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  • 101.
    Civitelli, Livia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Sandin, Linnea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Nelson, Erin
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap.
    Iqbal Khattak, Sikander
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties2016Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, nr 17, s. 9233-9243Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aggregation of the amyloid-(beta) peptide (A beta) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the A beta peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the A beta fibrillation pathway may be a valid approach to reduce A beta cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic A beta species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting A beta-mediated cytotoxicity. Moreover, p-FTAA bound to early formed A beta species and induced a rapid formation of beta-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable A beta species that were nontoxic which indicates that p-FTAA might have therapeutic potential.

  • 102.
    Concepcion Gil-Rodriguez, Maria
    et al.
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    Deardorff, Matthew A.
    Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA.
    Ansari, Morad
    University of Edinburgh, Scotland.
    Tan, Christopher A.
    University of Chicago, IL 60637 USA.
    Parenti, Ilaria
    Medical University of Lubeck, Germany; University of Milan, Italy.
    Baquero-Montoya, Carolina
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain; Hospital Pablo Tobon Uribe, Colombia.
    Ousager, Lilian B.
    Odense University Hospital, Denmark.
    Puisac, Beatriz
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    Hernandez-Marcos, Maria
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    Esperanza Teresa-Rodrigo, Maria
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    Marcos-Alcalde, Inigo
    Centre Biol Molecular Severo Ochoa CSIC UAM, Spain.
    Wesselink, Jan-Jaap
    Biomol Informat SL Campus UAM, Spain.
    Lusa-Bernal, Silvia
    Biomol Informat SL Campus UAM, Spain.
    Bijlsma, Emilia K.
    Leiden University, Netherlands.
    Braunholz, Diana
    Medical University of Lubeck, Germany.
    Bueno-Martinez, Ines
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain; Hospital Clin University of Lozano Blesa, Spain.
    Clark, Dinah
    Childrens Hospital Philadelphia, PA 19104 USA.
    Cooper, Nicola S.
    Birmingham Womens Hospital, England.
    Curry, Cynthia J.
    University of Calif San Francisco, CA USA.
    Fisher, Richard
    James Cook University, England.
    Fryer, Alan
    Liverpool Womens Hospital, England; Alder Hey Childrens Hospital, England.
    Ganesh, Jaya
    Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA.
    Gervasini, Cristina
    University of Milan, Italy.
    Gillessen-Kaesbach, Gabriele
    Medical University of Lubeck, Germany.
    Guo, Yiran
    Childrens Hospital Philadelphia, PA 19104 USA.
    Hakonarson, Hakon
    University of Penn, PA 19104 USA; Childrens Hospital Philadelphia, PA 19104 USA.
    Hopkin, Robert J.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kaur, Maninder
    Childrens Hospital Philadelphia, PA 19104 USA.
    Keating, Brendan J.
    University of Penn, PA 19104 USA; Childrens Hospital Philadelphia, PA 19104 USA.
    Kibaek, Maria
    HC Andersen Childrens Hospital, Denmark.
    Kinning, Esther
    So Gen Hospital, Scotland.
    Kleefstra, Tjitske
    Radboud University of Nijmegen, Netherlands.
    Kline, Antonie D.
    Greater Baltimore Medical Centre, MD USA.
    Kuchinskaya, Ekaterina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Larizza, Lidia
    University of Milan, Italy.
    Li, Yun R.
    Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA.
    Liu, Xuanzhu
    BGI Shenzhen, Peoples R China.
    Mariani, Milena
    University of Milano Bicocca, Italy.
    Picker, Jonathan D.
    Boston Childrens Hospital, MA USA; Boston Childrens Hospital, MA USA.
    Pie, Angeles
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    Pozojevic, Jelena
    Medical University of Lubeck, Germany.
    Queralt, Ethel
    Institute Invest Biomed Bellvitge IDIBELL LHospitalet, Spain.
    Richer, Julie
    Childrens Hospital Eastern Ontario, Canada; University of Ottawa, Canada.
    Roeder, Elizabeth
    University of Texas San Antonio, TX USA.
    Sinha, Anubha
    Birmingham Womens Hospital, England.
    Scott, Richard H.
    Great Ormond St Hospital Sick Children, England; UCL Institute Child Heatlh, England.
    So, Joyce
    CAMH, Canada; University of Health Network, Canada; Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Wusik, Katherine A.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Wilson, Louise
    Great Ormond St Hospital Sick Children, England.
    Zhang, Jianguo
    BGI Shenzhen, Peoples R China.
    Gomez-Puertas, Paulino
    Centre Biol Molecular Severo Ochoa CSIC UAM, Spain.
    Casale, Cesar H.
    National University of Rio Cuarto, Argentina.
    Stroem, Lena
    Karolinska Institute, Sweden.
    Selicorni, Angelo
    University of Milano Bicocca, Italy.
    Ramos, Feliciano J.
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain; Hospital Clin University of Lozano Blesa, Spain.
    Jackson, Laird G.
    Drexel University, PA 19104 USA.
    Krantz, Ian D.
    Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA.
    Das, Soma
    University of Chicago, IL 60637 USA.
    Hennekam, Raoul C. M.
    University of Amsterdam, Netherlands.
    Kaiser, Frank J.
    Medical University of Lubeck, Germany.
    FitzPatrick, David R.
    University of Edinburgh, Scotland.
    Pie, Juan
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes2015Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 4, s. 454-462Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for approximate to 1%-2% of CdLS-like phenotypes.

  • 103.
    Conti, Luca
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Renhorn, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gabrielsson, Anders
    KTH Royal Institute Technology, Sweden.
    Turesson, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Liin, Sara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lindahl, Erik
    KTH Royal Institute Technology, Sweden; Stockholm University, Sweden.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 27562Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Voltage-gated potassium channels open at depolarized membrane voltages. A prolonged depolarization causes a rearrangement of the selectivity filter which terminates the conduction of ions - a process called slow or C-type inactivation. How structural rearrangements in the voltage-sensor domain (VSD) cause alteration in the selectivity filter, and vice versa, are not fully understood. We show that pulling the pore domain of the Shaker potassium channel towards the VSD by a Cd2+ bridge accelerates C-type inactivation. Molecular dynamics simulations show that such pulling widens the selectivity filter and disrupts the K+ coordination, a hallmark for C-type inactivation. An engineered Cd2+ bridge within the VSD also affect C-type inactivation. Conversely, a pore domain mutation affects VSD gating-charge movement. Finally, C-type inactivation is caused by the concerted action of distant amino acid residues in the pore domain. All together, these data suggest a reciprocal communication between the pore domain and the VSD in the extracellular portion of the channel.

  • 104.
    Coomans, Marijke B.
    et al.
    Leiden Univ, Netherlands.
    Dirven, Linda
    Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands.
    Aaronson, Neil K.
    Netherlands Canc Inst, Netherlands.
    Baumert, Brigitta G.
    Univ Hosp Bonn, Germany; Maastricht Univ, Netherlands; Maastricht Univ, Netherlands.
    Van Den Bent, Martin
    Erasmus MC Canc Inst, Netherlands.
    Bottomley, Andrew
    European Org Res Treatment Canc, Belgium.
    Brandes, Alba A.
    Azienda USL IRCCS, Italy.
    Chinot, Olivier
    Aix Marseille Univ, France.
    Coens, Corneel
    European Org Res Treatment Canc, Belgium.
    Gorlia, Thierry
    European Org Res and Treatment Canc Headquarters, Belgium.
    Herrlinger, Ulrich
    Univ Bonn, Germany.
    Keime-Guibert, Florence
    Pitie Salpetriere Hosp Grp, France.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Martinelli, Francesca
    European Org Res Treatment Canc, Belgium.
    Stupp, Roger
    Northwestern Univ, IL 60611 USA.
    Talacchi, Andrea
    San Giovanni Addolorata Hosp, Italy.
    Weller, Michael
    Univ Hosp, Switzerland; Univ Zurich, Switzerland.
    Wick, Wolfgang
    Univ Hosp Heidelberg, Germany; Univ Hosp Heidelberg, Germany; German Canc Res Ctr, Germany.
    Reijneveld, Jaap C.
    Univ Amsterdam, Netherlands.
    Taphoorn, Martin J. B.
    Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands.
    Symptom clusters in newly diagnosed glioma patients: which symptom clusters are independently associated with functioning and global health status?2019Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 21, nr 11, s. 1447-1457Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients functioning. Methods. Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders. Results. Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5-10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (amp;gt;= 10 points difference) physical, role, and social functioning (betas ranged from -11.3 to -15.9, all P amp;lt; 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of -12.3, P amp;lt; 0.001), independent of other factors. Conclusions. Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients functioning as measured with a self-report questionnaire.

