortex and hippocampal CA1 region. We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex. We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location. We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity.

  • 1067.
    Zelano, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Mikulovic, Sanja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Patra, Kalicharan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Kühnemund, Malte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Larhammar, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Emilsson, Lina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Leao, Richardson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Kullander, Klas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants2013Inngår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 239, s. 73-81Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.

  • 1068. Zeller, Bernward
    et al.
    Glosli, Heidi
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ha, Shau-Yin
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Hasle, Henrik
    Abrahamsson, Jonas
    Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 x 10(9)/l. The NOPHO experience 1984-20142017Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, nr 3, s. 448-456Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC > 200 x 10/l). Eighty-six patients (10%) had WBC 100-199 x 10(9)/l and 57 (6%) had WBC >= 200 x 10(9)/l. Patients with WBC >= 200 x 10(9)/l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 x 10(9)/l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.

  • 1069.
    Zeng, Chenjie
    et al.
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Guo, Xingyi
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Long, Jirong
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Kuchenbaecker, Karoline B.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Droit, Arnaud
    Univ Laval, Prote Ctr, CHU Quebec Res Ctr, Quebec City, PQ G1K 7P4, Canada.;Univ Laval, Dept Mol Med, Quebec City, PQ G1K 7P4, Canada..
    Michailidou, Kyriaki
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Ghoussaini, Maya
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Kar, Siddhartha
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Freeman, Adam
    St Vincent Hosp, Dept Surg, Melbourne, Vic, Australia..
    Hopper, John L.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia..
    Milne, Roger L.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia.;Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia..
    Bolla, Manjeet K.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Wang, Qin
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Dennis, Joe
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Agata, Simona
    IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy..
    Ahmed, Shahana
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Aittomaki, Kristiina
    Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland..
    Andrulis, Irene L.
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Anton-Culver, Hoda
    Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA..
    Antonenkova, Natalia N.
    NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus..
    Arason, Adalgeir
    Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland.;Univ Iceland, Fac Med, BMC Biomed Ctr, Reykjavik, Iceland..
    Arndt, Volker
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany..
    Arun, Banu K.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Arver, Brita
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden..
    Bacot, Francois
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Barrowdale, Daniel
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Baynes, Caroline
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Beeghly-Fadiel, Alicia
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Benitez, Javier
    Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain.;Ctr Invest Red Enfermedades Raras, Valencia, Spain..
    Bermisheva, Marina
    Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia..
    Blomqvist, Carl
    Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland..
    Blot, William J.
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA.;Int Epidemiol Inst, Rockville, MD USA..
    Bogdanova, Natalia V.
    Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany..
    Bojesen, Stig E.
    Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark.;Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Bonanni, Bernardo
    Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy..
    Borresen-Dale, Anne-Lise
    Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway.;Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway..
    Brand, Judith S.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.;Univ Tubingen, Tubingen, Germany.;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany..
    Brennan, Paul
    Int Agcy Res Canc, Lyon, France..
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany..
    Broeks, Annegien
    Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway.;Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands..
    Bruening, Thomas
    Inst Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accident, Bochum, Germany..
    Burwinkel, Barbara
    Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany.;German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany..
    Buys, Saundra S.
    Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA..
    Cai, Qiuyin
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Caldes, Trinidad
    Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain..
    Campbell, Ian
    Peter MacCallum Canc Ctr, Canc Gene Lab, Melbourne, Vic, Australia..
    Carpenter, Jane
    Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW, Australia..
    Chang-Claude, Jenny
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.;Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany..
    Choi, Ji-Yeob
    Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea.;Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea.;Seoul Natl Univ, Canc Res Inst, Seoul, South Korea..
    Claes, Kathleen B. M.
    Univ Ghent, Ctr Med Genet, Ghent, Belgium..
    Clarke, Christine
    Univ Sydney, Westmead Millenium Inst Med Res, Sydney, NSW, Australia..
    Cox, Angela
    Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England..
    Cross, Simon S.
    Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England..
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Daly, Mary B.
    Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA..
    de la Hoya, Miguel
    Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain..
    De Leeneer, Kim
    Univ Ghent, Ctr Med Genet, Ghent, Belgium..
    Devilee, Peter
    Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands..
    Diez, Orland
    Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona, Spain.;Univ Autonoma Barcelona, Barcelona, Spain..
    Domchek, Susan M.
    Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Doody, Michele
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Dorfling, Cecilia M.
    Univ Pretoria, Dept Genet, Pretoria, South Africa..
    Doerk, Thilo
    Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany..
    dos-Santos-Silva, Isabel
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England..
    Dumont, Martine
    Univ Laval, Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada..
    Dwek, Miriam
    Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England..
    Dworniczak, Bernd
    Inst Human Genet, Munster, Germany..
    Egan, Kathleen
    H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL USA..
    Eilber, Ursula
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany..
    Einbeigi, Zakaria
    Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden..
    Ejlertsen, Bent
    Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark..
    Ellis, Steve
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Frost, Debra
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Lalloo, Fiona
    Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Genet Med, Manchester, Lancs, England..
    Fasching, Peter A.
    Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany.;Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA..
    Figueroa, Jonine
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Flyger, Henrik
    Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark..
    Friedlander, Michael
    Australia New Zealand GOG, ANZ GOTG Coordinating Ctr, Camperdown, NSW, Australia..
    Friedman, Eitan
    Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel..
    Gambino, Gaetana
    Univ Pisa, Deparment Lab Med, Sect Genet Oncol, Pisa, Italy.;Univ Hosp Pisa, Pisa, Italy..
    Gao, Yu-Tang
    Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China..
    Garber, Judy
    Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA..
    Garcia-Closas, Montserrat
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA.;Inst Canc Res, Div Genet & Epidemiol, London, England..
    Gehrig, Andrea
    Univ Wurzburg, Inst Human Genet, Wurzburg, Germany..
    Damiola, Francesca
    Univ Lyon, CNRS, INSERM, Ctr Rech Cancerol Lyon,U1052,UMR5286, Lyon, France..
    Lesueur, Fabienne
    Mines ParisTech, Inst Curie, INSERM, Genet Epidemiol Canc Team,U900, F-75248 Paris, France..
    Mazoyer, Sylvie
    Univ Lyon, CNRS, INSERM, Ctr Rech Cancerol Lyon,U1052,UMR5286, Lyon, France..
    Stoppa-Lyonnet, Dominique
    Inst Curie, Dept Tumor Biol, Paris, France.;INSERM, Inst Curie, U830, Paris, France.;Univ Paris 05, Sorbonne Paris Cite, Paris, France..
    Giles, Graham G.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia.;Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia..
    Godwin, Andrew K.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.;Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA..
    Goldgar, David E.
    Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT USA..
    Gonzalez-Neira, Anna
    Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain..
    Greene, Mark H.
    NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA..
    Guenel, Pascal
    INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France.;Univ Paris 11, Villejuif, France..
    Haeberle, Lothar
    Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany..
    Haiman, Christopher A.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Hallberg, Emily
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Hamann, Ute
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany..
    Hansen, Thomas V. O.
    Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark..
    Hart, Steven
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Hartikainen, Jaana M.
    Kuopio Univ Hosp, Ctr Canc, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland..
    Hartman, Mikael
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore..
    Hassan, Norhashimah
    Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia.;Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia..
    Healey, Sue
    QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia..
    Hogervorst, Frans B. L.
    Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands..
    Verhoef, Senno
    Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands..
    Hendricks, Carolyn B.
    Suburban Hosp, Bethesda, MD USA.;City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Duarte, CA USA..
    Hillemanns, Peter
    Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany..
    Hollestelle, Antoinette
    Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands..
    Hulick, Peter J.
    NorthShore Univ HealthSyst, Ctr Med Genet, Evanston, IL USA..
    Hunter, David J.
    Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Imyanitov, Evgeny N.
    NN Petrov Inst Oncol, St Petersburg, Russia..
    Isaacs, Claudine
    Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA..
    Ito, Hidemi
    Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan..
    Jakubowska, Anna
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Janavicius, Ramunas
    State Res Inst, Ctr Innovat Med, Vilnius, Lithuania..
    Jaworska-Bieniek, Katarzyna
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Jensen, Uffe Birk
    Aarhus Univ Hosp, Dept Clin Genet, Aarhus N, Denmark..
    John, Esther M.
    Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA.;Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA.;Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA..
    Beauparlant, Charles Joly
    Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada.;Univ Laval, Quebec City, PQ, Canada..
    Jones, Michael
    Inst Canc Res, Div Genet & Epidemiol, London, England..
    Kabisch, Maria
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany..
    Kang, Daehee
    Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea.;Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea.;Seoul Natl Univ, Canc Res Inst, Seoul, South Korea..
    Karlan, Beth Y.
    Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA..
    Kauppila, Saila
    Univ Oulu, Oulu Univ Hosp, Dept Pathol, Oulu, Finland..
    Kerin, Michael J.
    Natl Univ Ireland, Sch Med, Galway, Ireland..
    Khan, Sofia
    Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland..
    Khusnutdinova, Elza
    Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia.;Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia..
    Knight, Julia A.
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON, Canada.;Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada..
    Konstantopoulou, Irene
    Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece..
    Kraft, Peter
    Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Kwong, Ava
    Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China.;Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China..
    Laitman, Yael
    Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel..
    Lambrechts, Diether
    Vesalius Res Ctr, Leuven, Belgium.;Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium..
    Lazaro, Conxi
    Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain..
    Le Marchand, Loic
    Univ Hawaii, Ctr Canc, Honolulu, HI USA..
    Lee, Chuen Neng
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Lee, Min Hyuk
    Soonchunhyang Univ & Hosp, Dept Surg, Seoul, South Korea..
    Lester, Jenny
    Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA..
    Li, Jingmei
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Liljegren, Annelie
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden..
    Lindblom, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lophatananon, Artitaya
    Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England..
    Lubinski, Jan
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Mai, Phuong L.
    NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA..
    Mannermaa, Arto
    Kuopio Univ Hosp, Ctr Canc, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland..
    Manoukian, Siranoush
    INT, Fdn IRCCS Ist Ricovero Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy..
    Margolin, Sara
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Marme, Frederik
    Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany.;Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany..
    Matsuo, Keitaro
    Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka, Japan..
    McGuffog, Lesley
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Meindl, Alfons
    Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany..
    Menegaux, Florence
    INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France.;Univ Paris 11, Villejuif, France..
    Montagna, Marco
    IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy..
    Muir, Kenneth
    Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England.;Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England..
    Mulligan, Anna Marie
    Univ Hlth Network, Lab Med Program, Toronto, ON, Canada.;Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada..
    Nathanson, Katherine L.
    Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Neuhausen, Susan L.
