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  • 251.
    Andersson, Ken G.
    et al.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Ståhl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR: 2377 affibody molecule labeled with 99mTc using a peptide-based cysteine-containing chelator2016In: International journal of oncology, ISSN 1791-2423, Vol. 49, no 6, p. 2285-2293Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide 99mTc should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with 99mTc using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, 99mTc-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that 99mTc-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6±1 and 2.5±0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8±0.4 and 8±3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of 99mTc-labeled ZEGFR:2377 for imaging of EGFR in vivo.

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  • 252. Andersson, Ken G.
    et al.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Malm, Magdalena
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lofblom, John
    Stahl, Stefan
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Comparative evaluation of 111In-labeled NOTA‑conjugated affibody molecules for visualization of HER3 expression in malignant tumors2015In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 34, no 2, p. 1042-1048Article in journal (Refereed)
    Abstract [en]

    Expression of human epidermal growth factor receptor type 3 (HER3) in malignant tumors has been associated with resistance to a variety of anticancer therapies. Several anti-HER3 monoclonal antibodies are currently under pre-clinical and clinical development aiming to overcome HER3-mediated resistance. Radionuclide molecular imaging of HER3 expression may improve treatment by allowing the selection of suitable patients for HER3-targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. In a recent study, we selected affibody molecules with affinity to HER3 at a low picomolar range. The aim of the present study was to develop an anti-HER3 affibody molecule suitable for labeling with radiometals. The HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA HER3-specific affibody molecules were labeled with indium-111 (In-111) and assessed in vitro and in vivo for imaging properties using single photon emission computed tomography (SPECT). Labeling of HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA with In-111 provided stable conjugates. In vitro cell tests demonstrated specific binding of the two conjugates to HER3-expressing BT-474 breast carcinoma cells. In mice bearing BT-474 xenografts, the tumor uptake of the two conjugates was receptor-specific. Direct in vivo comparison of In-111-HEHEHE-Z08698-NOTA and In-111-HEHEHE-Z08699-NOTA demonstrated that the two conjugates provided equal radioactivity uptake in tumors, although the tumor-to-blood ratio was improved for In-111-HEHEHE-Z08698-NOTA [12 +/- 3 vs. 8 +/- 1,4 h post injection (p.i)] due to more efficient blood clearance. In-111-HEHEHE-Z08698-NOTA is a promising candidate for imaging of HER3-expression in malignant tumors using SPECT. Results of the present study indicate that this conjugate could be used for patient stratification for anti-HER3 therapy.

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  • 253. Andersson, Marlene
    et al.
    Chen, Gefei
    Otikovs, Martins
    Landreh, Michael
    Nordling, Kerstin
    Kronqvist, Nina
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jornvall, Hans
    Knight, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Ridderstrale, Yvonne
    Holm, Lena
    Meng, Qing
    Jaudzems, Kristaps
    Chesler, Mitchell
    Johansson, Jan
    Rising, Anna
    Carbonic Anhydrase Generates CO2 and H+ That Drive Spider Silk Formation Via Opposite Effects on the Terminal Domains2014In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 12, no 8, p. e1001921-Article in journal (Refereed)
    Abstract [en]

    Spider silk fibers are produced from soluble proteins (spidroins) under ambient conditions in a complex but poorly understood process. Spidroins are highly repetitive in sequence but capped by nonrepetitive N- and C-terminal domains (NT and CT) that are suggested to regulate fiber conversion in similar manners. By using ion selective microelectrodes we found that the pH gradient in the silk gland is much broader than previously known. Surprisingly, the terminal domains respond in opposite ways when pH is decreased from 7 to 5: Urea denaturation and temperature stability assays show that NT dimers get significantly stabilized and then lock the spidroins into multimers, whereas CT on the other hand is destabilized and unfolds into ThT-positive beta-sheet amyloid fibrils, which can trigger fiber formation. There is a high carbon dioxide pressure (pCO(2)) in distal parts of the gland, and a CO2 analogue interacts with buried regions in CT as determined by nuclear magnetic resonance (NMR) spectroscopy. Activity staining of histological sections and inhibition experiments reveal that the pH gradient is created by carbonic anhydrase. Carbonic anhydrase activity emerges in the same region of the gland as the opposite effects on NT and CT stability occur. These synchronous events suggest a novel CO2 and proton-dependent lock and trigger mechanism of spider silk formation.

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  • 254.
    Andersson, Sandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Validation of antibodies for tissue based immunoassays2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In situ protein detection in human tissues using antibodies reveals the cellular protein localization, and affinity-based proteomic studies can help to discover proteins involved in the development of diseases. However, antibodies often suffer from cross-reactivity, and the lack of positive and negative tissue controls for uncharacterized proteins complicates the mapping of the proteome. The aim of this thesis is thus to improve the methodology for validating antibodies used for immunostaining on formalin-fixed paraffin-embedded tissues.

    Two of the papers include comparisons between mRNA-expression and immunostaining of corresponding protein. In paper I, ISH and IHC staining patterns were compared on consecutive TMA-slides. The study of well-characterized genes showed that ISH could be used for validation of antibodies. ISH was further used for antibody evaluation, and could validate four out of nine antibodies showing potentially interesting staining patterns. In paper III, transcriptomic data generated by RNA-sequencing were used to identify tissue specific expression in lymphohematopoietic tissues. An increased expression in one or more of these tissues compared to other tissue types was seen for 693 genes, and these were further compared to the staining patterns of corresponding proteins in tissues.

    Antibody labeling is necessary for many immunoassays. In paper II, two techniques for antibody-biotinylation were compared, aiming to find a stringent labeling method for antibodies used for immunostaining on TMAs. The ZBPA-method, binding specifically to Fc-part of antibodies, was found to be superior to the Lightning Link-biotinylation kit targeting amine groups, since labeling of amine groups on stabilizing proteins in the antibody buffer causes unspecific staining.

    The localization of the estrogen receptor beta (ERβ) in human normal and cancer tissues was studied in paper IV. Thorough evaluation of 13 antibodies using positive and negative control cell lines showed that only one antibody, PPZ0506, is specific for ERβ in all three immunoassays used. Contradictory to previously published data, tissue profiling using PPZ0506 showed that ERβ is expressed in a limited number of normal and cancer tissues.

    In conclusion, the present investigations present tools for validation of antibodies used for large-scale studies of protein expression in tissues.

    List of papers
    1. Scalable In Situ Hybridization on Tissue Arrays for Validation of Novel Cancer and Tissue-Specific Biomarkers
    Open this publication in new window or tab >>Scalable In Situ Hybridization on Tissue Arrays for Validation of Novel Cancer and Tissue-Specific Biomarkers
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    2012 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 3, p. e32927-Article in journal (Refereed) Published
    Abstract [en]

    Tissue localization of gene expression is increasingly important for accurate interpretation of large scale datasets from expression and mutational analyses. To this end, we have (1) developed a robust and scalable procedure for generation of mRNA hybridization probes, providing >95% first-pass success rate in probe generation to any human target gene and (2) adopted an automated staining procedure for analyses of formalin-fixed paraffin-embedded tissues and tissue microarrays. The in situ mRNA and protein expression patterns for genes with known as well as unknown tissue expression patterns were analyzed in normal and malignant tissues to assess procedure specificity and whether in situ hybridization can be used for validating novel antibodies. We demonstrate concordance between in situ transcript and protein expression patterns of the well-known pathology biomarkers KRT17, CHGA, MKI67, PECAM1 and VIL1, and provide independent validation for novel antibodies to the biomarkers BRD1, EZH2, JUP and SATB2. The present study provides a foundation for comprehensive in situ gene set or transcriptome analyses of human normal and tumor tissues.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-174583 (URN)10.1371/journal.pone.0032927 (DOI)000303062000022 ()
    Available from: 2012-05-29 Created: 2012-05-22 Last updated: 2021-06-14Bibliographically approved
    2. Antibodies Biotinylated Using a Synthetic Z-domain from Protein A Provide Stringent In Situ Protein Detection
    Open this publication in new window or tab >>Antibodies Biotinylated Using a Synthetic Z-domain from Protein A Provide Stringent In Situ Protein Detection
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    2013 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 61, no 11, p. 773-784Article in journal (Refereed) Published
    Abstract [en]

    Antibody-based protein profiling on a global scale using immunohistochemistry constitutes an emerging strategy for mapping of the human proteome, which is crucial for an increased understanding of biological processes in the cell. Immunohistochemistry is often performed indirectly using secondary antibodies for detection, with the benefit of signal amplification. Direct immunohistochemistry instead brings the advantage of multiplexing; however, it requires labeling of the primary antibody. Many antibody-labeling kits do not specifically target IgG and may therefore cause labeling of stabilizing proteins present in the antibody solution. A new conjugation method has been developed that utilizes a modified Z-domain of protein A (ZBPA) to specifically target the Fc part of antibodies. The aim of the present study was to compare the ZBPA conjugation method and a commercially available labeling kit, Lightning-Link, for in situ protein detection. Fourteen antibodies were biotinylated with each method and stained using immunohistochemistry. For all antibodies tested, ZBPA biotinylation resulted in distinct immunoreactivity without off-target staining, regardless of the presence of stabilizing proteins in the buffer, whereas the majority of the Lightning-Link biotinylated antibodies displayed a characteristic pattern of nonspecific staining. We conclude that biotinylated ZBPA domain provides a stringent method for antibody biotinylation, advantageous for in situ protein detection in tissues.

    Keywords
    antibody, biotin, conjugation, protein detection, tissue microarray
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-211012 (URN)10.1369/0022155413502360 (DOI)000326066300001 ()
    Available from: 2013-11-20 Created: 2013-11-19 Last updated: 2017-12-06Bibliographically approved
    3. The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues
    Open this publication in new window or tab >>The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues
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    2014 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 12, p. e115911-Article in journal (Refereed) Published
    Abstract [en]

    Background: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue-specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas-strategy that combines high throughput transcriptomics with affinity-based proteomics. Results: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59. Conclusions: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images.