  • 105.
    Coomans, Marijke
    et al.
    Leiden Univ, Netherlands.
    Dirven, Linda
    Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands.
    Aaronson, Neil K.
    Netherlands Canc Inst, Netherlands.
    Baumert, Brigitta G.
    Univ Hosp Bonn, Germany; Maastricht Univ, Netherlands; Maastricht Univ, Netherlands.
    van den Bent, Martin
    Erasmus MC Canc Inst, Netherlands.
    Bottomley, Andrew
    European Org Res Treatment Canc, Belgium.
    Brandes, Alba A.
    Azienda USL IRCCS Inst Neurol Sci, Italy.
    Chinot, Olivier
    Aix Marseille Univ, France.
    Coens, Corneel
    European Org Res and Treatment Canc Headquarters, Belgium.
    Gorlia, Thierry
    Univ Bonn, Germany; Univ Bonn, Germany.
    Herrlinger, Ulrich
    Grp Hop Pitie Salpetriere, France.
    Keime-Guibert, Florence
    Groupe Hôpital Pitié-Salpetrière, Paris, France.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Martinelli, Francesca
    Northwestern Univ, IL 60611 USA.
    Stupp, Roger
    Azienda Osped San Giovanni Addolorata, Italy.
    Talacchi, Andrea
    Univ Hosp, Switzerland; Univ Zurich, Switzerland.
    Weller, Michael
    Univ Hosp Heidelberg, Germany; German Consortium Translat Canc Res DKTK, Germany.
    Wick, Wolfgang
    Univ Amsterdam, Netherlands.
    Reijneveld, Jaap C.
    Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands.
    Taphoorn, Martin J. B.
    Leiden University Medical Center, Leiden, Netherlands; Haaglanden Medical Center, Den Haag, Netherlands.
    The added value of health-related quality of life as a prognostic indicator of overall survival and progression-free survival in glioma patients: a meta-analysis based on individual patient data from randomised controlled trials2019Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 116, s. 190-198Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Prognostic value of health-related quality of life (HRQoL) data may be important to inform patients in clinical practice and to guide clinical decision-making. Our study investigated the added prognostic value of HRQoL for overall survival (OS) and progression-free survival (PFS) in a large heterogeneous sample of glioma patients, besides known prognostic factors. Methods: We included individual baseline data from previously published randomised controlled trials (RCTs) in glioma patients in which HRQoL was assessed through the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BN20 questionnaires. Multivariable Cox regression models (stratified for newly diagnosed versus recurrent disease) were constructed, first with clinical variables (age, sex, tumour type, performance status, allocated treatment and extent of resection) only and subsequently with HRQoL variables added, separately for OS and PFS. The added prognostic value of HRQoL was calculated using C-indices. Results: Baseline HRQoL and clinical data from 15 RCTs were included, comprising 5217 patients. In the model including both clinical and HRQoL variables, better cognitive and role functioning and less motor dysfunction were independently associated with longer OS, whereas better role and cognitive functioning, less nausea and vomiting and more appetite loss were independently associated with prolonged PFS. However, C-indices indicated only a small prognostic improvement of the models for OS and PFS when adding HRQoL to the clinical prognostic variables (+1.1% for OS and +.7% for PFS). Conclusion: Our findings demonstrate that several baseline HRQoL variables are independently prognostic for OS and PFS, yet the added value of HRQoL to the known clinical prognostic variables was small. (C) 2019 Elsevier Ltd. All rights reserved.

  • 106.
    Cordeddu, Viviana
    et al.
    Ist Super Sanita, Italy; University of G dAnnunzio, Italy.
    Yin, Jiani C.
    University of Toronto, Canada; University of Toronto, Canada.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik. Linköpings universitet, Medicinska fakulteten.
    Virtanen, Carl
    University of Toronto, Canada; University of Toronto, Canada.
    Drunat, Severine
    Hop Robert Debre, France.
    Lepri, Francesca
    Bambino Gesu Pediat Hospital, Italy.
    De Luca, Alessandro
    Casa Sollievo Sofferenza Hospital, Italy.
    Rossi, Cesare
    St Orsola Marcello Malpighi Hospital, Italy.
    Ciolfi, Andrea
    Ist Super Sanita, Italy.
    Pugh, Trevor J.
    University of Toronto, Canada; University of Toronto, Canada.
    Bruselles, Alessandro
    Ist Super Sanita, Italy.
    Priest, James R.
    Stanford University, CA 94305 USA; Stanford University, CA 94305 USA.
    Pennacchio, Len A.
    University of Calif Berkeley, CA 94720 USA; US Department Energy Joint Genome Institute, CA 94598 USA.
    Lu, Zhibin
    University of Toronto, Canada; University of Toronto, Canada.
    Danesh, Arnavaz
    University of Toronto, Canada; University of Toronto, Canada.
    Quevedo, Rene
    University of Toronto, Canada; University of Toronto, Canada.
    Hamid, Alaa
    University of Toronto, Canada; University of Toronto, Canada.
    Martinelli, Simone
    Ist Super Sanita, Italy.
    Pantaleoni, Francesca
    Ist Super Sanita, Italy.
    Gnazzo, Maria
    Bambino Gesu Pediat Hospital, Italy.
    Daniele, Paola
    Casa Sollievo Sofferenza Hospital, Italy.
    Lissewski, Christina
    Otto von Guericke University, Germany.
    Bocchinfuso, Gianfranco
    University of Roma Tor Vergata, Italy.
    Stella, Lorenzo
    University of Roma Tor Vergata, Italy.
    Odent, Sylvie
    Hop SUD, France.
    Philip, Nicole
    Hop Enfants la Timone, France.
    Faivre, Laurence
    Hop Enfants, France.
    Vlckova, Marketa
    Charles University of Prague, Czech Republic; University Hospital Motol, Czech Republic.
    Seemanova, Eva
    Charles University of Prague, Czech Republic; University Hospital Motol, Czech Republic.
    Digilio, Cristina
    Bambino Gesu Pediat Hospital, Italy.
    Zenker, Martin
    Otto von Guericke University, Germany.
    Zampino, Giuseppe
    University of Cattolica Sacro Cuore, Italy.
    Verloes, Alain
    Hop Robert Debre, France.
    Dallapiccola, Bruno
    Bambino Gesu Pediat Hospital, Italy.
    Roberts, Amy E.
    Boston Childrens Hospital, MA 02115 USA; Boston Childrens Hospital, MA 02115 USA.
    Cave, Helene
    Hop Robert Debre, France; University of Paris Diderot, France.
    Gelb, Bruce D.
    Icahn School Medical Mt Sinai, NY 10029 USA; Icahn School Medical Mt Sinai, NY 10029 USA; Icahn School Medical Mt Sinai, NY 10029 USA.
    Neel, Benjamin G.
    University of Toronto, Canada; University of Toronto, Canada; NYU, NY 10016 USA.
    Tartaglia, Marco
    Ist Super Sanita, Italy; Bambino Gesu Pediat Hospital, Italy.
    Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome2015Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 11, s. 1080-1087Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