    City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA..
    Nevanlinna, Heli
    Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland..
    Newcomb, Polly A.
    Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA.;Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA USA..
    Nord, Silje
    Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway..
    Nussbaum, Robert L.
    Univ Calif San Francisco, Dept Med Genet, San Francisco, CA 94143 USA..
    Offit, Kenneth
    Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA.;Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA..
    Olah, Edith
    Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary..
    Olopade, Olufunmilayo I.
    Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA..
    Olswold, Curtis
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Osorio, Ana
    Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain.;Biomed Network Rare Dis CIBERER, Madrid, Spain..
    Papi, Laura
    Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy..
    Park-Simon, Tjoung-Won
    Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany..
    Paulsson-Karlsson, Ylva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Peeters, Stephanie
    Univ Hosp Gasthuisberg, Leuven, Belgium..
    Peissel, Bernard
    INT, Fdn IRCCS Ist Ricovero Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy..
    Peterlongo, Paolo
    Fdn Ist FIRC Italian Fdn Canc Res Oncol Mol, IFOM, Milan, Italy..
    Peto, Julian
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England..
    Pfeiler, Georg
    Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria.;Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria..
    Phelan, Catherine M.
    H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA..
    Presneau, Nadege
    Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England..
    Radice, Paolo
    INT, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy..
    Rahman, Nazneen
    Inst Canc Res, Sect Canc Genet, London, England..
    Ramus, Susan J.
    Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Rashid, Muhammad Usman
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany.;SKMCH & RC, Dept Basic Sci, Lahore, Pakistan..
    Rennert, Gad
    Clalit Natl Israeli Canc Control Ctr, Haifa, Israel.;Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel.;B Rappaport Fac Med, Haifa, Israel..
    Rhiem, Kerstin
    Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany.;Univ Hosp Cologne, CIO, CMMC, Cologne, Germany..
    Rudolph, Anja
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany..
    Salani, Ritu
    Ohio State Univ, Coll Med, Obstet & Gynecol, Columbus, OH 43210 USA..
    Sangrajrang, Suleeporn
    Natl Canc Inst, Bangkok, Thailand..
    Sawyer, Elinor J.
    Kings Coll London, Guys Hosp, Res Oncol, London, England..
    Schmidt, Marjanka K.
    Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands..
    Schmutzler, Rita K.
    Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany.;Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany.;Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany.;Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany..
    Schoemaker, Minouk J.
    Inst Canc Res, Div Genet & Epidemiol, London, England..
    Schuermann, Peter
    Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany..
    Seynaeve, Caroline
    Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands..
    Shen, Chen-Yang
    China Med Univ, Sch Publ Hlth, Taichung, Taiwan.;Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan..
    Shrubsole, Martha J.
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Shu, Xiao-Ou
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Sigurdson, Alice
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Singer, Christian F.
    Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria..
    Slager, Susan
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA..
    Soucy, Penny
    Ctr Hosp Univ Quebec Res Ctr, Quebec City, PQ, Canada.;Univ Laval, Quebec City, PQ, Canada..
    Southey, Melissa
    Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia..
    Steinemann, Doris
    Univ Lyon, CNRS, INSERM, Ctr Rech Cancerol Lyon,U1052,UMR5286, Lyon, France.;Hannover Med Sch, Hannover, Germany..
    Swerdlow, Anthony
    Inst Canc Res, Div Genet & Epidemiol, London, England.;Inst Canc Res, Div Breast Canc Res, London, England..
    Szabo, Csilla I.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Tchatchou, Sandrine
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada..
    Teixeira, Manuel R.
    Portuguese Oncol Inst, Dept Genet, Oporto, Portugal.;Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal..
    Teo, Soo H.
    Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia.;Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia..
    Terry, Mary Beth
    Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA..
    Tessier, Daniel C.
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Teule, Alex
    Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Genet Counseling Unit, Barcelona, Spain..
    Thomassen, Mads
    Odense Univ Hosp, Dept Clin Genet, Odense C, Denmark..
    Tihomirova, Laima
    Latvian Biomed Res & Study Ctr, Riga, Latvia..
    Tischkowitz, Marc
    McGill Univ, Program Canc Genet, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Dept Oncol, Montreal, PQ, Canada.;Univ Cambridge, Sch Med, Cambridge, England..
    Toland, Amanda E.
    Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH USA..
    Tung, Nadine
    Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA..
    Turnbull, Clare
    Inst Canc Res, Sect Canc Genet, London, England..
    van den Ouweland, Ans M. W.
    Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands..
    van Rensburg, Elizabeth J.
    Univ Pretoria, Dept Genet, Pretoria, South Africa..
    ven den Berg, David
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA.;Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA..
    Wang-Gohrke, Shan
    Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany..
    Weitzel, Jeffrey N.
    City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA USA..
    Whittemore, Alice S.
    Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA.;Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA..
    Winqvist, Robert
    Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Chem, Oulu, Finland.;Univ Oulu, Bioctr Oulu, Oulu, Finland.;Ctr NordLab Oulu, Northern Finland Lab, Lab Canc Genet & Tumor Biol, Oulu, Finland..
    Wong, Tien Y.
    Natl Univ Singapore, Singapore Eye Res Inst, Singapore, Singapore..
    Wu, Anna H.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Yannoukakos, Drakoulis
    Aristotle Univ Thessaloniki, Sch Med, Papageorgiou Hosp, Dept Med Oncol, Thessaloniki, Greece..
    Yu, Jyh-Cherng
    Natl Taiwan Univ Hosp, Dept Surg, Taipei, Taiwan..
    Pharoah, Paul D. P.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.;Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Hall, Per
    Univ Laval, Prote Ctr, CHU Quebec Res Ctr, Quebec City, PQ G1K 7P4, Canada.;Univ Laval, Dept Mol Med, Quebec City, PQ G1K 7P4, Canada..
    Chenevix-Trench, Georgia
    QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia.;Univ Melbourne, Peter MacCallum Canc Inst, Melbourne, Vic, Australia..
    Dunning, Alison M.
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Simard, Jacques
    Univ Laval, Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada..
    Couch, Fergus J.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA..
    Antoniou, Antonis C.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
    Easton, Douglas F.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.;Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England..
    Zheng, Wei
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA..
    Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus2016Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 18, artikkel-id 64Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