    National Category
    Other Medical Sciences not elsewhere specified Clinical Laboratory Medicine
    Research subject
    Pathology
    Identifiers
    urn:nbn:se:uu:diva-243679 (URN)10.1371/journal.pone.0115911 (DOI)000347239900109 ()25541736 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation, KAW2008.0143
    Available from: 2015-02-19 Created: 2015-02-11 Last updated: 2022-01-28Bibliographically approved
    4. Estrogen receptor beta profiling in human tissues following extensive antibody validation
    Open this publication in new window or tab >>Estrogen receptor beta profiling in human tissues following extensive antibody validation
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Estrogen receptor beta, ER-beta, IHC, antibody validation, TMA
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-251340 (URN)
    Available from: 2015-04-21 Created: 2015-04-15 Last updated: 2015-10-01
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  • 255.
    Andersson, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Konrad, Anna
    Ashok, Nikhil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hober, Sophia
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Antibodies Biotinylated Using a Synthetic Z-domain from Protein A Provide Stringent In Situ Protein Detection2013In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 61, no 11, p. 773-784Article in journal (Refereed)
    Abstract [en]

    Antibody-based protein profiling on a global scale using immunohistochemistry constitutes an emerging strategy for mapping of the human proteome, which is crucial for an increased understanding of biological processes in the cell. Immunohistochemistry is often performed indirectly using secondary antibodies for detection, with the benefit of signal amplification. Direct immunohistochemistry instead brings the advantage of multiplexing; however, it requires labeling of the primary antibody. Many antibody-labeling kits do not specifically target IgG and may therefore cause labeling of stabilizing proteins present in the antibody solution. A new conjugation method has been developed that utilizes a modified Z-domain of protein A (ZBPA) to specifically target the Fc part of antibodies. The aim of the present study was to compare the ZBPA conjugation method and a commercially available labeling kit, Lightning-Link, for in situ protein detection. Fourteen antibodies were biotinylated with each method and stained using immunohistochemistry. For all antibodies tested, ZBPA biotinylation resulted in distinct immunoreactivity without off-target staining, regardless of the presence of stabilizing proteins in the buffer, whereas the majority of the Lightning-Link biotinylated antibodies displayed a characteristic pattern of nonspecific staining. We conclude that biotinylated ZBPA domain provides a stringent method for antibody biotinylation, advantageous for in situ protein detection in tissues.

  • 256.
    Andersson, Sandra
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Danielsson, Angelika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhlen, Mathias
    Asplund, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 12, p. e115911-Article in journal (Refereed)
    Abstract [en]

    Background: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue-specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas-strategy that combines high throughput transcriptomics with affinity-based proteomics. Results: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59. Conclusions: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images.

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  • 257.
    Andersson, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sundberg, Mårten
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Pristovsek, Nusa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Clausson, Carl-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramström, Margareta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Söderbert, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Estrogen receptor beta profiling in human tissues following extensive antibody validationManuscript (preprint) (Other academic)
  • 258.
    Andersson, Sandra
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sundberg, Mårten
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Pristovsek, Nusa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ibrahim, Ahmed
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Natl Res Ctr, Div Pharmaceut Ind, Dokki 12622, Egypt..
    Jonsson, Philip
    Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Human Oncol & Pathogenesis Program, New York, NY 10065 USA..
    Katona, Borbala
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Clausson, Carl-Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zieba, Agata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramström, Margareta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Williams, Cecilia
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Karolinska Inst, Dept Biosci & Nutr, S-14183 Stockholm, Sweden..
    Asplund, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Insufficient antibody validation challenges oestrogen receptor beta research2017In: Nature Communications, E-ISSN 2041-1723, Vol. 8, article id 15840Article in journal (Refereed)
    Abstract [en]

    The discovery of oestrogen receptor beta (ER beta/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ER alpha (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ER beta antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ER beta in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ER beta protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.

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  • 259. Andersson, Sonia
    et al.
    Mints, Miriam
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gustavsson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Lambe, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Uneven distribution of human papillomavirus 16111 cervical carcinoma in situ and squamous cell carcinoma in older females: A retrospective database study2014In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 8, no 4, p. 1528-1532Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) 16 is the dominant cofactor in cervical cancer development. The present report investigated the age-specific prevalence of HPV16 in cervical carcinoma in situ (CIS) in females attending organised cervical cancer screening. A retrospective observational study was performed based on individual data from two databases. A total of 162 females aged between 20 and 65 years from Uppsala County, Sweden with CIS and an HPV test conducted between 2010 and 2011, preceding or concomitant to CIS diagnosis, were included. Females with cervical squamous cell carcinoma (SCC; n=35) were used for comparison. In total, 96% (n=156) of females with CIS were positive for high-risk HPV; HPV16 was the most prevalent (44.5%), followed by HPV33/52/58 (19.5%), HPV31 (13.1%) and HPV18145 (9.5%). HPV16 was most frequently detected in females with CIS aged between 20 and 29 years (73.6%) and least frequently detected in those aged between 50 and 65 years (33.3%), with a statistically significant age-specific difference (P=0.001). Among the HPV16-positive females, multiple infections were most frequent in the younger age groups. The prevalence of HPV16 in females with CIS decreased with age, whereas a high prevalence of HPV16 remained in females with SCC. These results may indicate that HPV16 has increased oncogenic potential in older females.

  • 260.
    Andersson, Therese M. -L.
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Johansson, Anna L. V.
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Fredriksson, Irma
    Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, Stockholm, Sweden..
    Lambe, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.
    Cancer during pregnancy and the postpartum period: A population-based study2015In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 121, no 12, p. 2072-2077Article in journal (Refereed)
    Abstract [en]

    BACKGROUNDThe purpose of this study was to assess patterns of cancer occurrence during pregnancy and the postpartum period. METHODSThis was a register-based study using data from the Swedish Multi-Generation Register and the National Cancer Register from 1963 to 2007. Pregnancy-associated cancer (PAC) was defined as a malignancy detected during pregnancy or within 2 years of delivery and was assessed in 7 time windows: pregnancy, trimesters 1-3, 0-6 months, 7-12 months, and second year postpartum. Population incidence rates by 5-year age groups and periods were used to estimate the expected number of PACs for each site. The observed versus the expected (O/E) number of cases was estimated with 95% confidence intervals (CI). RESULTSThe 3 most common malignancies during pregnancy were melanoma (n=232), breast (n=139) and cervical cancer (n=139). With a slightly different rank order, these cancers are also the most common in women of childbearing age. The number of observed cases during pregnancy was lower than expected for all cancers, with a combined O/E ratio for all sites of 0.46 (95% CI, 0.43-0.49). The O/E ratio was close to 1 during all postpartum intervals, including 0-6 months (0.93; 95% CI, 0.88-0.98), 7-12 months (0.96; 95% CI, 0.91-1.01), and during the second year after delivery (0.95; 95% CI, 0.92-0.99). CONCLUSIONSThe rate of cancer during pregnancy was lower than expected for all sites, a finding that could not be explained entirely by delayed diagnosis. A rebound in the number of observed cases after delivery was restricted to melanoma, nervous system malignancies, and breast and thyroid cancer. Cancer 2015;121:2072-2077. (c) 2015 American Cancer Society. Fewer cancers than expected are found during pregnancy, a finding that cannot be explained entirely by delayed diagnosis.

  • 261. Andersson, Torbjörn
    et al.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lindgren, PG
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Effects of Interferon on Tumor Tissue Content in Liver Metastases of Human Carcinoid Tumors1990In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 50, p. 3413-3415Article in journal (Refereed)
    Abstract [en]

    In 21 patients ultrasound-guided cutting biopsies, from carcinoid metastases of the liver, were taken before and after therapy with α-interferon. Each biopsy was examined under light microscopy and the amount of tumor tissue and connective tissue was quantified and then correlated to objective response to interferon therapy. A significant reduction of the amount of tumor tissue, in spite of unaltered metastatic size and a corresponding increase in connective tissue, was seen after interferon therapy. A more pronounced reduction of tumor tissue occurred after long-term interferon therapy. A positive correlation between objective therapy response and tumor tissue reduction was also present. Patients responding poorly, or not at all, to therapy did not show any significant decrease in tumor tissue.

    Since treatment with immune response modifiers is expected to increase in the near future, it is important to choose the right investigations for therapy monitoring, and since all patients in this investigation had unchanged tumor size on repeated radiological examinations, it is obvious that microscopic examination of core biopsies is a better method for evaluating effects of long-term therapy than tumor size measurement with radiological techniques. Further, the results may indicate that interferon exerts a cytotoxic effect on carcinoid tumor cells in vivo.

  • 262.
    Ando, Koji
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Bunkyo Ku, Tokyo 1138602, Japan.
    Shih, Yu-Huan
    Univ Massachusetts, Dept Mol Cell & Canc Biol, Med Sch, Worcester, MA 01650 USA.
    Ebarasi, Lwaki
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.
    Grosse, Ann
    Univ Massachusetts, Dept Mol Cell & Canc Biol, Med Sch, Worcester, MA 01650 USA.
    Portman, Daneal
    Univ Massachusetts, Dept Mol Cell & Canc Biol, Med Sch, Worcester, MA 01650 USA.
    Chiba, Ayano
    Natl Cerebral & Cardiovasc Ctr Res Inst, Dept Cell Biol, Suita, Osaka 5648565, Japan.
    Mattonet, Kenny
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, Ludwigstr 43, D-61231 Bad Nauheim, Germany.
    Gerri, Claudia
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, Ludwigstr 43, D-61231 Bad Nauheim, Germany; Francis Crick Inst, Human Embryo & Stem Cell Lab, 1 Midland Rd, London NW1 1AT, England.
    Stainier, Didier Y. R.
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, Ludwigstr 43, D-61231 Bad Nauheim, Germany.
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr Res Inst, Dept Cell Biol, Suita, Osaka 5648565, Japan.
    Fukuhara, Shigetomo
    Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Bunkyo Ku, Tokyo 1138602, Japan.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge MedH, Neo, Campus Flemingsberg,Blickagagen 16,Hiss S,Plan 7, SE-14157 Huddinge, Sweden.
    Lawson, Nathan D.
    Univ Massachusetts, Dept Mol Cell & Canc Biol, Med Sch, Worcester, MA 01650 USA.
    Conserved and context-dependent roles for pdgfrb signaling during zebrafish vascular mural cell development2021In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 479, p. 11-22Article in journal (Refereed)
    Abstract [en]

    Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle cells. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these zebrafish mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects.

  • 263.
    Ando, Koji
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan.;Natl Cerebral & Cardiovasc Ctr Res Inst, Dept Regenerat Med & Tissue Engn, 6-1 Kishibe Shinmachi, Suita, Osaka 5648565, Japan..
    Tong, Lei
    Yale Sch Med, Dept Neurol, New Haven, CT USA..
    Peng, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vazquez-Liebanas, Elisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Chiyoda, Hirohisa
    Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan.;Natl Cerebral & Cardiovasc Ctr Res Inst, Dept Regenerat Med & Tissue Engn, 6-1 Kishibe Shinmachi, Suita, Osaka 5648565, Japan..
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Liu, Jianping
    Karolinska Inst, Dept Med Huddinge MedH, Campus Flemingsburg,Blickagangen 16, S-14157 Huddinge, Sweden..
    Kawakami, Koichi
    Natl Inst Genet, Lab Mol & Dev Biol, 1111 Yata, Mishima, Shizuoka 4118540, Japan.;SOKENDAI Grad Univ Adv Studies, Dept Genet, 1111 Yata, Mishima, Shizuoka 4118540, Japan..
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, 6-1 Kishibe Shinmachi, Suita, Osaka 5648565, Japan..
    Fukuhara, Shigetomo
    Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan..
    Grutzendler, Jaime
    Yale Sch Med, Dept Neurol, New Haven, CT USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge MedH, Campus Flemingsburg,Blickagangen 16, S-14157 Huddinge, Sweden..
    KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling2022In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 57, no 11, p. 1383-1399.e7Article in journal (Refereed)
    Abstract [en]

    Loss- or gain-of-function mutations in ATP-sensitive potassium channel (K-ATP)-encoding genes, KCNJ8 and ABCC9, cause human central nervous system disorders with unknown pathogenesis. Here, using mice, zebrafish, and cell culture models, we investigated cellular and molecular causes of brain dysfunctions derived from altered K-ATP channel function. We show that genetic/chemical inhibition or activation of KCNJ8/ABCC9-containing K-ATP channel function leads to brain-selective suppression or promotion of arterial/arteriolar vascular smooth muscle cell (VSMC) differentiation, respectively. We further show that brain VSMCs develop from KCNJ8/ABCC9-containing K-ATP channel-expressing mural cell progenitor and that K-ATP channel cell autonomously regulates VSMC differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels. Consistent with defective VSMC development, Kcnj8 knockout mice showed deficiency in vasoconstrictive capacity and neuronal-evoked vasodilation leading to local hyperemia. Our results demonstrate a role for KCNJ8/ABCC9-containing K-ATP channels in the differentiation of brain VSMC, which in turn is necessary for fine-tuning of cerebral blood flow.