  • 107.
    Couch, Fergus J.
    et al.
    Mayo Clin, MN 55905 USA; Mayo Clin, MN 55905 USA.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Mendoza-Fandino, Gustavo A.
    University of S Florida, FL 33612 USA.
    Nord, Silje
    Radiumhosp, Norway.
    Lilyquist, Janna
    Mayo Clin, MN 55905 USA.
    Olswold, Curtis
    Mayo Clin, MN 55905 USA.
    Hallberg, Emily
    Mayo Clin, MN 55905 USA.
    Agata, Simona
    IRCCS, Italy.
    Ahsan, Habibul
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    Aittomaeki, Kristiina
    University of Helsinki, Finland.
    Ambrosone, Christine
    Roswell Pk Cancer Institute, NY 14263 USA.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    Landspitali University Hospital, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Lars
    Institute Qual and Efficiency Health Care IQWiG, Germany.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Blank, Stephanie V.
    NYU, NY 10016 USA.
    Blomqvist, Carl
    University of Helsinki, Finland; University of Helsinki, Finland.
    Bogdanova, Natalia V.
    Hannover Medical Sch, Germany.
    Bojesen, Stig E.
    Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; National Centre Tumor Disease NCT, Germany.
    Burwinkel, Barbara
    Heidelberg University, Germany.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Caldes, Trinidad
    IdISSC, Spain.
    Caligo, Maria A.
    University of Pisa, Italy; University Hospital Pisa, Italy.
    Canzian, Federico
    German Cancer Research Centre, Germany.
    Carpenter, Jane
    University of Sydney, Australia.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany.
    Chanock, Stephen J.
    NCI, MD 20850 USA.
    Chung, Wendy K.
    Columbia University, NY 10032 USA; Columbia University, NY 10032 USA.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cox, Angela
    University of Sheffield, England.
    Cross, Simon S.
    University of Sheffield, England.
    Cunningham, Julie M.
    Mayo Clin, MN 55905 USA.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    de la Hoya, Miguel
    IdISSC, Spain.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall dHebron, Spain; University of Autonoma Barcelona, Spain.
    Ding, Yuan C.
    City Hope National Medical Centre, CA 91010 USA.
    Dolcetti, Riccardo
    CRO Aviano National Cancer Institute, Italy.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    dos-Santos-Silva, Isabel
    University of London London School Hyg and Trop Med, England.
    Dumont, Martine
    Centre Hospital University of Quebec, Canada; University of Laval, Canada.
    Dunning, Alison M.
    University of Cambridge, England.
    Eccles, Diana M.
    University of Southampton, England.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ekici, Arif B.
    University of Erlangen Nurnberg, Germany; Comprehens Cancer Centre EMN, Germany.
    Eliassen, Heather
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Ellis, Steve
    University of Cambridge, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany.
    Figueroa, Jonine
    NCI, MD 20850 USA.
    Flesch-Janys, Dieter
    University of Clin Hamburg Eppendorf, Germany; University of Clin Hamburg Eppendorf, Germany.
    Foersti, Asta
    German Cancer Research Centre, Germany; Lund University, Sweden.
    Fostira, Florentia
    National Centre Science Research Demokritos, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Friebel, Tara
    University of Philadelphia, PA 19104 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gabrielson, Marike
    Karolinska Institute, Sweden.
    Gammon, Marilie D.
    University of N Carolina, NC 27599 USA.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90095 USA; Jonsson Comprehens Cancer Centre, CA 90095 USA.
    Gapstur, Susan M.
    Amer Cancer Soc, GA 30303 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Gaudet, Mia M.
    Amer Cancer Soc, GA 30303 USA.
    Gayther, Simon A.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Gerdes, Anne-Marie
    Copenhagen University Hospital, Denmark.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia.
    Glendon, Gord
    Mt Sinai Hospital, Canada.
    Godwin, Andrew K.
    University of Kansas, KS 66205 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre CNIO, Spain.
    Greene, Mark H.
    NCI, MD 20850 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Gunter, Marc
    University of London Imperial Coll Science Technology and Med, England.
    Haeberle, Lothar
    University of Erlangen Nurnberg, Germany.
    Haiman, Christopher A.
    University of So Calif, CA 90033 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Hart, Steven
    Mayo Clin, MN 55905 USA.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heikkinen, Tuomas
    Heidelberg University, Germany; University of Helsinki, Finland.
    Henderson, Brian E.
    University of So Calif, CA 90033 USA.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hooning, Maartje J.
    Erasmus University, Netherlands.
    Hoover, Robert N.
    NCI, MD 20850 USA.
    Hopper, John L.
    University of Melbourne, Australia.
    Humphreys, Keith
    Karolinska Institute, Sweden.
    Hunter, David J.
    Harvard University, MA 02115 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Oncology Research Institute, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20007 USA.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    James, Paul
    Peter MacCallum Cancer Centre, Australia; University of Melbourne, Australia.
    Janavicius, Ramunas
    State Research Institute, Lithuania.
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Jones, Michael
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kar, Siddhartha
    University of Cambridge, England.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland; University of Helsinki, Finland.
    Khaw, Kay-Tee
    University of Cambridge, England.
    Kibriya, Muhammad G.
    University of Chicago, IL 60637 USA.
    Knight, Julia A.
    Mt Sinai Hospital, Canada.
    Ko, Yon-Dschun
    Evangel Kliniken Bonn gGmbH, Germany.
    Konstantopoulou, Irene
    National Centre Science Research Demokritos, Greece.
    Kosma, Veli-Matti
    University of Eastern Finland, Finland.
    Kristensen, Vessela
    Radiumhosp, Norway.
    Kwong, Ava
    Hong Kong Hereditary Breast Cancer Family Registry, Peoples R China; University of Hong Kong, Peoples R China.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium.
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain.
    Lee, Eunjung
    University of So Calif, CA 90032 USA.
    Le Marchand, Loic
    University of Cancer Centre, HI 96813 USA.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Lindor, Noralane
    Mayo Clin, AZ 85259 USA.
    Lindstrom, Sara
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Liu, Jianjun
    Genome Institute Singapore, Singapore.
    Long, Jirong
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mai, Phuong L.
    NCI, MD 20850 USA.
    Makalic, Enes
    University of Melbourne, Australia.
    Malone, Kathleen E.
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98195 USA.
    Mannermaa, Arto
    University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Margolin, Sara
    Karolinska University Hospital, Sweden.
    Marme, Frederik
    Heidelberg University, Germany.
    Martens, John W. M.
    Erasmus MC Cancer Institute, Netherlands.
    McGuffog, Lesley
    University of Cambridge, England.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Miller, Austin
    Roswell Pk Cancer Institute, NY 14263 USA.
    Milne, Roger L.
    Cancer Council Victoria, Australia.
    Miron, Penelope
    Case Western Reserve University, OH 44106 USA.
    Montagna, Marco
    IRCCS, Italy.
    Mazoyer, Sylvie
    University of Lyon, France.
    Mulligan, Anna M.
    University of Health Network, Canada; University of Toronto, Canada.
    Muranen, Taru A.
    Heidelberg University, Germany; University of Helsinki, Finland.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Neuhausen, Susan L.