  • 1070.
    Zhang, Wei Wei
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Microangiopathies of the human brain b immunohistochemical studies on extracellular matrix components in arterial vessels and endothelin1997Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Microangiopathies may cause ischemic brain lesions and are of fundamental importance in vascular dementia. Risk factors include high age, hypertension, diabetes and Alzheimer's disease. In addition, recent studies have focused on autosomal dominant types of arteriopathy causing leukoencephalopathy,psychiatric disturbances, stroke and dementia (CADASIL). This thesis concerns various collagens andbasal lamina components which are deposited in vascular walls of cases presenting cerebral microangiopathy. In addition, endothelin-like immunoreactivity has been studied in CADASIL cases andsome other brain diseases.

    CADASIL cases described by Sourander and Wålinder (1977) were re-investigated. Those with longduration of the disease presented marked expression of fibrillary collagen types I, Ill, V and VI and of thebasal lamina components, collagen type IV and laminin. Deposits appeared also in non-familial casespresenting hyalinosis and in cases with the Binswanger type of leukoencephalopathy. Media degeneration and deposition of fibrillary collagens will in CADASIL, Binswanger's disease and hyalinosis graduallytransform the vessels to obliterated stiff tubings which can not properly regulate blood flow. On the otherhand, many vessels in cases with amyloid angiopathy did not show accumulations of collagens I, Ill and V. Such vessels may be more prone to rupture and cerebral hemorrhages than those in which fibrillarycollagens have been deposited. Finally, studies on CADASIL cases, other cases with brain infarcts, lacunas and Alzheimer's disease demonstrated an endothelin-like immunoreactivity in reactive perivascular astrocytes. The idea was therefore proposed that during the course of brain lesions activated astrocytes start a production of endothelin-1 which after release may reach nearby microvessels and inducevaseconstriction leading to additional brain injury.