  • 264.
    Ando, Koji
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan.
    Wang, Weili
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld , Australia.
    Peng, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Chiba, Ayano
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka , Japan.
    Lagendijk, Anne K.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Barske, Lindsey
    Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem, Dept Stem Cell Biol & Regenerat Med, Keck Sch Med, Los Angeles, CA USA.
    Crump, J. Gage
    Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem, Dept Stem Cell Biol & Regenerat Med, Keck Sch Med, Los Angeles, CA USA.
    Stainier, Didier Y. R.
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, Bad Nauheim, Germany.
    Lendahl, Urban
    Karolinska Inst, Dept Cell & Mol Biol, Biomedicum, Stockholm, Sweden; Karolinska Inst, Dept Med, ICMC, Huddinge, Sweden.
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Hogan, Benjamin M.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Fukuhara, Shigetomo
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan; Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Musashi Kosugi Hosp, Kawasaki, Kanagawa, Japan.
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan; Natl Cerebral & Cardiovasc Ctr, AMED CREST, Dept Cell Biol, Suita, Osaka, Japan.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med, ICMC, Huddinge, Sweden.
    Peri-arterial specification of vascular mural cells from naive mesenchyme requires Notch signaling2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 2, article id UNSP dev165589Article in journal (Refereed)
    Abstract [en]

    Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naive pdgfrb(low) mesenchymal cells. The emergence of peri-arterial pdgfrb(high) MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrb(high) MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrb(high) MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.

  • 265.
    Andrade, Fernanda
    et al.
    Univ Porto, i3S Inst Invest & Inovacao Saude, Rua Alfredo Allen 208, Porto, Portugal.;Univ Porto, INEB Inst Nacl Engn Biomed, Rua Alfredo Allen 208, P-4200180 Porto, Portugal.;Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain..
    Rafael, Diana
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Inst Salud Carlos III, Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Zaragoza, Spain..
    Vilar-Hernandez, Mireia
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain..
    Montero, Sara
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Inst Salud Carlos III, Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Zaragoza, Spain..
    Martinez-Trucharte, Francesc
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain..
    Seras-Franzoso, Joaquin
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain..
    Diaz-Riascos, Zamira, V
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Univ Autonoma Barcelona, Vall dHebron Inst Recerca, CIBBIM Nanomed, Funct Validat & Preclin Res FVPR, Barcelona, Spain..
    Boullosa, Ana
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Univ Autonoma Barcelona, Vall dHebron Inst Recerca, CIBBIM Nanomed, Funct Validat & Preclin Res FVPR, Barcelona, Spain..
    Garcia-Aranda, Natalia
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Univ Autonoma Barcelona, Vall dHebron Inst Recerca, CIBBIM Nanomed, Funct Validat & Preclin Res FVPR, Barcelona, Spain..
    Camara-Sanchez, Patricia
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Univ Autonoma Barcelona, Vall dHebron Inst Recerca, CIBBIM Nanomed, Funct Validat & Preclin Res FVPR, Barcelona, Spain..
    Arango, Diego
    Univ Autonoma Barcelona, Vall dHebron Res Inst, CIBBIM Nanomed, Biomed Res Digest Tract Tumors Grp, Barcelona, Spain..
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Abasolo, Ibane
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Inst Salud Carlos III, Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Zaragoza, Spain.;Univ Autonoma Barcelona, Vall dHebron Inst Recerca, CIBBIM Nanomed, Funct Validat & Preclin Res FVPR, Barcelona, Spain..
    Sarmento, Bruno
    Univ Porto, i3S Inst Invest & Inovacao Saude, Rua Alfredo Allen 208, Porto, Portugal.;Univ Porto, INEB Inst Nacl Engn Biomed, Rua Alfredo Allen 208, P-4200180 Porto, Portugal.;Inst Invest & Formacao Avancada Ciencias & Tecnol, CESPU, Rua Cent Gandra 1317, P-4585116 Gandra, Portugal..
    Schwartz, Simo, Jr.
    Univ Autonoma Barcelona, Mol Biol & Biochem Res Ctr Nanomed CIBBIM Nanomed, Vall dHebron Inst Recerca, Drug Delivery & Targeting Grp, Barcelona, Spain.;Inst Salud Carlos III, Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Zaragoza, Spain..
    Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo2021In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 331, p. 198-212Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is a highly prevalent disease worldwide. Patient survival is hampered by tumor relapse and the appearance of drug-resistant metastases, which are sustained by the presence of cancer stem cells (CSC). Specific delivery of anti-CSC chemotherapeutic drugs to tumors by using targeted drug delivery systems that can also target CSC sub-population might substantially improve current clinical outcomes. CD44v6 is a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation process. Here, we show that CD44v6-targeted polymeric micelles (PM) loaded with niclosamide (NC S), a drug against CSC, is a good therapeutic strategy against colorectal CSC and circulating tumor cells (CTC) in vivo. HCT116 cells were sorted according to their CD44v6 receptor expression into CD44v6+ (high) and CDv44v6- (low) subpopulations. Accordingly, CD44v6+ cells presented stemness properties, such as overexpression of defined stemness markers (ALDH1A1, CD44v3 and CXCR4) and high capacity to form colonspheres in low attachment conditions. NC S-loaded PM functionalized with an antibody fragment against CD44v6 (Fab-CD44v6) presented adequate size, charge, and encapsulation efficiency. In addition, Fab-CD44v6 significantly increased PM internalization in CD44v6+ cells. Further, encapsulation of NCS improved its effectiveness in vitro, particularly against colonspheres, and allowed to increase its intravenous dosage in vivo by increasing the amount of NCS able to be administered without causing toxicity. Remarkably, functionalized PM accumulate in tumors and significantly reduce CTC in vivo. In conclusion, CD44v6 targeted PM meet the essential conditions to become an efficient anti-CSC therapy.

  • 266.
    Andrade, Luis E. C.
    et al.
    Univ Fed Sao Paulo, Escola Paulista Med, Dept Med, Rheumatol Div, Rua Botucatu 740, BR-04023062 Sao Paulo, SP, Brazil;Fleury Med & Hlth Labs, Immunol Div, Sao Paulo, Brazil.
    Klotz, Werner
    Med Univ Innsbruck, Dept Internal Med 2, Innsbruck, Austria.
    Herold, Manfred
    Med Univ Innsbruck, Dept Internal Med 2, Innsbruck, Austria.
    Conrad, Karsten
    Tech Univ Dresden, Inst Immunol, Dresden, Germany.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fritzler, Marvin J.
    Univ Calgary, Cumming Sch Med, Dept Med, Calgary, AB, Canada.
    von Mühlen, Carlos A.
    Brazilian Soc Autoimmun, Porto Alegre, RS, Brazil.
    Satoh, Minoru
    Univ Occupat & Environm Hlth, Dept Clin Nursing, Kitakyushu, Fukuoka, Japan.
    Damoiseaux, Jan
    Maastricht Univ, Med Ctr, Cent Diagnost Lab, Maastricht, Netherlands.
    Cruvinel, Wilson de Melo
    Univ Catolica Goias, Goiania, Go, Brazil.
    Chan, Edward K. L.
    Univ Florida, Dept Oral Biol, Gainesville, FL 32610 USA.
    International consensus on antinuclear antibody patterns: definition of the AC-29 pattern associated with antibodies to DNA topoisomerase I2018In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 56, no 10, p. 1783-1788Article in journal (Refereed)
    Abstract [en]

    The indirect immunofluorescence assay (IFA) on HEp-2 cells is the reference method for autoantibody screening. The HEp-2 IFA pattern provides useful information on the possible autoantibodies in the sample. The International Consensus on Antinuclear Antibody Patterns (ICAP) initiative seeks to define and harmonize the nomenclature of HEp-2 IFA patterns. The most relevant and usual patterns have been assigned an alphanumeric code from anti-cell (AC)-1 to AC-28 and were organized into a classification algorithm (www.ANApatterns.org). The systemic sclerosis-associated autoantibodies to DNA topoisomerase I (Topo I) produce a peculiar composite 5-element HEp-2 IFA pattern (Topo I-like pattern) comprising the staining of the nucleus, metaphase chromatin plate, nucleolar organizing region, cytoplasm and nucleolus. In a recent assessment of the European Consensus Finding Study Group on autoantibodies, a well-defined anti-Topo I sample was blindly analyzed and classified according to ICAP AC patterns by 43 participant laboratories across Europe. There were wide variations among these laboratories in reporting nuclear, nucleolar and cytoplasmic patterns, indicating the inadequacy of the existing AC patterns to report the Topo I-like pattern. Several ICAP member laboratories independently demonstrated the overall consistency of the HEp-2 IFA Topo I-like pattern using HEp-2 slides from different manufacturers. The ICAP committee reviewed 24 candidate images and selected the four most representative images to be available on the ICAP website. The proper recognition of the AC-29 pattern should trigger suspicion of the presence of anti-Topo I antibodies, which may engender appropriate analyte-specific reflex tests to confirm the autoantibody specificity.