    City Hope National Medical Centre, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nordestgaard, Borge G.
    Copenhagen University Hospital, Denmark.
    Nussbaum, Robert L.
    Invitae Corp, CA 94107 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Mayo Clin, MN 55905 USA.
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain.
    Park, Sue K.
    Seoul National University, South Korea; Seoul National University, South Korea.
    Peeters, Petra H.
    University of Medical Centre, Netherlands; University of London Imperial Coll Science Technology and Med, England.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Peterlongo, Paolo
    Fdn Ist FIRC Oncology Mol, Italy.
    Peto, Julian
    University of London London School Hyg and Trop Med, England.
    Phelan, Catherine M.
    University of S Florida, FL 33612 USA.
    Pilarski, Robert
    Ohio State University, OH 43210 USA.
    Poppe, Bruce
    University of Ghent, Belgium.
    Pylkaes, Katri
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy.
    Rahman, Nazneen
    Institute Cancer Research, England.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Rappaport, Christine
    Medical University of Vienna, Austria.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel; B Rappaport Fac Med, Israel.
    Richardson, Andrea
    Johns Hopkins University, MD 21205 USA.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Romieu, Isabelle
    Int Agency Research Canc, France.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Rutgers, Emiel J.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Sanchez, Maria-Jose
    University of Granada, Spain; CIBER Epidemiol and Salud Public CIBERESP, Spain.
    Santella, Regina M.
    Columbia University, NY 10032 USA.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schmidt, Daniel F.
    University of Melbourne, Australia.
    Schmidt, Marjanka K.
    Antoni van Leeuwenhoek Hospital, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Schumacher, Fredrick
    University of So Calif, CA 90033 USA.
    Scott, Rodney
    John Hunter Hospital, Australia.
    Senter, Leigha
    Ohio State University, OH 43210 USA.
    Sharma, Priyanka
    University of Kansas, KS 66205 USA.
    Simard, Jacques
    University of Laval, Canada.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    University of Lyon, France; Hospital Civils Lyon, France.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa
    University of Melbourne, Australia.
    Steinemann, Doris
    Hannover Medical Sch, Germany.
    Stenmark-Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; University of Paris 05, France.
    Swerdlow, Anthony
    Institute Cancer Research, England.
    Szabo, Csilla I.
    NHGRI, MD 20892 USA.
    Tamimi, Rulla
    Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Tapper, William
    University of Southampton, England.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo-Hwang
    Cancer Research Initiat Fdn, Malaysia; University of Malaya, Malaysia.
    Terry, Mary B.
    Columbia University, NY 10032 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Thompson, Deborah
    University of Cambridge, England.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Toland, Amanda E.
    Ohio State University, OH 43210 USA.
    Tollenaar, Robert A. E. M.
    Leiden University, Netherlands.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Truong, Therese
    CESP Centre Research Epidemiol and Populat Heatlh, France.
    Tsimiklis, Helen
    University of Melbourne, Australia.
    Teule, Alex
    IDIBELL Catalan Institute Oncol, Spain.
    Tumino, Rosario
    Civ MP Arezzo Hospital, Italy; Civ MP Arezzo Hospital, Italy.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Turnbull, Clare
    Institute Cancer Research, England.
    Ursin, Giski
    Institute Populat Based Cancer Research, Norway.
    van Deurzen, Carolien H. M.
    Erasmus University, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Varon-Mateeva, Raymonda
    Charite, Germany.
    Wang, Zhaoming
    NCI, MD 20877 USA.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weiderpass, Elisabete
    Karolinska Institute, Sweden; Institute Populat Based Cancer Research, Norway; University of Tromso, Norway; Folkhalsan Research Centre, Finland.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Whittemore, Alice
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital, Belgium.
    Winqvist, Robert
    University of Oulu, Finland; University of Oulu, Finland; University of Oulu, Finland.
    Yang, Xiaohong R.
    NCI, MD 20892 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yao, Song
    Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
    Pilar Zamora, M.
    Hospital University of La Paz, Spain.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA; Vanderbilt University, TN 37203 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Kraft, Peter
    Harvard University, MA 02115 USA; Harvard University, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55905 USA.
    Slager, Susan
    Mayo Clin, MN 55905 USA.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Pharoah, Paul D. P.
    University of Cambridge, England.
    Monteiro, Alvaro A. N.
    University of S Florida, FL 33612 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20850 USA.
    Easton, Douglas F.
    University of Cambridge, England.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, nr 11375, s. 1-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  • 108.
    Cristobal, Susana
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tedesco, Sara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bayat, Narges
    Stockholm University.
    Danielsson, Gabriela
    Stockholm University.
    Buque, Xavier
    Basque country University, Spain.
    Aspichueta, Patricia
    Basque Country University, Spain.
    Fresnedo, Olatz
    Basque Country University, Spain.
    Proteomic and lipidomic analysis of primary mouse hepatocytes exposed to metal and metal oxide nanoparticles2015Inngår i: Journal of Integrated OMICS, ISSN 2182-0287, Vol. 5, nr 1, s. 44-57Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The global analysis of the cellular lipid and protein content upon exposure to metal and metal oxide nanoparticles (NPs) can provide an overviewof the possible impact of exposure. Proteomic analysis has been applied to understand the nanoimpact however the relevance of the alterationon the lipidic proOle has been underestimated. In our study, primary mouse hepatocytes were treated with ultra-small (US) TiO2-USNPsas well as ZnO-NPs, CuO-NPs and Ag-NPs. e protein extracts were analysed by 2D-DIGE and quantiOed by imaging soPware and the selecteddi9erentially expressed proteins were identiOed by nLC-ESI-MS/MS. In parallel, lipidomic analysis of the samples was performed usingthin layer chromatography (TLC) and analyzed by imaging soPware. Our Ondings show an overall ranking of the nanoimpact at the cellularand molecular level: TiO2-USNPs<ZnO-NPs<Ag-NPs<CuO-NPs. CuO-NPs and Ag-NPs were cytotoxic while ZnO-NPs and CuO-NPs hadoxidative capacity. TiO2-USNPs did not have oxidative capacity and were not cytotoxic. e most common cellular impact of the exposurewas the down-regulation of proteins. e proteins identiOed were involved in urea cycle, lipid metabolism, electron transport chain, metabolismsignaling, cellular structure and we could also identify nuclear proteins. CuO-NPs exposure decreased phosphatidylethanolamine andphosphatidylinositol and caused down-regulation of electron transferring protein subunit beta. Ag-NPs exposure caused increased of totallipids and triacylglycerol and decrease of sphingomyelin. TiO2-USNPs also caused decrease of sphingomyelin as well as up-regulation of ATPsynthase and electron transferring protein alfa. ZnO-NPs a9ected the proteome in a concentration-independent manner with down-regulationof RNA helicase. ZnO-NPs exposure did not a9ect the cellular lipids. To our knowledge this work represents the Orst integrated proteomic andlipidomic approach to study the e9ect of NPs exposure to primary mouse hepatocytes in vitro.