    Structural as well as humoral factors are both most likely important for the production of brain lesionsin cases presenting cerebral microangiopathies.

  • 1071.
    Zhang, Xiao-Qun
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Functional Studies on the PDGFR α gene promoter and effects of autocrine PDGF-A stimulation in vivo2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Platelet-derived growth factor receptor α (PDGFRα) plays an important role during embryogenesis. After implantation, the patterns of expression of Pdgfrα and its ligand Pdgf-A undergo an "autocrine-paracrine transition", in that Pdgf-A becomes expressed in the ectoderm and epithelia, while Pdgfrα is expressed in the adjacent mesenchymal tissue. In human tumors, such as malignant glioma, both PDGF and PDGFRα are overexpressed within the same tissue, indicating that an autocrine PDGF loop is generated in the tumors. This thesis is focused on the in vivo functionality of the PDGFRα gene (PDGFRA) promoter, arid on the effect of autocrine PDGF-A stimulation in transgenic n-iice during embryogenesis.

    To test the in vivo promoter function of a human PDGFRA 2.2 kb 5' flanking fragment, we generated transgenic mouse lines and found that the 2.2 kb fragment was able to promote lacZ reporter gene expression in most of the endogenous Pdgfra expressing tissues. Absence of expression and "ectopic" expression of the transgenic lacZ were also observed. To investigate the autocrine PDGF effect, we produced autocrine PDGF-As (A short-chain) transient transgenic embryos. These transgenic embryos carried a 6 kb mouse Pdgfra 5' flanking sequence linked to a human PDGF-As cDNA. The pattern of expression of the PDGF-As transgene mRNA was similar to that of lacZ. Some of the transgenic embryos exhibited severe abnormal phenotypes, such as midline fusion defects in the cephalic and craniofacial region and small body size, and these embryos die at mid-gestation stage. These findings indicate that a paracrine pattern of expression and the dosage of PDGF are important for sustaining normal embryo development, especially with regard to the middline fusion in craniofacial regions.

    The possible signaling pathways that may be involved in regulating Pdgfra activity were also studied by comparison of patterns of mRNA expression of Gli, Ptc, and Paxl with that of Pdgfra. The results pointed to the possibility that the Shh signaling pathway may be involved in the regulation of Pdgfra expression for example during early bone and foregut development. The specific regulatory mechanisms may vary for different tissues.

  • 1072.
    Zhang, Xiao-Qun
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    Afink, Gijs
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    Svensson, Kristian
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Zoologisk utvecklingsbiologi.
    Jacobs, Jacqueline J.L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    Gunther, T
    Forsberg-Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    vanZoelen, EJJ
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    Nister, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för patologi.
    Specific expression in mouse mesoderm- and neural crest-derived tissues of a human PDGFRA promoter/lacZ transgene1998Inngår i: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 70, nr 1-2, s. 167-180Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The platelet-derived growth factor alpha-receptor (PDGFR-alpha) displays a lineage-specific expression pattern in the mouse embryo and is required for normal development of mesoderm and cephalic neural crest derivatives. The purpose of the present study was to demonstrate the in vivo promoter function of genomic DNA fragments representing the 5'-flanking part of the human PDGFRA gene. 2.2, 0.9 and 0.4 kb PDGFRA promoter fragments, ligated to a lacZ reporter gene, were microinjected into fertilized mouse eggs and transgenic mouse lines were established. The expression patterns were basically similar in the 2.2 and 0.9 kb lines and overlapped grossly the endogenous Pdgfra gene expression pattern. The transgenic line with the highest expression level was chosen for detailed analysis. Expression was, as expected, mainly confined to tissues of mesodermal and neural crest origin. No expression was found in epithelial tissues of endo- or ectodermal origin. The promoter fragments were also active in neuroepithelium and in certain neuronal cell types that did not faithfully express PDGFR-alpha mRNA, while they failed to specify reporter expression in PDGFR-alpha expressing O-2A progenitor cells and other glial elements of the central nervous system. Thus, the isolated human PDGFRA promoter contains most but not all of the regulatory elements that are necessary to establish tissue specific gene expression during development.