  • 267.
    Andrade, Pedro
    et al.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Pinho, Catarina
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Perez i de lanuza, Guillem
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Afonso, Sandra
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Brejcha, Jindrich
    Charles Univ Prague, Fac Sci, Dept Philosophy & Hist Sci, Prague 12800 2, Czech Republic;Natl Museum, Dept Zool, Prague 19300, Czech Republic;Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pereira, Paulo
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Sabatino, Stephen J.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Bellati, Adriana
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Pellitteri-Rosa, Daniele
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Bosakova, Zuzana
    Charles Univ Prague, Fac Sci, Dept Analyt Chem, Prague 12843 2, Czech Republic.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Carretero, Miguel A.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Feiner, Nathalie
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Marsik, Petr
    Czech Univ Life Sci Prague, Fac Agrobiol Food & Nat Resources, Dept Food Sci, Prague 16521 6, Czech Republic.
    Pauperio, Francisco
    Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Salvi, Daniele
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Aquila, Dept Hlth Life & Environm Sci, I-67100 Laquila, Italy.
    Soler, Lucile
    Natl Bioinformat Infrastruct Sweden, Sci Life Lab, S-75123 Uppsala, Sweden.
    While, Geoffrey M.
    Univ Tasmania, Sch ol Biol Sci, Hobart, Tas 7005, Australia;Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
    Uller, Tobias
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Font, Enrique
    Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Carneiro, Miguel
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 12, p. 5633-5642Article in journal (Refereed)
    Abstract [en]

    Reptiles use pterin and carotenoid pigments to produce yellow, orange, and red colors. These conspicuous colors serve a diversity of signaling functions, but their molecular basis remains unresolved. Here, we show that the genomes of sympatric color morphs of the European common wall lizard (Podarcis muralis), which differ in orange and yellow pigmentation and in their ecology and behavior, are virtually undifferentiated. Genetic differences are restricted to two small regulatory regions near genes associated with pterin [sepiapterin reductase (SPR)] and carotenoid [beta-carotene oxygenase 2 (BCO2)] metabolism, demonstrating that a core gene in the housekeeping pathway of pterin biosynthesis has been coopted for bright coloration in reptiles and indicating that these loci exert pleiotropic effects on other aspects of physiology. Pigmentation differences are explained by extremely divergent alleles, and haplotype analysis revealed abundant transspecific allele sharing with other lacertids exhibiting color polymorphisms. The evolution of these conspicuous color ornaments is the result of ancient genetic variation and cross-species hybridization.

  • 268.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGFR alpha signaling is required for alveolar development in the mouse lung2017In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 145, p. S147-S147Article in journal (Other academic)
  • 269.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ehrencrona, Hans
    Gallini, Radiosa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lal, Mark
    Ding, Hao
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A2013In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 33, no 20, p. 4030-4040Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxyterminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-A(long) has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Delta ex6) incapable of producing PDGF-A(long) due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFR alpha), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Delta ex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-A(long) may play a physiological role.

  • 270.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Leonor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gallini, Radiosa
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fredriksson, Linda
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Nilsson, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Johansson, Bengt R.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Electron Microscopy Unit, S-40530 Gothenburg, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex2016In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, no 4, p. 461-474Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.

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  • 271.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Betsholtz, Christer
    Characterization of Platelet-Derived Growth Factor-A Expression in Mouse Tissues Using a lacZ Knock-In Approach2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 8, p. e105477-Article in journal (Refereed)
    Abstract [en]

    Expression of the platelet-derived growth factor A-chain gene (Pdgfa) occurs widely in the developing mouse, where it is mainly localized to various epithelial and neuronal structures. Until now, in situ mRNA hybridization (ISH) has been the only reliable method to identify Pdgfa expression in tissue sections or whole mount preparations. Validated protocols for in situ detection of PDGF-A protein by immunohistochemistry is lacking. In particular, this has hampered understanding of Pdgfa expression pattern in adult tissues, where ISH is technically challenging. Here, we report a gene targeted mouse Pdgfa allele, Pdgfa(ex4COIN), which is a combined conditional knockout and reporter allele. Cre-mediated inversion of the COIN cassette inactivates Pdgfa coding while simultaneously activating a beta-galactosidase (lacZ) reporter under endogenous Pdgfa transcription control. The generated Pdgfa(ex4COIN-INV-lacZ) allele can next be used to identify cells carrying a Pdgfa null allele, as well as to map endogenous Pdgfa expression. We evaluated the Pdgfa(ex4COIN-INV-lacZ) allele as a reporter for endogenous Pdgfa expression patterns in mouse embryos and adults. We conclude that the expression pattern of Pdgfa(ex4COIN-INV-lacZ) recapitulates known expression patterns of Pdgfa. We also report on novel embryonic and adult Pdgfa expression patterns in the mouse and discuss their implications for Pdgfa physiology.

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  • 272.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hansson, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Afink, G B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nistér, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Platelet-derived growth factor receptor-alpha in ventricular zone cells and in developing neurons.2001In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 17, no 6Article in journal (Refereed)
    Abstract [en]

    Cells in the early neuroepithelium differentiate and give rise to all cells in the central nervous system (CNS). The ways from a multipotent CNS stem cell to specialized neurons and glia are not fully understood. Using immunohistochemistry we found that neuroepithelial cells express the platelet-derived growth factor receptor-alpha (PDGFR-alpha) in the neural plate at embryonic day 8.5 and onwards in the neural tube. The protein was polarized to ventricular endfeet. Furthermore, PDGFR-alpha expression was localized to cells undergoing early neuronal development. We also found PDGFR-alpha expression in developing granule cells in the postnatal cerebellum, in Purkinje cells in the adult cerebellum and on processes of developing dorsal root ganglion cells. Previous reports mainly describe PDGFR-alpha expression in oligodendrocyte precursors and glial cells. We believe, in line with a few previous reports, that the PDGFR-alpha in addition marks a pool of undifferentiated cells, which are able to differentiate into neurons.

  • 273.
    Andreaggi, Kimberly
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology. Armed Forces Medical Examiner System’s Armed Forces DNA Identification Laboratory (AFMES-AFDIL), Dover Air Force Base, DE 19902, USA;SNA International, LLC, Alexandria, VI 22314, USA.
    Bodner, Martin
    Institute of Legal Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria.
    Ring, Joseph D.
    Armed Forces Medical Examiner System’s Armed Forces DNA Identification Laboratory (AFMES-AFDIL), Dover Air Force Base, DE 19902, USA;SNA International, LLC, Alexandria, VI 22314, USA.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gyllensten, Ulf B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Parson, Walther
    Institute of Legal Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria;Forensic Science Program, The Pennsylvania State University, University Park, State College, PA 16801, USA.
    Marshall, Charla
    Armed Forces Medical Examiner System’s Armed Forces DNA Identification Laboratory (AFMES-AFDIL), Dover Air Force Base, DE 19902, USA;Forensic Science Program, The Pennsylvania State University, University Park, State College, PA 16801, USA.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Complete Mitochondrial DNA Genome Variation in the Swedish Population2023In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 14, no 11, p. 1989-1989Article in journal (Refereed)
    Abstract [en]

    The development of complete mitochondrial genome (mitogenome) reference data for inclusion in publicly available population databases is currently underway, and the generation of more high-quality mitogenomes will only enhance the statistical power of this forensically useful locus. To characterize mitogenome variation in Sweden, the mitochondrial DNA (mtDNA) reads from the SweGen whole genome sequencing (WGS) dataset were analyzed. To overcome the interference from low-frequency nuclear mtDNA segments (NUMTs), a 10% variant frequency threshold was applied for the analysis. In total, 934 forensic-quality mitogenome haplotypes were characterized. Almost 45% of the SweGen haplotypes belonged to haplogroup H. Nearly all mitogenome haplotypes (99.1%) were assigned to European haplogroups, which was expected based on previous mtDNA studies of the Swedish population. There were signature northern Swedish and Finnish haplogroups observed in the dataset (e.g., U5b1, W1a), consistent with the nuclear DNA analyses of the SweGen data. The complete mitogenome analysis resulted in high haplotype diversity (0.9996) with a random match probability of 0.15%. Overall, the SweGen mitogenomes provide a large mtDNA reference dataset for the Swedish population and also contribute to the effort to estimate global mitogenome haplotype frequencies.

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  • 274.
    Andreasson, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sun, Xiao-Feng
    Willén, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Zhang, Zhi-Yong
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Histopathological Classification of Pseudomyxoma Peritonei and the Prognostic Importance of PINCH Protein2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 4, p. 1443-1448Article in journal (Refereed)
    Abstract [en]

    Aim:

    The aims of this study were i) to assess a new and more detailed histopathological classification and to analyze concordance between pathologists in the histopathological classification of pseudomyxoma peritonei (PMP); ii) to analyze the expression in the stroma of the particularly interesting new cysteine-histidine (PINCH) protein and its prognostic importance in PMP.

    Materials and Methods:

    Surgical specimens from 81 patients, classified according to the Ronnett et al histopathological classification were compared to a new system with four groups ranging from indolent to aggressive growth patterns. PINCH protein expression was analyzed and was related to clinical variables.

    Results:

    The new four-group classification provided better prognostic information than the classification according to Ronnett et al. (p=0.04). Expression of the PINCH protein in the stroma was found in 83% of the cases and was associated with high tumor burden (p=0.002) and a poor prognosis (p=0.04).

    Conclusion:

    The proposed new PMP classification system may provide additional prognostic information. PINCH protein is expressed in PMP and has prognostic information.

  • 275.
    Andriopoulos, Thanos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women's and children's health), Clinical Psychology in Healthcare.
    Olsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women's and children's health), Clinical Psychology in Healthcare.
    Hägg Sylvén, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women's and children's health), Clinical Psychology in Healthcare.
    Sjöström, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Informatics and Media, Information Systems.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women's and children's health), Clinical Psychology in Healthcare.
    Grönqvist, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women's and children's health), Clinical Psychology in Healthcare.
    Commencement of and Retention in Web-Based Interventions and Response to Prompts and Reminders: Longitudinal Observational Study Based on Two Randomized Controlled Trials2021In: Journal of Medical Internet Research, E-ISSN 1438-8871, Vol. 23, no 3, article id e24590Article in journal (Refereed)
    Abstract [en]

    Background: Web-based interventions are effective for several psychological problems. However, recruitment, adherence, and missing data are challenges when evaluating these interventions. Objective: This study aimed to describe the use patterns during the commencement phase, possible retention patterns (continuation of data provision), and responses to prompts and reminders among participants in 2 randomized controlled trials (RCTs) evaluating web-based interventions. Methods: Data on use patterns logged in 2 RCTs aiming to reduce symptoms of anxiety and depression among adult patients recently diagnosed with cancer (AdultCan RCT) and patients with a recent myocardial infarction (Heart RCT) were analyzed. The web-based intervention in the AdultCan trial consisted of unguided self-help and psychoeducation and that in the Heart trial consisted of therapist-supported cognitive behavioral therapy. In total, 2360 participants' use patterns at first log-in, including data collection at baseline (ie, commencement) and at 2 follow-ups, were analyzed. Both the intervention and comparison groups were analyzed. Results: At commencement, 70.85% (909/1283) and 86.82% (935/1077) of the participants in AdultCan and Heart RCTs, respectively, logged in and completed baseline data collection after receiving a welcome email with log-in credentials. The median duration of the first log-in was 44 minutes and 38 minutes in AdultCan and Heart RCTs, respectively. Slightly less than half of the participants' first log-ins were completed outside standard office hours. More than 80% (92/114 and 103/111) of the participants in both trials explored the intervention within 2 weeks of being randomized to the treatment group, with a median duration of 7 minutes and 47 minutes in AdultCan and Heart RCTs, respectively. There was a significant association between intervention exploration time during the first 2 weeks and retention in the Heart trial but not in the AdultCan trial. However, the control group was most likely to retain and provide complete follow-up data. Across the 3 time points of data collection explored in this study, the proportion of participants responding to all questionnaires within 1 week from the prompt, without a reminder, varied between 35.45% (413/1165) and 66.3% (112/169). After 2 reminders, up to 97.6% (165/169) of the participants responded. Conclusions: Most participants in both RCTs completed the baseline questionnaires within 1 week of receiving the welcome email. Approximately half of them answered questions at baseline data collection outside office hours, suggesting that the time flexibility inherent in web-based interventions contributes to commencement and use. In contrast to what was expected, the intervention groups generally had lower completion rates than the comparison groups. About half of the participants completed the questionnaires without a reminder, but thereafter, reminders contributed to both baseline and follow-up retention, suggesting they were effective. Strategies to increase commencement of and retention in eHealth interventions are important for the future development of effective interventions and relevant research.