  • 109.
    Dahlrot, R. H.
    et al.
    Odense Univ Hosp, Denmark.
    Dowsett, J.
    Odense Univ Hosp, Denmark.
    Fosmark, S.
    Odense Univ Hosp, Denmark.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Henriksson, R.
    Umea Univ, Sweden; Reg Canc Ctr Stockholm Gotland, Sweden.
    Boldt, H.
    Odense Univ Hosp, Denmark.
    de Stricker, K.
    Odense Univ Hosp, Denmark.
    Sorensen, M. D.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Poulsen, H. S.
    Rigshosp, Denmark.
    Lysiak, Malgorzata
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för verksamhetsstöd och utveckling, Regionalt Cancercentrum.
    Hansen, S.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Kristensen, B. W.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis2018Inngår i: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 44, nr 2, s. 172-184Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status. Methods: MGMT protein expression was quantified in tumour cells in 171 GBMs from the population-based Region of Southern Denmark (RSD)cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM-patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules. Results: When divided at the median, patients with low expression of MGMT protein (AF-low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS-cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF-low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF-low had the best outcome; median OS 23.1 and 20.0 months, respectively. Conclusion: Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour-specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice.

  • 110.
    Dand, Nick
    et al.
    Kings Coll London, England.
    Mucha, Soeren
    Christian Albrechts University of Kiel, Germany.
    Tsoi, Lam C.
    University of Michigan, MI 48109 USA.
    Mahil, Satveer K.
    Kings Coll London, England.
    Stuart, Philip E.
    University of Michigan, MI USA.
    Arnold, Andreas
    University of Medical Greifswald, Germany.
    Baurecht, Hansjoerg
    University Hospital Schleswigholstein, Germany.
    David Burden, A.
    University of Glasgow, Scotland.
    Callis Duffin, Kristina
    University of Utah, UT USA.
    Chandran, Vinod
    University of Toronto, Canada; University of Health Network, Canada.
    Curtis, Charles J.
    NIHR, England; Maudsley NHS Fdn Trust, England; Kings Coll London, England; Kings Coll London, England.
    Das, Sayantan
    University of Michigan, MI 48109 USA.
    Ellinghaus, David
    Christian Albrechts University of Kiel, Germany.
    Ellinghaus, Eva
    Christian Albrechts University of Kiel, Germany.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Esko, Tonu
    University of Tartu, Estonia.
    Gladman, Dafna D.
    University of Toronto, Canada; University of Health Network, Canada.
    Griffiths, Christopher E. M.
    University of Manchester, England.
    Gudjonsson, Johann E.
    University of Michigan, MI USA.
    Hoffman, Per
    University of Basel, Switzerland; University of Bonn, Germany.
    Homuth, Georg
    University of Med, Germany; Ernst Moritz Arndt University of Greifswald, Germany.
    Hueffmeier, Ulrike
    University Hospital Schleswigholstein, Germany; Friedrich Alexander University of Erlangen Nurnberg, Germany.
    Krueger, Gerald G.
    University of Utah, UT USA.
    Laudes, Matthias
    Christian Albrechts University of Kiel, Germany.
    Hyuck Lee, Sang
    NIHR, England; Maudsley NHS Fdn Trust, England; Kings Coll London, England; Kings Coll London, England.
    Lieb, Wolfgang
    Christian Albrechts University of Kiel, Germany.
    Lim, Henry W.
    Henry Ford Hospital, MI 48202 USA.
    Loehr, Sabine
    Friedrich Alexander University of Erlangen Nurnberg, Germany.
    Mrowietz, Ulrich
    Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
    Mueller-Nurayid, Martina
    Helmholtz Zentrum Munich, Germany.
    Noethen, Markus
    University of Bonn, Germany.
    Peters, Annette
    Helmholtz Zentrum Munich, Germany.
    Rahman, Proton
    Mem University of Newfoundland, Canada.
    Reis, Andre
    Friedrich Alexander University of Erlangen Nurnberg, Germany.
    Reynolds, Nick J.
    Newcastle University, England; Newcastle Hospital NHS Fdn Trust, England.
    Rodriguez, Elke
    University Hospital Schleswigholstein, Germany.
    Schmidt, Carsten O.
    University of Medical Greifswald, Germany.
    Spain, Sarah L.
    Kings Coll London, England.
    Strauch, Konstantin
    Helmholtz Zentrum Munich, Germany.
    Tejasvi, Trilokraj
    University of Michigan, MI USA.
    Voorhees, John J.
    University of Michigan, MI USA.
    Warren, Richard B.
    University of Manchester, England.
    Weichenthal, Michael
    University of Medical Centre Schleswig Holstein, Germany.
    Weidinger, Stephan
    University Hospital Schleswigholstein, Germany.
    Zawistowski, Matthew
    University of Michigan, MI 48109 USA.
    Nair, Rajan P.
    University of Michigan, MI USA.
    Capon, Francesca
    Kings Coll London, England.
    Smith, Catherine H.
    Kings Coll London, England.
    Trembath, Richard C.
    Kings Coll London, England.
    Abecasis, Goncalo R.
    University of Michigan, MI 48109 USA.
    Elder, James T.
    University of Michigan, MI USA; Ann Arbor Vet Hospital, MI USA.
    Franke, Andre
    Christian Albrechts University of Kiel, Germany.
    Simpson, Michael A.
    Kings Coll London, England.
    Barker, Jonathan N.
    Kings Coll London, England.
    Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling2017Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, nr 21, s. 4301-4313Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

  • 111.
    Danielsen, Kjersti
    et al.
    UiT, Norway; Univ Hosp North Norway, Norway.
    Duvetorp, Albert
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Skanes Univ Sjukhus, Sweden.
    Iversen, Lars
    Aarhus Univ Hosp, Denmark.
    Ostergaard, Mikkel
    Univ Copenhagen, Denmark.
    Seifert, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Ryhov Hosp, Sweden.
    Steinar Tveit, Kare
    Haukeland Hosp, Norway.
    Skov, Lone
    Univ Copenhagen, Denmark.
    Prevalence of Psoriasis and Psoriatic Arthritis and Patient Perceptions of Severity in Sweden, Norway and Denmark: Results from the Nordic Patient Survey of Psoriasis and Psoriatic Arthritis2019Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 99, nr 1, s. 18-25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Optimal clinical management of psoriasis and psoriatic arthritis (PsA) requires understanding of the impact on patients. The NORdic PAtient survey of Psoriasis and PsA (NORPAPP) aimed to obtain current data on disease prevalence and patient perceptions in Sweden, Denmark and Norway. Among 22,050 individuals questioned, the reported prevalence of psoriasis and/or PsA was 9.7% (5.7% physician-diagnosed plus 4.0% self-diagnosed only); prevalence was similar in Sweden (9.4%) and Denmark (9.2%) but significantly higher in Norway (11.9%). Of those reporting a physicians diagnosis, 74.6% reported psoriasis alone, 10.3% PsA alone and 15.1% both. Patients with PsA perceived their disease to be more severe than those with psoriasis; patients with PsA and psoriasis reported greater disease severity than those with each condition alone. Patients perceptions of psoriasis severity correlated weakly (Spearmans rho 0.42) with clinical severity; both patient perceptions and clinical measures are important in the assessment and management of psoriasis.

  • 112.
    Danø, Sune
    et al.
    Copenhagen University.
    Madsen, Mads F
    Copenhagen University.
    Schmidt, Henning
    Chalmers Technical University.
    Cedersund, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Reduction of a biochemical model with preservation of its basic dynamic properties.2006Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, nr 21, s. 4862-4877Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The complexity of full-scale metabolic models is a major obstacle for their effective use in computational systems biology. The aim of model reduction is to circumvent this problem by eliminating parts of a model that are unimportant for the properties of interest. The choice of reduction method is influenced both by the type of model complexity and by the objective of the reduction; therefore, no single method is superior in all cases. In this study we present a comparative study of two different methods applied to a 20D model of yeast glycolytic oscillations. Our objective is to obtain biochemically meaningful reduced models, which reproduce the dynamic properties of the 20D model. The first method uses lumping and subsequent constrained parameter optimization. The second method is a novel approach that eliminates variables not essential for the dynamics. The applications of the two methods result in models of eight (lumping), six (elimination) and three (lumping followed by elimination) dimensions. All models have similar dynamic properties and pin-point the same interactions as being crucial for generation of the oscillations. The advantage of the novel method is that it is algorithmic, and does not require input in the form of biochemical knowledge. The lumping approach, however, is better at preserving biochemical properties, as we show through extensive analyses of the models.

  • 113.
    Das, Jyotirmoy
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten.
    Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects2019Inngår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, nr 6, s. 589-601Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The protection against tuberculosis induced by the Bacille Calmette Guerin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively (responders). These macrophages also showed production of Interleukin-1 beta (IL-1 beta) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1 beta production, was strongly correlated with the DMG pattern.

  • 114.
    Dietrich-Zagonel, Franciele
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Hammerman, Malin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Tätting, Love
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Dietrich, Fabricia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Blomgran, Parmis
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Eliasson, Pernilla T.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Stimulation of Tendon Healing With Delayed Dexamethasone Treatment Is Modified by the Microbiome2018Inngår i: American Journal of Sports Medicine, ISSN 0363-5465, E-ISSN 1552-3365, Vol. 46, nr 13, s. 3281-3287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    The immune system reflects the microbiome (microbiota). Modulation of the immune system during early tendon remodeling by dexamethasone treatment can improve rat Achilles tendon healing. The authors tested whether changes in the microbiota could influence the effect of dexamethasone treatment.

    Hypothesis:

    A change in microbiome would influence the response to dexamethasone on regenerate remodeling, specifically tendon material properties (peak stress).