  • 1073.
    Zhao, Hongxing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Chen, Maoshan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Tellgren-Roth, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Fluctuating expression of microRNAs in adenovirus infected cells2015Inngår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 478, s. 99-111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The changes in cellular microRNA (miRNA) expression during the course of an adenovirus type 2 infection in human lung fibroblast were studied by deep RNA sequencing. Expressions of 175 miRNAs with over 100 transcripts per million nucleotides were changed more than 1.5-fold. The expression patterns of these miRNAs changed dramatically during the course of the infection, from upregulation of the miRNAs known as tumor suppressors (such as miR-22, miR-320, let-7, miR-181b, and miR-155) and down-regulation of oncogenic miRNAs (such as miR-21 and miR-31) early to downregulation of tumor suppressor miRNAs (such as let-7 family, mir-30 family, 23/27 cluster) and upregulation of oncogenic miRNAs (include miR-125, miR-27, miR-191) late after infection. The switch in miRNA expression pattern occurred when adenovirus DNA replication started. Furthermore, deregulation of cellular miRNA expression was a step-wise and special sets of miRNAs were deregulated in different phases of infection.

  • 1074.
    Zhao, Hongxing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Chen, Moashan
    Bergström Lind, Sara
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Distinct temporal changes in host cell lncRNA expression during the course of an adenovirus infection2016Inngår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 492, s. 242-250Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The deregulation of cellular long non-coding RNA (lncRNA) expression during a human adenovirus infection was studied by deep sequencing. Expression of lncRNAs increased substantially following the progression of the infection. Among 645 significantly expressed lncRNAs, the expression of 398 was changed more than 2-fold. More than 80% of them were up-regulated and 80% of them were detected during the late phase. Eased on the genomic locations of the deregulated lncRNAs in relation to known mRNAs and miRNAs, they were predicted to be involved in growth, structure, apoptosis and wound healing in the early phase, cell proliferation in the intermediate phase and protein synthesis, modification and transport in the late phase. The most significant functions of cellular RNA-binding proteins, previously shown to interact with the deregulated lncRNAs identified here, are involved in RNA splicing, nuclear export and translation events. We hypothesize that adenoviruses exploit the lncRNA network to optimize their reproduction.

  • 1075.
    Zhao, Ning-Wei
    KTH, Skolan för bioteknologi (BIO).
    Interleukin (IL)-35 is raising our expectations2010Inngår i: Revista médica de Chile (Impresa), ISSN 0034-9887, E-ISSN 0717-6163, Vol. 138, nr 6, s. 758-766Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Purpose: To elucidate and discuss the role of IL-35 in immunity to parasitic and bacterial infections as well as in autoimmunity in terms of its anti-inflammatory properties, we highlight significant findings on this novel member of the IL-12 family. Methods: Studies using genetically deficient mice have greatly enhanced our understanding of the biology of IL-35. On the basis of data derived from the analysis of these genetically deficient mice published by NIH, we focus on the key features of this heterodimeric cytokine, especially its relation to the other IL-12 family members, and discuss its potential relevance to the clinical usage. Principal findings: IL-35 is required for the CD4(+)CD25(+) Treg cells-mediated immune regulation, the alleviation of some inflammatory responses, as well as the expansion of CD4(+)CD25(-) Teff cells simultaneously. Moreover, administration or augmentation of IL-35 suppresses some diseases of autoimmune or allergic origin like collagen-induced arthritis or Helicobacter- induced colitis in animal models, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. However, some questions involving it are still unclear, including the composition of IL-35 receptor, IL-35-related cell signaling pathway, the different expression patterns of IL-35 between human and murine T cells, etc. Conclusion: As our understanding of the IL-35 is rapidly growing and changing, it will bring us more therapeutic strategies towards some intractable immune diseases such as Lupus Erythematosus.