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  • 276.
    Andréasson, H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Real-Time DNA Quantification of Nuclear and Mitochondrial DNA in Forensic Analysis2002In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 33, no 2, p. 402-411Article in journal (Refereed)
    Abstract [en]

    The rapid development of molecular genetic analysis tools has made it possible to analyze most biological materialfound at the scene of a crime. Evidence materials containing DNA quantities too low to be analyzed using nuclear markers can be analyzed using the highly abundant mtDNA. However, there is a shortage of sensitive nDNA and mtDNA quantification assays. In this study, an assay for the quantification of very small amounts of DNA, based on the real-time Taq-Man assay, has been developed. This analysis will provide an estimate of the total number of nDNA copies and the total number of mtDNA molecules in a particular evidence material. The quantification is easy to perform, fast, and requires a minimum of the valuable DNA extracted from the evidence materiaL The results will aid in the evaluation of whether the specific sample is suitable for nDNA or mtDNA analysis. Furthermore, the optimal amount of DNA to be used in further analysis can be estimated ensuring that the analysis is successful and that the DNA is retained for future independent analysis. This assay has significant advantages over existing techniques because of its high sensitivity, accuracy, and the combined analysis of nDNA and mtDNA. Moreover, it has the potential to provide additional information about the presence of inhibitors in forensic samples. Subsequent mitochondrial and nuclear analysis of quantified samples illustrated the potential to predict the number of DNA copies required for a successful analysis in a certain typing assay.

  • 277.
    Andréasson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Rapid quantification and sex determination of forensic evidence materials2003In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 48, no 6, p. 1280-1287Article in journal (Refereed)
    Abstract [en]

    DNA quantification of forensic evidence is very valuable for an optimal use of the available biological material. Moreover, sex determination is of great importance as additional information in criminal investigations as well as in identification of missing persons, no suspect cases, and ancient DNA studies. While routine forensic DNA analysis based on short tandem repeat markers includes a marker for sex determination, analysis of samples containing scarce amounts of DNA is often based on mitochondrial DNA, and sex determination is not performed. In order to allow quantification and simultaneous sex determination on minute amounts of DNA, an assay based on real-time PCR analysis of a marker within the human amelogenin gene has been developed. The sex determination is based on melting curve analysis, while an externally standardized kinetic analysis allows quantification of the nuclear DNA copy number in the sample. This real-time DNA quantification assay has proven to be highly sensitive, enabling quantification of single DNA copies. Although certain limitations were apparent, the system is a rapid, cost-effective, and flexible assay for analysis of forensic casework samples.

  • 278.
    Andréasson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Asp, Allan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Alderborn, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mitochondrial sequence analysis for forensic identification using Pyrosequencing technology2002In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 32, no 1, p. 124-6, 128, 130-3Article in journal (Refereed)
    Abstract [en]

    Over recent years, requests for mtDNA analysis in the field of forensic medicine have notably increased, and the results of such analyses have proved to be very useful in forensic cases where nuclear DNA analysis cannot be performed. Traditionally, mtDNA has been analyzed by DNA sequencing of the two hypervariable regions, HVI and HVII, in the D-loop. DNA sequence analysis using the conventional Sanger sequencing is very robust but time consuming and labor intensive. By contrast, mtDNA analysis based on the pyrosequencing technology provides fast and accurate results from the human mtDNA present in many types of evidence materials in forensic casework. The assay has been developed to determine polymorphic sites in the mitochondrial D-loop as well as the coding region to further increase the discrimination power of mtDNA analysis. The pyrosequencing technology for analysis of mtDNA polymorphisms has been tested with regard to sensitivity, reproducibility, and success rate when applied to control samples and actual casework materials. The results show that the method is very accurate and sensitive; the results are easily interpreted and provide a high success rate on casework samples. The panel of pyrosequencing reactions for the mtDNA polymorphisms were chosen to result in an optimal discrimination power in relation to the number of bases determined.

  • 279.
    Andréasson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lundberg, Hans
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Nuclear and mitochondrial DNA quantification of various forensic materials2006In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 164, no 1, p. 56-64Article in journal (Refereed)
    Abstract [en]

    Due to the different types and quality of forensic evidence materials, their DNA content can vary substantially, and particularly low quantities can impact the results in an identification analysis. In this study, the quantity of mitochondrial and nuclear DNA was determined in a variety of materials using a previously described real-time PCR method. DNA quantification in the roots and distal sections of plucked and shed head hairs revealed large variations in DNA content particularly between the root and the shaft of plucked hairs. Also large intra- and inter-individual variations were found among hairs. In additions DNA content was estimated in samples collected from fingerprints and accessories. The quantification of DNA on various items also displayed large variations, with some materials containing large amounts of nuclear DNA while no detectable nuclear DNA and only limited amounts of mitochondrial DNA were seen in others. Using this sensitive real-time PCR quantification assay, a better understanding was obtained regarding DNA content and variation in commonly analysed forensic evidence materials and this may guide the forensic scientist as to the best molecular biology approach for analysing various forensic evidence materials.

  • 280.
    Andréasson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nilsson, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Styrman, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Forensic mitochondrial coding region analysis for increased discrimination using pyrosequencing technology2007In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 1, no 1, p. 35-43Article in journal (Refereed)
    Abstract [en]

    Analysis of mitochondrial DNA (mtDNA) is very useful when nuclear DNA analysis fails due to degradation or insufficient amounts of DNA in forensic analysis. However, mtDNA analysis has a lower discrimination power compared to what can be obtained by nuclear DNA (nDNA) analysis, potentially resulting in multiple individuals showing identical mtDNA types in the HVI/HVII region. In this study, the increase in discrimination by analysis of mitochondrial coding regions has been evaluated for identical or similar HVI/HVII sequences. A pyrosequencing-based system for coding region analysis, comprising 17 pyrosequencing reactions performed on 15 PCR fragments, was utilised. This assay was evaluated in 135 samples, resulting in an average read length of 81 nucleotides in the pyrosequencing analysis. In the sample set, a total of 52 coding region SNPs were identified, of which 18 were singletons. In a group of 60 samples with 0 or 1 control region difference from the revised Cambridge reference sequence (rCRS), only 12 samples could not be resolved by at least two differences using the pyrosequencing assay. Thus, the use of this pyrosequencing-based coding region assay has the potential to substantially increase the discriminatory power of mtDNA analysis.

  • 281.
    Angiolini, Francesca
    et al.
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy;GSK Vaccines Srl, Siena, Italy.
    Belloni, Elisa
    CNR, Ist Genet Mol, Pavia, Italy.
    Giordano, Marco
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Campioni, Matteo
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Forneris, Federico
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Paola, Paronetto Maria
    Univ Roma Foro Italico, Dept Movement Human & Hlth Sci, Rome, Italy.
    Lupia, Michela
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Brandas, Chiara
    CNR, Ist Genet Mol, Pavia, Italy.
    Pradella, Davide
    CNR, Ist Genet Mol, Pavia, Italy;Univ Pavia, Pavia, Italy.
    Di Matteo, Anna
    CNR, Ist Genet Mol, Pavia, Italy.
    Giampietro, Costanza
    FIRC Inst Mol Oncol, Milan, Italy;Swiss Fed Inst Technol, Dept Mech & Proc Engn, Lab Thermodynam Emerging Technol, Zurich, Switzerland.
    Jodice, Giovanna
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Luise, Chiara
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Bertalot, Giovanni
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Freddi, Stefano
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Malinverno, Matteo
    FIRC Inst Mol Oncol, Milan, Italy.
    Irimia, Manuel
    Barcelona Inst Sci & Technol, Ctr Genom Regulat, Barcelona, Spain;Univ Pompeu Fabra, Barcelona, Spain;Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain.
    Moulton, Jon D.
    Gene Tools LLC, Philomath, OR USA.
    Summerton, James
    Gene Tools LLC, Philomath, OR USA.
    Chiapparino, Antonella
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Ghilardi, Carmen
    IRCCS, Ist Ric Farmacol Mario Negri, Lab Biol & Treatment Metastasis, Milan, Italy.
    Giavazzi, Raffaella
    IRCCS, Ist Ric Farmacol Mario Negri, Lab Biol & Treatment Metastasis, Milan, Italy.
    Nyqvist, Daniel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.
    Gabellini, Davide
    IRCCS, San Raffaele Sci Inst, Div Genet & Cell Biol, Milan, Italy.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. FIRC Inst Mol Oncol, Milan, Italy.
    Cavallaro, Ugo
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Ghigna, Claudia
    CNR, Ist Genet Mol, Pavia, Italy.
    A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e44305Article in journal (Refereed)
    Abstract [en]

    The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

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  • 282.
    Angius, Andrea
    et al.
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Uva, Paolo
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Oppo, Manuela
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Buers, Insa
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Persico, Ivana
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Onano, Stefano
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Cuccuru, Gianmauro
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Van Allen, Margot I.
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada;BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada;Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Hulait, Gurdip
    BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada.
    Aubertin, Gudrun
    Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Muntoni, Francesco
    UCL Great Ormond St Hosp, Dubowitz Neuromuscular Ctr, London, England;Univ Hosp Wales, Inst Med Genet, Cardiff, S Glam, Wales.
    Fry, Andrew E.
    Annerén, Göran
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Stattin, Evalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Palomares-Bralo, Maria
    Santos-Simarro, Fernando
    Cucca, Francesco
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Crisponi, Giangiorgio
    Clin St Anna, Cagliari, Italy.
    Rutsch, Frank
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Crisponi, Laura
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses2019In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, no 5, p. 607-614Article in journal (Refereed)
    Abstract [en]

    Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.