    Study Design:

    Controlled laboratory study.

    Methods:

    Specific opportunist and pathogen-free female rats were housed separately (n = 41) or together with specific pathogen-free rats carrying opportunistic microbes such as Staphylococcus aureus (n = 41). After 6 weeks, all co-housed rats appeared healthy but now carried S aureus. Changes in the gut bacterial flora were tested by API and RapID biochemical tests. All rats (clean and contaminated) underwent Achilles tendon transection under aseptic conditions. Flow cytometry was performed 8 days postoperatively on tendon tissue. Sixty rats received subcutaneous dexamethasone or saline injections on days 5 through 9 after transection. The tendons were tested mechanically on day 12. The predetermined primary outcome was the interaction between contamination and dexamethasone regarding peak stress, tested by 2-way analysis of variance.

    Results:

    Dexamethasone increased peak stress in all groups but more in contaminated rats (105%) than in clean rats (53%) (interaction, P = .018). A similar interaction was found for an estimate of elastic modulus (P = .021). Furthermore, dexamethasone treatment reduced transverse area but had small effects on peak force and stiffness. In rats treated with saline only, contamination reduced peak stress by 16% (P = .04) and elastic modulus by 35% (P = .004). Contamination led to changes in the gut bacterial flora and higher levels of T cells (CD3+CD4+) in the healing tendon (P < .05).

    Conclusion:

    Changes in the microbiome influence tendon healing and enhance the positive effects of dexamethasone treatment during the early remodeling phase of tendon healing.

    Clinical Relevance:

    The positive effect of dexamethasone on early tendon remodeling in rats is strikingly strong. If similar effects could be shown in humans, immune modulation by a few days of systemic corticosteroids, or more specific compounds, could open new approaches to rehabilitation after tendon injury.

  • 115.
    Domert, Jakob
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rao, Sahana Bhima
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance2014Inngår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, s. 82-92Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

  • 116.
    Domert, Jakob
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Sackmann, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Severinsson, Emelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Gothenburg, Sweden.
    Bergstrom, Joakim
    Uppsala University, Sweden.
    Ingelsson, Martin
    Uppsala University, Sweden.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes2016Inngår i: PLOS ONE, ISSN 1932-6203, Vol. 11, nr 12, artikkel-id e0168700Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Parkinsons disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

  • 117.
    Domi, Esi
    et al.
    University of Camerino, Italy.
    Uhrig, Stefanie
    Heidelberg University, Germany.
    Soverchia, Laura
    University of Camerino, Italy.
    Spanagel, Rainer
    Heidelberg University, Germany.
    Hansson, Anita C.
    Heidelberg University, Germany.
    Barbier, Estelle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Ubaldi, Massimo
    University of Camerino, Italy.
    Genetic Deletion of Neuronal PPAR gamma Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPAR gamma Function2016Inngår i: JOURNAL OF NEUROSCIENCE, ISSN 0270-6474, Vol. 36, nr 50, s. 12611-12623Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PPAR gamma is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPAR gamma is activated by thiazolidinediones such as pioglitazone and is targeted to treat insulin resistance. PPAR gamma is densely expressed in brain areas involved in regulation of motivational and emotional processes. Here, we investigated the role of PPAR gamma in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPAR gamma by pioglitazone did not affect basal anxiety, but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPAR gamma (PPAR gamma(NestinCre)), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPAR gamma antagonist, elicited a marked anxiogenic response in PPAR gamma wild-type (WT), but not in PPAR gamma(NestinCre) knock-out (KO) mice. Using c-Fos immunohistochemistry, we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala (AMY) and the hippocampus (HIPP) of PPAR gamma(NestinCre) KO mice compared with WT mice. No differences were found between WT and KO mice in hypothalamic regions responsible for hormonal response to stress or in blood corticosterone levels. Microinjection of pioglitazone into the AMY, but not into the HIPP, abolished the anxiogenic response elicited by acute stress. Results also showed that, in both regions, PPAR gamma colocalizes with GABAergic cells. These findings demonstrate that neuronal PPAR gamma is involved the regulation of the stress response and that the AMY is a key substrate for the anxiolytic effect of PPAR gamma

  • 118.
    Durrieu, Lucía
    et al.
    IFIByNE, DFBMC, FCEN, UBA, Buenos Aires, Argentine.
    Johansson, Rikard
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Bush, Alan
    IFIByNE, DFBMC, FCEN, UBA, Buenos Aires, Argentine.
    Janzén, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gollvik, Martin
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik.
    Cedersund, Gunnar
    Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik.
    Colman-Lerner, Alejandro
    IFIByNE, DFBMC, FCEN, UBA, Buenos Aires, Argentine.
    Quantification of nuclear transport in single cells2014Annet (Annet vitenskapelig)
    Abstract [en]

    Regulation of nuclear transport is a key cellular function involved in many central processes, such as gene expression regulation and signal transduction. Rates of protein movement between cellular compartments can be measured by FRAP. However, no standard and reliable methods to calculate transport rates exist. Here we introduce a method to extract import and export rates, suitable for noisy single cell data. This method consists of microscope procedures, routines for data processing, an ODE model to fit to the data, and algorithms for parameter optimization and error estimation. Using this method, we successfully measured import and export rates in individual yeast. For YFP, average transport rates were 0.15 sec-1. We estimated confidence intervals for these parameters through likelihood profile analysis. We found large cell-to-cell variation (CV = 0.79) in these rates, suggesting a hitherto unknown source of cellular heterogeneity. Given the passive nature of YFP diffusion, we attribute this variation to large differences among cells in the number or quality of nuclear pores. Owing to its broad applicability and sensitivity, this method will allow deeper mechanistic insight into nuclear transport processes and into the largely unstudied cell-to-cell variation in kinetic rates.

  • 119.
    Dutta, Ravi Kumar
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Gimm, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Genetics of primary hyperaldosteronism2016Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 23, nr 10, s. R437-R454Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

  • 120.
    Dutta, Ravi Kumar
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Welander, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Brauckhoff, Michael
    Haukeland University Hospital, Bergen; University of Bergen, Norway .
    Walz, Martin
    Klinikum Essen Mitte, Essen, Germany .
    Alesina, Piero
    Klinikum Essen Mitte, Essen, Germany .
    Arnesen, Thomas
    Haukeland University Hospital, Bergen; University of Bergen, Norway.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Gimm, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Complementary somatic mutations of KCNJ5, ATP1A1, and ATP2B3 in sporadic aldosterone producing adrenal adenomas2014Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, nr 1, s. L1-L4Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 121.
    Duvetorp, Albert
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Skanes Univ Sjukhus, Sweden.
    Ostergaard, M.
    Univ Copenhagen, Denmark.
    Skov, L.
    Univ Copenhagen, Denmark.
    Seifert, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Ryhov Hosp, Sweden.
    Tveit, K. S.
    Haukeland Hosp, Norway.
    Danielsen, K.
    UiT Arctic Univ Norway, Norway; Univ Hosp North Norway, Norway.
    Iversen, Lars
    Aarhus Univ Hosp, Denmark.
    Quality of life and contact with healthcare systems among patients with psoriasis and psoriatic arthritis: results from the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP)2019Inngår i: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 311, nr 5, s. 351-360Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Psoriasis (skin psoriasis, PsO) is a chronic inflammatory condition. In about one-third of cases, the joints are affected (psoriatic arthritis, PsA). Both conditions, especially PsA, profoundly impact patients health-related quality of life (HRQoL). To describe the impact of psoriasis on HRQoL and patients contact with the healthcare system in Sweden, Denmark, and Norway, the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP) asked 22,050 adults randomly selected in Sweden, Denmark and Norway if they had psoriasis. 1264 individuals who reported physician-diagnosed PsO/PsA were invited to the full survey; 1221 responded (74.6% diagnosed with PsO alone; 25.4% with PsA +/- PsO). Respondents with PsA most frequently consulted a rheumatologist; however, 14.3% had never seen a rheumatologist. Respondents with PsO alone most frequently consulted a general practitioner and 10.7% had never seen a dermatologist (although those with severe symptoms visited dermatologists more often). Negative impacts on HRQoL were reported by 38.1% of respondents with PsO [mostly limitations on clothing (22.6%), sleep disorders (16%), and depression/anxiety (16%)] and by 73% of respondents with PsA [mostly limitations on clothing (41.8%), sports/leisure (44.0%), or daily routine (45.1%) and sleeping disorders]. Absence from work/education was more common with PsA +/- PsO (51.9%) than PsO alone (15.1%). In this survey in Sweden, Denmark, and Norway, the impact of psoriasis on the respondents HRQoL was profound and was greater for PsA than for PsO, as was sickness absence. Sleeping disorders and depression were common and should not be overlooked.