  • 1076.
    ZhaoZM,
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Jin, L
    Fu, YX
    Ramsay, M
    Jenkins, T
    Leskinen, E
    Pamilo, P
    Trexler, M
    Patthy, L
    Jorde, LB
    Ramos-Onsins, S
    Yu, N
    Li, WH
    Worlwide DNA sequence variation in a 10-kilobase noncoding region on human chromosome 222000Inngår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol. 97, nr 21, s. 11354-11358Artikkel i tidsskrift (Fagfellevurdert)
  • 1077. Zheng, Hou-Feng
    et al.
    Duncan, Emma L.
    Yerges-Armstrong, Laura M.
    Eriksson, Joel
    Bergström, Ulrica
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Leo, Paul J.
    Leslie, William D.
    Goltzman, David
    Blangero, John
    Hanley, David A.
    Carless, Melanie A.
    Streeten, Elizabeth A.
    Lorentzon, Mattias
    Brown, Matthew A.
    Spector, Tim D.
    Pettersson-Kymmer, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Ohlsson, Claes
    Mitchell, Braxton D.
    Richards, J. Brent
    Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm2013Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 50, nr 7, s. 473-478Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. Aim To identify genetic variants associated with forearm BMD and forearm fractures. Methods BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. Results We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5x10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01x10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. Conclusions These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

  • 1078. Zhong, Jia
    et al.
    Karlsson, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Wang, Guan
    Li, Jun
    Guo, Yichen
    Lin, Xinyi
    Zemplenyi, Michele
    Sanchez-Guerra, Marco
    Trevisi, Letizia
    Urch, Bruce
    Speck, Mary
    Liang, Liming
    Coull, Brent A
    Koutrakis, Petros
    Silverman, Frances
    Gold, Diane R
    Wu, Tangchun
    Baccarelli, Andrea A
    B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial2017Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 13, s. 3503-3508Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 μg/m(3)) under placebo, and PM2.5 (250 μg/m(3)) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4(+) T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks.

  • 1079.
    Zhu, DQ, Chapuisat, M, Pamilo, P
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi. CONSERVATION BIOLOGY AND GENETICS.
    Highly variable social organization of colonies in the ant Formica cinerea.2003Inngår i: HereditasArtikkel i tidsskrift (Fagfellevurdert)
  • 1080.
    Zieba, Agata
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Sjöstedt, Evelina
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi. Uppsala Univ, Dept Womens & Childrens Hlth, S-75185 Uppsala, Sweden..
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Hallström, Björn M.
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Oskarsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tolf, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling2015Inngår i: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 19, nr 11, s. 659-668Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The human uterus includes the complex endometrial mucosa, the endometrium that undergoes dynamic, hormone-dependent alterations throughout the life of fertile females. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to analyze gene expression patterns in the normal endometrium. Human endometrial tissues from five women were used for deep sequencing (RNA-Seq). The mRNA and protein expression data from the endometrium were compared to 31 (RNA) and 44 (protein) other normal tissue types, to identify genes with elevated expression in the endometrium and to localize the expression of corresponding proteins at a cellular resolution. Based on the expression levels of transcripts, we could classify all putative human protein coding genes into categories defined by expression patterns and found altogether 101 genes that showed an elevated pattern of expression in the endometrium, with only four genes showing more than five-fold higher expression levels in the endometrium compared to other tissues. In conclusion, our analysis based on transcriptomics and antibody-based protein profiling reports here comprehensive lists of genes with elevated expression levels in the endometrium, providing important starting points for a better molecular understanding of human reproductive biology and disease.

  • 1081.
    Zieba, Agata
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wählby, Carolina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Centrum för bildanalys. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hjelm, Fredrik
    Jordan, Lee
    Berg, Jonathan
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pardali, Katerina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Bright-Field Microscopy Visualization of Proteins and Protein Complexes by In Situ Proximity Ligation with Peroxidase Detection2010Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 56, nr 1, s. 99-110Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    The in situ proximity ligation assay (PLA) allows a protein or protein complex to be represented as an amplifiable DNA molecule. Recognition is mediated by proximity probes consisting of antibodies coupled with oligonucleotides. Upon dual binding of the proximity probes, the oligonucleotides direct the formation of a circular DNA molecule, which is then amplified by rolling-circle replication. The localized concatemeric product is then detected with fluorescent probes. The in situ PLA enables localized detection of individual native proteins or interacting protein pairs in fixed cells or tissue sections, thus providing an important tool for basic and clinical research.

    METHODS:

    We used horseradish peroxidase (HRP)conjugated oligonucleotides to couple in situ PLA with enzymatic visualization of the localized detection event.

    RESULTS:

    We demonstrate the detection of protein complexes, both in cells and in tissue sections, and show that we can quantify the complexes with image-analysis software specially developed for recognizing HRP signals in bright-field microscopy images. We show that fluorescence and HRP signals produce equivalent results, both ill cultured cells and in tissue samples.