  • 283.
    Angsten, Gertrud
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Christofferson, Rolf H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Resolution of infantile intestinal pseudo-obstruction in a boy2017In: Journal of Pediatric Surgery Case Reports, E-ISSN 2213-5766, Vol. 24, p. 28-34Article in journal (Refereed)
    Abstract [en]

    A term boy with spontaneous passage of meconium exhibited episodes of abdominal distension and diarrhea. Due to failure to thrive and suspicion of Hischsprung's disease he was referred to our university hospital at five months of age. Rectal biopsies were normal. Laparotomy revealed dilation of the small bowel and colon without any mechanical obstruction. Full thickness bowel biopsies were taken and a loop ileostomy was constructed. Histopathology revealed fibrosing myopathy, Cajal cell hypertrophy, and neuronal degeneration in both the large and small bowel. The small bowel showed mastocytosis without inflammation. A central venous catheter was placed for vascular access, replaced three times and later switched to a subcutaneous venous port. Catheters were locked after use with vancomycin-heparin and later taurolidine. The individually tailored home parenteral nutrition contained unsaturated fatty acid lipids to reduce cholestasis. Initial insufficient growth was improved after correction of partial parenteral nutrition based on a metabolic balance study. The ileostomy was revised once and finally taken down at 11 years of age following one year without parenteral support. At follow-up at 13 years of age he has episodes of moderate abdominal pain and has entered puberty and reports a high quality of life. (C) 2017 The Authors. Published by Elsevier Inc.

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  • 284.
    Anju,
    et al.
    Univ Delhi, Dept Chem, North Campus, Delhi 110007, India.; Def Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India..
    Chaturvedi, Shubhra
    Def Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India..
    Chaudhary, Vishakha
    Univ Delhi, Dept Chem, North Campus, Delhi 110007, India.;Def Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India..
    Pant, Pradeep
    Indian Inst Technol, Dept Chem, New Delhi 110016, India..
    Jha, Preeti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Kumaran, Senthil S.
    All India Inst Med Sci, New Delhi 110029, India..
    Hussain, Firasat
    Univ Delhi, Dept Chem, North Campus, Delhi 110007, India..
    Mishra, Anil Kumar
    Def Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India..
    5-HT1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging: Synthesis, physico-chemical and MR studies2021In: Bioorganic chemistry, ISSN 0045-2068, Vol. 106, article id 104487Article in journal (Refereed)
    Abstract [en]

    Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T-1 or T-2 contrast. This work reports the synthesis and evaluation of 5-HT1A targeted PARACEST MRI contrast agent using 1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide (DO3AM) as the bifunctional chelator, and 5-HT1A-antagonist methoxyphenyl piperazine (MPP) as a targeting unit. The multistep synthesis led to the MPP conjugated DO3AM with 60% yield. CEST-related physicochemical parameters were evaluated after loading DO3AM-MPP with paramagnetic MRI active lanthanides: Gadolinium (Gd-DO3AM-MPP) and Europium (Eu-DO3AM-MPP). Luminescence lifetime measurements with Eu-DO3AM-MPP and computational DFT studies using Gd-DO3AM-MPP revealed the coordination of one water molecule (q = 1.43) with metal-water distance (r(M)-H2O) of 2.7 angstrom and water residence time (tau(m)) of 0.23 ms. The dissociation constant of K-d 62 +/- 0.02 pM as evaluated from fluorescence quenching of 5-HT1A (protein) and docking score of -4.81 in theoretical evaluation reflect the binding potential of the complex Gd-DO3AM-MPP with the receptor 5-HT1A. Insights of the docked pose reflect the importance of NH2 (amide) and aromatic ring in Gd-DO3AM-MPP while interacting with Ser 374 and Phe 370 in the antagonist binding pocket of 5-HT1A. Gd-DO3AM-MPP shows longitudinal relaxivity 5.85 mM(-1)s(-1) with a water residence lifetime of 0.93 ms in hippocampal homogenate containing 5-HT1A. The potentiometric titration of DO3AM-MPP showed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. The in vitro and in vivo studies confirmed the minimal cytotoxicity and presential binding of Gd-DO3AM-MPP with 5-HT1A receptor in the hippocampus region of the mice. Summarizing, the complex Gd-DO3AM-MPP can have a potential for CEST imaging of 5-HT1A receptors.

  • 285.
    Antoni, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Axelsson, Jan
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lindsjö, Lars
    Kero, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Granstam, Sven-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Rosengren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Vedin, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    In Vivo Visualization of Amyloid Deposits in the Heart with 11C-PIB and PET2013In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 2, p. 213-220Article in journal (Refereed)
    Abstract [en]

    Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-11C]2-(4′-methylamino-phenyl)-6-hydroxybenzothiazole (11C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of 11C-PIB PET in systemic amyloidosis affecting the heart.

    Methods:

    Patients (n = 10) diagnosed with systemic amyloidosis—including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type—and healthy volunteers (n = 5) were investigated with PET/CT using 11C-PIB to study cardiac amyloid deposits and with 11C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention.

    Results:

    Myocardial 11C-PIB uptake was visually evident in all patients 15–25 min after injection and was not seen in any volunteer. A significant difference in 11C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with 11C-PIB. No correlation between 11C-PIB retention index and myocardial blood flow as measured with 11C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient.

    Conclusion:

    11C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

  • 286. Antoniou, Antonis C.
    et al.
    Kartsonaki, Christiana
    Sinilnikova, Olga M.
    Soucy, Penny
    McGuffog, Lesley
    Healey, Sue
    Lee, Andrew
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Cattaneo, Elisa
    Barile, Monica
    Pensotti, Valeria
    Pasini, Barbara
    Dolcetti, Riccardo
    Giannini, Giuseppe
    Putignano, Anna Laura
    Varesco, Liliana
    Radice, Paolo
    Mai, Phuong L.
    Greene, Mark H.
    Andrulis, Irene L.
    Glendon, Gord
    Ozcelik, Hilmi
    Thomassen, Mads
    Gerdes, Anne-Marie
    Kruse, Torben A.
    Jensen, Uffe Birk
    Crueger, Dorthe G.
    Caligo, Maria A.
    Laitman, Yael
    Milgrom, Roni
    Kaufman, Bella
    Paluch-Shimon, Shani
    Friedman, Eitan
    Loman, Niklas
    Harbst, Katja
    Lindblom, Annika
    Arver, Brita
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Melin, Beatrice
    Nathanson, Katherine L.
    Domchek, Susan M.
    Rebbeck, Timothy
    Jakubowska, Ania
    Lubinski, Jan
    Gronwald, Jacek
    Huzarski, Tomasz
    Byrski, Tomasz
    Cybulski, Cezary
    Gorski, Bohdan
    Osorio, Ana
    Ramon y Cajal, Teresa
    Fostira, Florentia
    Andres, Raquel
    Benitez, Javier
    Hamann, Ute
    Hogervorst, Frans B.
    Rookus, Matti A.
    Hooning, Maartje J.
    Nelen, Marcel R.
    van der Luijt, Rob B.
    van Os, Theo A. M.
    van Asperen, Christi J.
    Devilee, Peter
    Meijers-Heijboer, Hanne E. J.
    Garcia, Encarna B. Gomez
    Peock, Susan
    Cook, Margaret
    Frost, Debra
    Platte, Radka
    Leyland, Jean
    Evans, D. Gareth
    Lalloo, Fiona
    Eeles, Ros
    Izatt, Louise
    Adlard, Julian
    Davidson, Rosemarie
    Eccles, Diana
    Ong, Kai-ren
    Cook, Jackie
    Douglas, Fiona
    Paterson, Joan
    Kennedy, M. John
    Miedzybrodzka, Zosia
    Godwin, Andrew
    Stoppa-Lyonnet, Dominique
    Buecher, Bruno
    Belotti, Muriel
    Tirapo, Carole
    Mazoyer, Sylvie
    Barjhoux, Laure
    Lasset, Christine
    Leroux, Dominique
    Faivre, Laurence
    Bronner, Myriam
    Prieur, Fabienne
    Nogues, Catherine
    Rouleau, Etienne
    Pujol, Pascal
    Coupier, Isabelle
    Frenay, Marc
    Hopper, John L.
    Daly, Mary B.
    Terry, Mary B.
    John, Esther M.
    Buys, Saundra S.
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F.
    Tea, Muy-Kheng
    Pfeiler, Georg
    Dressler, Anne Catharina
    Hansen, Thomas v. O.
    Jonson, Lars
    Ejlertsen, Bent
    Barkardottir, Rosa Bjork
    Kirchhoff, Tomas
    Offit, Kenneth
    Piedmonte, Marion
    Rodriguez, Gustavo
    Small, Laurie
    Boggess, John
    Blank, Stephanie
    Basil, Jack
    Azodi, Masoud
    Toland, Amanda Ewart
    Montagna, Marco
    Tognazzo, Silvia
    Agata, Simona
    Imyanitov, Evgeny
    Janavicius, Ramunas
    Lazaro, Conxi
    Blanco, Ignacio
    Pharoah, Paul D. P.
    Sucheston, Lara
    Karlan, Beth Y.
    Walsh, Christine S.
    Olah, Edith
    Bozsik, Aniko
    Teo, Soo-Hwang
    Seldon, Joyce L.
    Beattie, Mary S.
    van Rensburg, Elizabeth J.
    Sluiter, Michelle D.
    Diez, Orland
    Schmutzler, Rita K.
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ruehl, Ina
    Varon-Mateeva, Raymonda
    Kast, Karin
    Deissler, Helmut
    Niederacher, Dieter
    Arnold, Norbert
    Gadzicki, Dorothea
    Schoenbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Aittomaki, Kristiina
    Dumont, Martine
    Chiquette, Jocelyne
    Tischkowitz, Marc
    Chen, Xiaoqing
    Beesley, Jonathan
    Spurdle, Amanda B.
    Neuhausen, Susan L.
    Ding, Yuan Chun
    Fredericksen, Zachary
    Wang, Xianshu
    Pankratz, Vernon S.
    Couch, Fergus
    Simard, Jacques
    Easton, Douglas F.
    Chenevix-Trench, Georgia
    Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 16, p. 3304-3321Article in journal (Refereed)
    Abstract [en]