  • 122.
    Duvetorp, Albert
    et al.
    Regional Jönköping County, Sweden.
    Slind Olsen, Renate
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Regional Jonköping County, Sweden.
    Nyström, Helena
    Regional Jonköping County, Sweden.
    Skarstedt, Marita
    Regional Jonköping County, Sweden.
    Dienus, Olaf
    Regional Jonköping County, Sweden.
    Mrowietz, Ulrich
    University of Medical Centre Schleswig Holstein, Germany.
    Soederman, Jan
    Regional Jonköping County, Sweden.
    Seifert, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Regional Jonköping County, Sweden.
    Expression of low-density lipoprotein-related receptors 5 and 6 (LRP5/6) in psoriasis skin2017Inngår i: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 26, nr 11, s. 1033-1038Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Low-density lipoprotein-related receptors 5 and 6 (LRP5/6) are transmembrane receptors with key functions in canonical Wnt signalling. Wnt ligands are thought to play an important role in innate immunity and psoriasis, and recent studies assigned LRP5/6 anti-inflammatory properties. The objective of this study was to investigate the expression of LRP5 and LRP6 in lesional and non-lesional skin in peripheral blood and in mononuclear cells of patients with chronic plaque type psoriasis compared with control individuals. To investigate the effect of UV-B radiation, LRP5/6 skin gene expression was analysed before and after narrowband UV-B treatment. Our results showed significantly decreased gene expression of LRP5 and LRP6 in lesional skin and in peripheral blood from patients with psoriasis compared with non-lesional skin and healthy control skin. Immunohistochemistry did not reveal differences in protein expression of LRP5/6. Narrowband UV-B treatment induced a significant increase in LRP5 and LRP6 gene expression in lesional skin. Decreased gene expression of LRP5/6 in lesional skin and upregulation after nb UV-B treatment suggest a possible role for LRP5/6 in psoriasis.

  • 123.
    Duvetorp, Albert
    et al.
    Regional Jönköping County, Sweden.
    Slind Olsen, Renate
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Regional Jonköping County, Sweden.
    Skarstedt, Marita
    Regional Jonköping County, Sweden.
    Söderman, Jan
    Regional Jonköping County, Sweden.
    Seifert, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Regional Jonköping County, Sweden.
    Psoriasis and Pro-angiogenetic Factor CD93: Gene Expression and Association with Gene Polymorphism Suggests a Role in Disease Pathogenesis2017Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, nr 8, s. 916-921Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CD93 is involved in angiogenesis and inflammation, both of which are key processes in the pathogenesis of psoriasis. CD93 was studied in serum, peripheral blood mononuclear cells and skin of patients with psoriasis and controls. Furthermore, allele frequencies for CD93 single-nucleotide polymorphisms rs2749812 and rs2749817 were assessed in patients with psoriasis compared with controls and the effect of narrow-band ultraviolet B (NB-UVB) treatment on CD93 gene expression was evaluated in the skin of patients with psoriasis. CD93 gene expression was significantly increased in lesional and non-lesional skin from patients with psoriasis compared with controls. Immunohistochemistry revealed CD93 staining in dermal endothelial cells in lesional skin, and psoriasis was significantly associated with rs2749817 CD93 gene polymorphism. NB-UVB treatment of patients with psoriasis did not alter skin CD93 gene expression. Increased protein expression of CD93 psoriatic skin and association with the rs2749817 polymorphism suggests that CD93 plays a role in psoriasis disease pathogenesis.

  • 124.
    Duvetorp, Albert
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Skane Univ Hosp, Sweden.
    Söderman, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Ryhov Cty Hosp, Sweden.
    Assarsson, Malin
    Ryhov Cty Hosp, Sweden.
    Skarstedt, Marita
    Ryhov Cty Hosp, Sweden.
    Svensson, Ake
    Skane Univ Hosp, Sweden.
    Seifert, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Ryhov Cty Hosp, Sweden.
    Observational study on Swedish plaque psoriasis patients receiving narrowband-UVB treatment show decreased S100A8/A9 protein and gene expression levels in lesional psoriasis skin but no effect on S100A8/A9 protein levels in serum2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 3, artikkel-id e0213344Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    S100A8 and S100A9 proteins are highly upregulated in patients with psoriasis and have been proposed as potential biomarkers for psoriasis. The present study was designed to analyze the effect of narrowband ultraviolet B therapy on these proteins. S100A8, S100A9 gene expression and S100A8/A9 heterocomplex protein levels were analyzed in lesional and non-lesional skin before and after narrowband-UVB treatment in patients with chronic plaque type psoriasis. In addition, disease severity was measured by psoriasis area and severity index (PASI) and serum protein levels of S100A8/A9 were repeatedly analyzed. Narrowband-UVB treatment significantly reduced S100A8, S100A9 gene expression and S100A8/A9 protein levels in lesional skin while serum levels showed no significant change. No correlation between PASI and serum S100A8/A9 protein levels was found. These results implicate a role of S100A8/A9 in the anti-inflammatory effect of narrowband-UVB. Serum S100A8/A9 levels do not respond to treatment suggesting that serum S100A8/A9 does not originate from psoriasis skin keratinocytes. Serum S100A8/A9 levels do not correlate with PASI questioning serum S100A8/A9 as a biomarker for psoriasis skin activity.

  • 125.
    Eklund, Daniel
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Welin, Amanda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Andersson, Henrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Stendahl, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Särndahl, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Human gene variants linked to enhanced NLRP3 activity limit intramacrophage growth of Mycobacterium tuberculosis2014Inngår i: The Journal of infectious diseases, ISSN 1537-6613, Vol. 209, nr 5, s. 749-753Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Activation of the NLRP3 inflammasome and subsequent generation of IL-1β is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host-protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequently infecting the cells by virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages.

  • 126.
    Ekman, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Bivik Eding, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Rundquist, Ingemar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    IL-17 and IL-22 Promote Keratinocyte Stemness in the Germinative Compartment in Psoriasis2019Inngår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 139, nr 7, s. 1564-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Psoriasis is an inflammatory skin disorder characterized by the hyperproliferation of basal epidermal cells. It is regarded as T-cell mediated, but the role of keratinocytes (KCs) in the disease pathogenesis has reemerged, with genetic studies identifying KC-associated genes. We applied flow cytometry on KCs from lesional and nonlesional epidermis to characterize the phenotype in the germinative compartment in psoriasis, and we observed an overall increase in the stemness markers CD29 (2.4-fold), CD44 (2.9-fold), CD49f (2.8-fold), and p63 (1.4-fold). We found a reduced percentage of cells positive for the early differentiation marker cytokeratin 10 and a greater fraction of CD29(+) and involucrin thorn cells in the psoriasis KCs than in nonlesional KCs. The up-regulation of stemness markers was more pronounced in the K10(+) cells. Furthermore, the psoriasis cells were smaller, indicating increased proliferation. Treatment with IL-17 and IL-22 induced a similar expression pattern of an up-regulation of p63, CD44, and CD29 in normal KCs and increased the colony-forming efficiency and long-term proliferative capacity, reflecting increased stem cell-like characteristics in the KC population. These data suggest that IL-17 and IL-22 link the inflammatory response to the immature differentiation and epithelial regeneration by acting directly on KCs to promote cell stemness.