    CONCLUSIONS:

    The combination of in situ PLA with bright-field detection and automated image analysis allows the signals present to be Counted in an automated fashion and thus provides a sensitive and specific method for quantification of proteins and protein complexes with bright-field microscopy. With this approach, in situ PLA can be used without the requirement for expensive fluorescence microscopes, thereby avoiding problems with nonspecific fluorescence while maintaining compatibility with conventional histologic staining.

  • 1082.
    Zou, Xiang
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Why Is It So Hard to Kill a Mast Cell?A Study of Mast Cell Activation and Survival2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Mast cells have a long life in tissues, where they are involved in inflammatory and hypersensitivity reactions. Activation through cross-linking of the high-affinity IgE-receptor (FcεRI) is a primary stimulus capable of degranulating mast cells, contributing to symptoms of allergy. The aim of this study was to investigate the mechanisms by which mast cells survive the allergic activation.

    The study confirmed on a continual single-cell basis that mast cells could indeed recover from the IgE-mediated degranulation and be activated again. For the second activation, kinetics of synthesis and release of certain mediators paralleled those of the initial activation. Mast cell survival was promoted due to a decreased level of apoptosis as a result of activation by FcεRI, suggesting that the activation initiated an anti-apoptotic program in mast cells. Given the potential survival- promoting role of nerve growth factor (NGF) in many cell types, we determined whether mast cells released and responded to NGF. It was found that mast cells expressed functional TrkA, the high-affinity receptor for NGF. Furthermore, the release of NGF was increased from degranulating mast cells in response to FcεRI cross-linking. Next, the possible effects of anti-apoptotic Bcl-2 family genes on mast cell survival were examined. Following FcεRI aggregation, transcripts of the pro-survival Bcl-2 homologue Al were remarkably up-regulated in mast cells. In contrast, degranulating mast cells from Al knock-out mice failed to exhibit survival advantage. These data strongly suggest that Al is required for mast call survival following allergic activation.

    In conclusion, stimuli causing an allergic reaction trigger mast cells to release NGF and up- regulate Al, which may contribute to the survival of mast cells. Our finding may be of significance in understanding the mechanisms underlying the long life-span of mast cells during allergic reactions and hence indicate possible therapeutic interventions.

  • 1083. Åberg, Karolina
    et al.
    Saetre, Peter
    Lindholm, Eva
    Ekholm, Birgit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Pettersson, Ulf
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Jazin, Elena
    Human QKI, a new candidate gene for schizophrenia involved in myelination2006Inngår i: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 141B, nr 1, s. 84-90Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 Mb region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.

  • 1084.
    Åström, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Åström, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Virtanen, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    A simple procedure for isolation of eukaryotic mRNA polyadenylation factors1991Inngår i: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 202, nr 3, s. 765-773Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have devised a simple chromatographic procedure which isolates five polyadenylation factors that are required for polyadenylation of eukaryotic mRNA. The factors were separated from each other by fractionation of HeLa cell nuclear extract in two consecutive chromatographic steps. RNA cleavage at the L3 polyadenylation site of human adenovirus 2 required at least four factors. Addition of adenosine residues required only two of these factors. The fractionation procedure separates two components that are both likely to be poly(A) polymerases. The candidate poly(A) polymerases were interchangeable and participated during both RNA cleavage and adenosine addition. They were discriminated from each other by chromatographic properties, heat sensitivity and divalent cation requirement. We have compared our data with published information and have been able to correlate the activities that we have isolated to previously identified polyadenylation factors. However, we have not been able to assign one of the candidate poly(A) polymerases to a previously identified poly(A) polymerase. This simple fractionation procedure can be used for generating an in vitro reconstituted system for polyadenylation within a short period of time.

  • 1085.
    Åström, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Åström, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Virtanen, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    In vitro deadenylation of mammalian mRNA by a HeLa cell 3' exonuclease1991Inngår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 10, nr 10, s. 3067-3071Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have identified a 3' exonuclease in HeLa cell extracts which deadenylates mammalian mRNA and leaves the mRNA body intact after poly(A) removal. Only homopolymeric adenosine tails located at the 3' end were efficiently removed by the exonuclease. The poly(A) removing activity did not require any specific sequences in the mRNA body either for poly(A) removal or for accumulation of the deadenylated mRNA. We conclude that the poly(A) removing activity is a 3' exonuclease since (i) reaction intermediates gradually lose the poly(A) tail, (ii) degradation is prevented by the presence of a cordycepin residue at the 3' end and (iii) RNAs having internally located poly(A) stretches are poor substrates for degradation. The possible involvement of the poly(A) removing enzyme in regulating mRNA translation and stability is discussed.

19202122 1051 - 1085 of 1085
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