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

  • 287. Antoniou, Antonis C.
    et al.
    Kuchenbaecker, Karoline B.
    Soucy, Penny
    Beesley, Jonathan
    Chen, Xiaoqing
    McGuffog, Lesley
    Lee, Andrew
    Barrowdale, Daniel
    Healey, Sue
    Sinilnikova, Olga M.
    Caligo, Maria A.
    Loman, Niklas
    Harbst, Katja
    Lindblom, Annika
    Arver, Brita
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Karlsson, Per
    Nathanson, Kate
    Domchek, Susan
    Rebbeck, Tim
    Jakubowska, Anna
    Lubinski, Jan
    Jaworska, Katarzyna
    Durda, Katarzyna
    Zlowowcka-Perlowska, Elzbieta
    Osorio, Ana
    Duran, Mercedes
    Andres, Raquel
    Benitez, Javier
    Hamann, Ute
    Hogervorst, Frans B.
    van Os, Theo A.
    Verhoef, Senno
    Meijers-Heijboer, Hanne E. J.
    Wijnen, Juul
    Garcia, Encarna B. Gomez
    Ligtenberg, Marjolijn J.
    Kriege, Mieke
    Collee, Margriet
    Ausems, Margreet G. E. M.
    Oosterwijk, Jan C.
    Peock, Susan
    Frost, Debra
    Ellis, Steve D.
    Platte, Radka
    Fineberg, Elena
    Evans, D. Gareth
    Lalloo, Fiona
    Jacobs, Chris
    Eeles, Ros
    Adlard, Julian
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Douglas, Fiona
    Brewer, Carole
    Hodgson, Shirley
    Morrison, Patrick J.
    Walker, Lisa
    Rogers, Mark T.
    Donaldson, Alan
    Dorkins, Huw
    Godwin, Andrew K.
    Bove, Betsy
    Stoppa-Lyonnet, Dominique
    Houdayer, Claude
    Buecher, Bruno
    de Pauw, Antoine
    Mazoyer, Sylvie
    Calender, Alain
    Leone, Melanie
    Bressac-de Paillerets, Brigitte
    Caron, Olivier
    Sobol, Hagay
    Frenay, Marc
    Prieur, Fabienne
    Ferrer, Sandra Fert
    Mortemousque, Isabelle
    Buys, Saundra
    Daly, Mary
    Miron, Alexander
    Terry, Mary Beth
    Hopper, John L.
    John, Esther M.
    Southey, Melissa
    Goldgar, David
    Singer, Christian F.
    Fink-Retter, Anneliese
    Tea, Muy-Kheng
    Kaulich, Daphne Geschwantler
    Hansen, Thomas V. O.
    Nielsen, Finn C.
    Barkardottir, Rosa B.
    Gaudet, Mia
    Kirchhoff, Tomas
    Joseph, Vijai
    Dutra-Clarke, Ana
    Offit, Kenneth
    Piedmonte, Marion
    Kirk, Judy
    Cohn, David
    Hurteau, Jean
    Byron, John
    Fiorica, James
    Toland, Amanda E.
    Montagna, Marco
    Oliani, Cristina
    Imyanitov, Evgeny
    Isaacs, Claudine
    Tihomirova, Laima
    Blanco, Ignacio
    Lazaro, Conxi
    Teule, Alex
    Del Valle, J.
    Gayther, Simon A.
    Odunsi, Kunle
    Gross, Jenny
    Karlan, Beth Y.
    Olah, Edith
    Teo, Soo-Hwang
    Ganz, Patricia A.
    Beattie, Mary S.
    Dorfling, Cecelia M.
    van Rensburg, Elizabeth Jansen
    Diez, Orland
    Kwong, Ava
    Schmutzler, Rita K.
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ditsch, Nina
    Arnold, Norbert
    Heidemann, Simone
    Niederacher, Dieter
    Preisler-Adams, Sabine
    Gadzicki, Dorothea
    Varon-Mateeva, Raymonda
    Deissler, Helmut
    Gehrig, Andrea
    Sutter, Christian
    Kast, Karin
    Fiebig, Britta
    Schaefer, Dieter
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Muranen, Taru A.
    Lesperance, Bernard
    Spurdle, Amanda B.
    Neuhausen, Susan L.
    Ding, Yuan C.
    Wang, Xianshu
    Fredericksen, Zachary
    Pankratz, Vernon S.
    Lindor, Noralane M.
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Bonanni, Bernardo
    Bernard, Loris
    Dolcetti, Riccardo
    Papi, Laura
    Ottini, Laura
    Radice, Paolo
    Greene, Mark H.
    Loud, Jennifer T.
    Andrulis, Irene L.
    Ozcelik, Hilmi
    Mulligan, Anna Marie
    Glendon, Gord
    Thomassen, Mads
    Gerdes, Anne-Marie
    Jensen, Uffe B.
    Skytte, Anne-Bine
    Kruse, Torben A.
    Chenevix-Trench, Georgia
    Couch, Fergus J.
    Simard, Jacques
    Easton, Douglas F.
    Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1, p. R33-Article in journal (Refereed)
    Abstract [en]

    Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).

    Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.

    Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).

    Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

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  • 288.
    Antonodimitrakis, Pantelis Clewemar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Neuroendocrine tumors with syndromic vasoactive intestinal polypeptide hypersecretion: a retrospective study2017In: International Journal of Endocrine Oncology, Vol. 4, no 1, p. 9-22Article in journal (Refereed)
    Abstract [en]

    Aim: Vasoactive intestinal polypeptide producing neuroendocrine tumors are rare and cause severe hormonal symptoms. Patients/methods: Eighteen patients with vasoactive intestinal polypeptide producing neuroendocrine tumors were analyzed with reviews of medical records, radiology and tumor tissue specimens. Results: Twelve patients (67%) had liver metastases at diagnosis. Chemotherapy, somatostatin analogs and interferon were given as medical therapies. Streptozocin/5-fluorouracil produced an objective response in 40% of the evaluable patients. Somatostatin analogs gave a clinical/biochemical response in eight out of nine patients. Transarterial embolization of the liver and peptide receptor radionuclide therapy was given to refractory cases. Sixteen patients died during the observation period. The median overall survival from diagnosis was 102 months. Conclusion: Systemic chemotherapy and somatostatin analogs should be given in cases of advanced disease or for hormonal symptoms.

  • 289.
    Anwar, Mohiemen
    et al.
    Chelsea & Westminster NHS Fdn Trust, ENT Dept, London, England..
    Arendt, Maja-Louise
    Univ Copenhagen, Dept Vet Clin Sci, Copenhagen, Denmark..
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Carlsson, Anette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alusi, Ghasan
    Ixogen Ltd, London, England..
    Öberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ixovex-1, a novel oncolytic E1B-mutated adenovirus2022In: Cancer Gene Therapy, ISSN 0929-1903, E-ISSN 1476-5500, Vol. 29, no 11, p. 1628-1635Article in journal (Refereed)
    Abstract [en]

    There is a great demand for improved oncolytic viruses that selectively replicate within cancer cells while sparing normal cells. Here, we describe a novel oncolytic adenovirus, Ixovex-1, that obtains a cancer-selective replication phenotype by modulating the level of expression of the different, alternatively spliced E1B mRNA isoforms. Ixovex-1 is a recombinant adenovirus that carries a single point mutation in the E1B-93R 3' splice acceptor site that results in overexpression of the E1B-156R splice isoform. In this paper, we studied the characteristics of this novel oncolytic adenovirus by validating its in vitro behaviour in a panel of normal cells and cancer cells. We additionally studied its anti-tumour efficacy in vivo. Ixovex-1 significantly inhibited tumour growth and prolonged survival of mice in an immune-deficient lung carcinoma tumour implantation model. In complementation experiments, overexpression of E1B-156R was shown to increase the oncolytic index of both Ad5wt and ONYX-015. In contrast to prior viruses of similar type, Ixovex-1 includes a functional E3B region for better in vivo efficacy. Throughout this study, the Ixovex-1 virus has been proven to be superior in competency compared to a virus with multiple deletions.

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  • 290.
    Apollonio, Benedetta
    et al.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Nicholas, Nicole S.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Salisbury, Jon
    Kings Coll Hosp London, London, England..
    Patten, Piers E.
    Kings Coll Hosp London, Haematol, London, England..
    Kassam, Shireen
    Kings Coll Hosp London, London, England..
    Devereux, Stephen
    Kings Coll Hosp London, Haematol, London, England..
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ramsay, Alan G.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Diffuse Large B-Cell Lymphoma (DLBCL) Tumor Cells Reprogram Lymphatic Fibroblasts into Cancer-Associated Fibroblasts (CAFs) That Contribute to Tumor Microenvironment (TME)-Driven Immune Privilege2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 291.
    Apollonio, Benedetta
    et al.
    Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.;Ist Tumori Giovanni Paolo II, Dept Rare Tumors & Melanoma, Lab Tumor Immunol & Immunotherapy, Viale O Flacco 65, I-70124 Bari, Italy..
    Spada, Filomena
    Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England..
    Petrov, Nedyalko
    Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England..
    Cozzetto, Domenico
    Guys & St Thomass NHS Fdn Trust, BRC Translat Bioinformat, London, England.;Kings Coll London, London, England.;Imperial Coll London, Fac Med, Div Digest Dis, London, England..
    Papazoglou, Despoina
    Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England..
    Jarvis, Peter
    Aristotle Univ Thessaloniki, Surg Dept 5, Thessaloniki, Greece..
    Kannambath, Shichina
    Kings Coll London, London, England.;Guys & St Thomass NHS Fdn Trust, BRC Genom Res Platform, London, England..
    Terranova-Barberio, Manuela
    Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Graham, Charlotte
    Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England..
    Benjamin, Reuben
    Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England..
    Phillips, Elisabeth
    Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England..
    Ellis, Richard
    Guys & St Thomass NHS Fdn Trust, BRC Adv Cytometry Platform, London, England..
    Nuamah, Rosamond
    Saqi, Mansoor
    Guys & St Thomass NHS Fdn Trust, BRC Translat Bioinformat, London, England.;Kings Coll London, London, England..
    Calado, Dinis P.
    Francis Crick Inst, Immun & Canc Lab, London, England..
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Sutton, Lesley A.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Salisbury, Jon
    Kings Coll Hosp NHS Fdn Trust, Dept Haematol, London, England..
    Zacharioudakis, Georgios
    Aristotle Univ Thessaloniki, Surg Dept 5, Thessaloniki, Greece..
    Vardi, Anna
    G Papanikolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanikolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Hagner, Patrick R.
    Bristol Myers Squibb, Summit, NJ USA..
    Gandhi, Anita K.
    Bristol Myers Squibb, Summit, NJ USA..
    Bacac, Marina
    Roche Innovat Ctr Zurich, Schlieren, Switzerland..
    Claus, Christina
    Roche Innovat Ctr Zurich, Schlieren, Switzerland..
    Umana, Pablo
    Roche Innovat Ctr Zurich, Schlieren, Switzerland..
    Jarrett, Ruth F.
    Univ Glasgow, MRC, Ctr Virus Res, Glasgow, Scotland..
    Klein, Christian
    Roche Innovat Ctr Zurich, Schlieren, Switzerland..
    Deutsch, Alexander
    Med Univ Graz, Div Hematol, Graz, Austria..
    Ramsay, Alan G.
    Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, London, England.;Guys Canc Ctr, Lymphoma Immunol, Innovat Hub, London SE1 9RT, England..
    Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma2023In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 133, no 13, article id e166070Article in journal (Refereed)
    Abstract [en]

    Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD'+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD'+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.

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  • 292.
    Aranda-Guillén, Maribel
    et al.
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Røyrvik, Ellen Christine
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.;Norwegian Inst Publ Hlth, Dept Genet & Bioinformat, Oslo, Norway..
    Fletcher-Sandersjöö, Sara
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Artaza, Haydee
    Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Botusan, Ileana Ruxandra
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Grytaas, Marianne A.
    Haukeland Hosp, Dept Med, Bergen, Norway..
    Hallgren, Åsa
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Breivik, Lars
    Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Pettersson, Maria
    Jørgensen, Anders P.
    Oslo Univ Hosp, Sect Specialized Endocrinol, Oslo, Norway..
    Lindstrand, Anna
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Vogt, Elinor
    Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Husebye, Eystein S.
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway..
    Bøe Wolff, Anette S.
    KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway..
    Bensing, Sophie
    Johansson, Stefan
    Haukeland Hosp, Dept Med Genet, Bergen, Norway..
    Eriksson, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.
    A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies2023In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 294, no 1, p. 96-109Article in journal (Refereed)
    Abstract [en]

    Background: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients.

    Methods: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI.

    Results: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies.

    Conclusions: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

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  • 293.
    Arasa, Jorge
    et al.
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Collado-Diaz, Victor
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Kritikos, Ioannis
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Medina-Sanchez, Jessica Danielly
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Friess, Mona Carina
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Sigmund, Elena Caroline
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Schineis, Philipp
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Hunter, Morgan Campbell
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Tacconi, Carlotta
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Paterson, Neil
    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany.;Univ Freiburg, Fac Biol, Freiburg, Germany.;Int Max Planck Res Sch Immunobiol Epigenet & Meta, Freiburg, Germany..
    Nagasawa, Takashi
    Osaka Univ, Grad Sch Frontier Biosci, Lab Stem Cell Biol & Dev Immunol, Osaka, Japan.;Osaka Univ, Grad Sch Med, Osaka, Japan..
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, Munster, Germany.;Westfalische Wilhelms Univ Munster, European Inst Mol Imaging, Munster, Germany..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Detmar, Michael
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Moser, Markus
    Max Planck Inst Biochem, Martinsried, Germany.;Tech Univ Munich, Inst Expt Hematol, Munich, Germany..
    Laemmermann, Tim
    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany..
    Halin, Cornelia
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland..
    Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation2021In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 218, no 7, article id e20201413Article in journal (Refereed)
    Abstract [en]

    Dendritic cell (DC) migration to draining lymph nodes (dLNs) is a slow process that is believed to begin with DCs approaching and entering into afferent lymphatic capillaries. From capillaries, DCs slowly crawl into lymphatic collectors, where lymph flow induced by collector contraction supports DC detachment and thereafter rapid, passive transport to dLNs. Performing a transcriptomics analysis of dermal endothelial cells, we found that inflammation induces the degradation of the basement membrane (BM) surrounding lymphatic collectors and preferential up-regulation of the DC trafficking molecule VCAM-1 in collectors. In crawl-in experiments performed in ear skin explants, DCs entered collectors in a CCR7- and beta 1 integrin-dependent manner. In vivo, loss of beta 1-integrins in DCs or of VCAM-1 in lymphatic collectors had the greatest impact on DC migration to dLNs at early time points when migration kinetics favor the accumulation of rapidly migrating collector DCs rather than slower capillary DCs. Taken together, our findings identify collector entry as a critical mechanism enabling rapid DC migration to dLNs in inflammation.

  • 294.
    Arce, Maximiliano
    et al.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile.
    Pinto, Mauricio P.
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Galleguillos, Macarena
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Munoz, Catalina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Lange, Soledad
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Ramirez, Carolina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Erices, Rafaela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Univ Mayor, Vicerrectoria Invest, Santiago 7510041, Chile.
    Gonzalez, Pamela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Velasquez, Ethel
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Comis Chilena Energia Nucl CCHEN, Santiago, Chile.
    Tempio, Fabian
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile.
    Lopez, Mercedes N.
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Salazar-Onfray, Flavio
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Cautivo, Kelly
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Kalergis, Alexis M.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Biomed Res Consortium Chile, Santiago 8331010, Chile.
    Cruz, Sebastian
    Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lladser, Alvaro
    Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lobos-Gonzalez, Lorena
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile;Univ Desarrollo, Fac Med, Regenerat Med Ctr, Clin Alemana, Santiago 7650568, Chile.
    Valenzuela, Guillermo
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Olivares, Nixa
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Saez, Claudia
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Koning, Tania
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Sanchez, Fabiola A.
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Fuenzalida, Patricia
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Godoy, Alejandro
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Roswell Pk Comprehens Canc Ctr, Dept Urol, Buffalo, NY 14203 USA.
    Contreras Orellana, Pamela
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Leyton, Lisette
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Lugano, Roberta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Quest, Andrew F. G.
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Owen, Gareth, I
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation2019In: Cancers, ISSN 2072-6694, Vol. 11, no 8, article id 1103Article in journal (Refereed)
    Abstract [en]

    Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.

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  • 295.
    Ardui, Simon
    et al.
    Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium..
    Ameur, Adam
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic, Australia..
    Vermeesch, Joris R.
    Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium..
    Hestand, Matthew S.
    Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium.;Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands.;Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA..
    Single molecule real-time (SMRT) sequencing comes of age: applications and utilities for medical diagnostics2018In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 5, p. 2159-2168Article in journal (Refereed)
    Abstract [en]

    Short read massive parallel sequencing has emerged as a standard diagnostic tool in the medical setting. However, short read technologies have inherent limitations such as GC bias, difficulties mapping to repetitive elements, trouble discriminating paralogous sequences, and difficulties in phasing alleles. Long read single molecule sequencers resolve these obstacles. Moreover, they offer higher consensus accuracies and can detect epigenetic modifications from native DNA. The first commercially available long read single molecule platform was the RS system based on PacBio's single molecule realtime (SMRT) sequencing technology, which has since evolved into their RSII and Sequel systems. Here we capsulize how SMRT sequencing is revolutionizing constitutional, reproductive, cancer, microbial and viral genetic testing.

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    fulltext
  • 296.
    Arendt, Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes2014In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 45, no 5, p. 716-722Article in journal (Refereed)
    Abstract [en]

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.

  • 297.
    Arendt, Maja Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Cambridge, Dept Vet Med, Cambridge, England..
    Melin, Malin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tonomura, Noriko
    Broad Inst MIT & Harvard, Cambridge, MA USA.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Koltookian, Michele
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Courtay-Cahen, Celine
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Flindall, Netty
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Bass, Joyce
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Boerkamp, Kim
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands..
    Megquir, Katherine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Youell, Lisa
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Murphy, Sue
    Anim Hlth Trust, Newmarket, Suffolk, England..
    McCarthy, Colleen
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    London, Cheryl
    Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA..
    Rutteman, Gerard R.
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands.;Vet Specialist Ctr De Wagenrenk, Wageningen, Netherlands..
    Starkey, Mike
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, article id e1005647Article in journal (Refereed)
    Abstract [en]

    Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10(-16)), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

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  • 298.
    Arendt, Maja Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Copenhagen, Dept Vet Clin Sci, Copenhagen, Denmark..
    Sakthikumar, Sharadha
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Melin, Malin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Elvers, Ingegerd
    Karolinska Hosp, Stockholm, Sweden..
    Rivera, Patricio
    Vettris Sundsvall, Sundsvall, Sweden..
    Larsen, Majbritt
    Evidensia Specialist Hosp, Helsingborg, Sweden..
    Saellström, Sara
    Swedish Univ Agr Sci, Uppsala, Sweden..
    Lingaas, Frode
    Norwegian Univ Life Sci, Vet Fac, As, Norway..
    Rönnberg, Henrik
    Swedish Univ Agr Sci, Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, article id 632Article in journal (Refereed)
    Abstract [en]

    Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.

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  • 299.
    Aresdahl, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Lindell, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Dukic, Milena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thor, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Congenital granular cell epulis: a case report2015In: Oral and Maxillofacial Surgery Cases, ISSN 2214-5419, Vol. 1, no 1, p. 8-11Article in journal (Refereed)
    Abstract [en]

    Congenital granular cell epulis (CGCE) is an uncommon benign lesion found in newborns. It has predominance for females with an 8:1 ratio in relation to males and is exclusively encountered in the oral cavity. The most affected oral site is located around the canine/incisor region of the maxillary alveolar ridge, where the lesion arises from the soft tissue as a solitary pedunculated mass. CGCE's histogenesis remains obscure and controversial. We present a rare case of 2 separate CGCE lesions adjacent to each other measuring 23 × 18 × 10 and 15 × 10 mm, positioned facially on the right maxillary alveolar process. The patient, a 2-day-old female newborn, did not experience any serious difficulty regarding breathing or deglutition. Complete surgical excision was the treatment of choice in this case, and the procedure was performed under both general and local anesthesia. Histologic and immunohistochemical analysis confirmed the diagnosis of CGCE. The patient showed satisfactory postoperative healing and excellent health at both the 10-day recall appointment and the 6-month follow-up.

  • 300.
    Argirion, Ilona
    et al.
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Pfeiffer, Ruth M.
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Proietti, Carla
    James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Mol Therapeut, Cairns, Qld, Australia..
    Coghill, Anna E.
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA.;H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Div Populat Sci, Tampa, FL USA..
    Yu, Kelly J.
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Middeldorp, Jaap M.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    Sarathkumara, Yomani D.
    James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Mol Therapeut, Cairns, Qld, Australia..
    Hsu, Wan-Lun
    Fu Jen Catholic Univ, Coll Med, Master Program Big Data Biomed, New Taipei, Taiwan.;Fu Jen Catholic Univ, Coll Med, Data Sci Ctr, New Taipei, Taiwan..
    Chien, Yin-Chu
    Acad Sinica, Genom Res Ctr, Taipei, Taiwan.;Natl Hlth Res Inst, Natl Inst Canc Res, Miaoli, Taiwan..
    Lou, Pei-Jen
    Natl Taiwan Univ Hosp & Coll Med, Dept Otolaryngol, Taipei, Taiwan..
    Wang, Cheng-Ping
    Natl Taiwan Univ Hosp & Coll Med, Dept Otolaryngol, Taipei, Taiwan..
    Rothman, Nathaniel
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Lan, Qing
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Chen, Chien-Jen
    Acad Sinica, Genom Res Ctr, Taipei, Taiwan.;Natl Taiwan Univ, Grad Inst Epidemiol & Prevent Med, Coll Publ Hlth, Taipei, Taiwan..
    Mbulaiteye, Sam M.
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Jarrett, Ruth F.
    Univ Glasgow, MRC, Ctr Virus Res, Glasgow, Lanark, Scotland..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden..
    Hjalgrim, Henrik
    Statens Serum Inst, Copenhagen, Denmark.;Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Hildesheim, Allan
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Doolan, Denise L.
    James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Mol Therapeut, Cairns, Qld, Australia..
    Liu, Zhiwei
    NCI, Div Canc Epidemiol & Genet, Rockville, MD USA..
    Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies2023In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 32, no 5, p. 687-696Article in journal (Refereed)
    Abstract [en]

    Background: Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL).

    Methods: Anti-EBV IgG and IgA antibody responses target-ing 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their associ-ation with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies repre-senting the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models.

    Results: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glyco-protein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types.Conclusions: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis.

    Impact: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.

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