    Fulltekst tilgjengelig fra 2020-01-23 08:00
  • 127.
    Ekman, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Vegfors, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis.2017Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, nr 4, s. 441-448Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis.

  • 128.
    Ekman, Bertil
    et al.
    Region Östergötland, Hjärt- och Medicincentrum, Endokrinmedicinska kliniken. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin.
    Wahlberg Topp, Jeanette
    Region Östergötland, Hjärt- och Medicincentrum, Endokrinmedicinska kliniken. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin.
    Landberg, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Medicinska fakulteten.
    Urine oligosaccharide pattern in patients with hyperprolactinaemia2015Inngår i: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 32, nr 8, s. 635-641Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Free milk-type oligosaccharides are produced during pregnancy and lactation and may have an impact on several cells in the immune system. Our aim was to investigate if patients with isolated hyperprolactinaemia, not related to pregnancy, also have increased synthesis and urinary excretion of milk-type oligosaccharides and to compare the excretion pattern with that found during pregnancy. Urine samples were collected as morning sample from 18 patients with hyperprolactinaemia, 13 healthy controls with normal prolactin levels and four pregnant women. After purification, lactose and free oligosaccharides were analysed and quantified by high-performance anion-exchange chromatography with pulsed amperometric detection. The identity of peaks was confirmed by exoglycosidase treatment and comparison with oligosaccharide standards. Prolactin was measured in serum collected between 09 and 11 a.m. by a standardized immunochemical method. Patients with hyperprolactinaemia had higher urinary excretion of lactose than normoprolactinemic controls and urinary lactose correlated positively to prolactin levels (r = 0.51, p less than 0.05). Increased levels of the fucosylated oligosaccharides 2-fucosyl lactose and lacto-di-fucotetraose were found in urine from three and two patients, respectively. The acidic oligosaccharide 3-sialyl lactose was found in high amount in urine from two patients with prolactin of greater than 10,000 mU/l. However, pregnant women in their third trimester had the highest concentration of all these oligosaccharides and excretion increased during pregnancy. This study is first to show that both lactose and certain fucosylated and sialylated milk-type oligosaccharides are increased in some patients with hyperprolactinaemia. It remains to elucidate the functional importance of these findings.

  • 129.
    Elfwing, Magnus
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Nätt, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Goerlich-Jansson, Vivian C.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan. Department of Animals in Science and Society, University of Utrecht, Faculty of Veterinary Medicine, Utrecht, The Netherlands.
    Persson, Mia
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Hjelm, Jonas
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Early stress causes sex-specific, life-long changes in behaviour, levels of gonadal hormones, and gene expression in chickens2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 5, artikkel-id e0125808Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Early stress can have long-lasting phenotypic effects. Previous research shows that male and female chickens differ in many behavioural aspects, and respond differently to chronic stress. The present experiment aimed to broadly characterize long-term sex differences in responses to brief events of stress experienced during the first weeks of life. Chicks from a commercial egg-laying hybrid were exposed to stress by inducing periods of social isolation during their first three weeks of life, followed by a broad behavioural, physiological and genomic characterization throughout life. Early stressed males, but not females, where more anxious in an open field-test, stayed shorter in tonic immobility and tended to have delayed sexual maturity, as shown by a tendency for lower levels of testosterone compared to controls. While early stressed females did not differ from non-stressed in fear and sexual maturation, they were more socially dominant than controls. The differential gene expression profile in hypothalamus was significantly correlated from 28 to 213 days of age in males, but not in females. In conclusion, early stress had a more pronounced long-term effect on male than on female chickens, as evidenced by behavioral, endocrine and genomic responses. This may either be attributed to inherent sex differences due to evolutionary causes, or possibly to different stress related selection pressures on the two sexes during commercial chicken breeding.

  • 130.
    Elinder, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Madeja, Michael
    University of Munster, Germany; Goethe University of Frankfurt, Germany.
    Zeberg, Hugo
    Karolinska Institute, Sweden.
    Arhem, Peter
    Karolinska Institute, Sweden.
    Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.12016Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, nr 8, s. 1679-1691Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels voltage dependences to a large extent are set by charged amino-acid residues of the extracellular linkers of the Kv channels, which electrostatically affect the charged amino-acid residues of the voltage sensor S4. Extracellular cations shift the conductance-versus-voltage curve, G(V), by interfering with these extracellular charges. We have explored these issues by analyzing the effects of the divalent strontium ion (Sr2+) on the voltage dependence of the G(V) curves of wild-type and chimeric Kv channels expressed in Xenopus oocytes, using the voltage-clamp technique. Out of seven Kv channels, Kv1.2 was found to be most sensitive to Sr2+ (50 mM shifted G(V) by +21.7 mV), and Kv2.1 to be the least sensitive (+7.8 mV). Experiments on 25 chimeras, constructed from Kv1.2 and Kv2.1, showed that the large Sr2+-induced G(V) shift of Kv1.2 can be transferred to Kv2.1 by exchanging the extracellular linker between S3 and S4 (L3/4) in combination with either the extracellular linker between S5 and the pore (L5/P) or that between the pore and S6 (LP/6). The effects of the linker substitutions were nonadditive, suggesting specific structural interactions. The free energy of these interactions was similar to 20 kJ/mol, suggesting involvement of hydrophobic interactions and/or hydrogen bonds. Using principles from double-layer theory we derived an approximate linear equation (relating the voltage shifts to altered ionic strength), which proved to well match experimental data, suggesting that Sr2+ acts on these channels mainly by screening surface charges. Taken together, these results highlight the extracellular surface potential at the voltage sensor as an important determinant of the channels voltage dependence, making the extracellular linkers essential targets for evolutionary selection.

  • 131.
    Ellegård, Sander
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Veenstra, Cynthia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fagerström, Victor
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Department of Surgery, Kalmar Hospital, Kalmar.
    Garsjo, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Gert, Krista
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sundquist, Marie
    Department of Surgery, Kalmar Hospital, Kalmar.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Wingren, Sten
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Elander, Nils
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab2019Inngår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 17, nr 3, s. 3371-3381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

  • 132.
    El-Schich, Zahra
    et al.
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Abdullah, Mohammad
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Shinde, Sudhirkumar
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Dizeyi, Nishtman
    Department of Translational Medicine, Lund University, Malmö, Sweden.
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Sellergren, Börje
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Gjörloff Wingren, Anette
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Different expression levels of glycans on leukemic cells-a novel screening method with molecularly imprinted polymers (MIP) targeting sialic acid.2016Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, nr 10, s. 13763-13768Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sialic acid (SA) is normally expressed on the cell membranes and is located at the terminal position of the sugar chains. SA plays an important role for regulation of the innate immunity, function as markers of the cells and can be recognized by a variety of receptors. Interestingly, the level of SA expression is increased on metastatic cancer cells. The availability of specific antibodies against SA is limited and, therefore, biomarker tools for detection of SA are lacking. We have recently presented a novel method for specific fluorescence labeling of SA molecular imprinted polymers (MIP). Here, we have performed an extended screening of SA expression by using SA-MIP and included four different chronic lymphocytic leukemia (CLL) cell lines, conveniently analyzed by flow cytometry and fluorescence microscopy. SA expression was detected in four cell lines at different levels, and the SA expression were verified with lectin-FITC. These results show that SA-MIP can be used as a plastic antibody for detection of SA using both flow cytometry and fluorescence microscopy. We suggest that SA-MIP can be used for screening of different tumor cells of various stages, including CLL cells.

  • 133.
    Elyas, Eli
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Institute Cancer Research, England; Institute Cancer Research, England; Royal Marsden NHS Fdn Trust, England.
    Grimwood, Alex
    Royal Surrey County Hospital, England.
    Erler, Janine T.
    University of Copenhagen, Denmark.
    Robinson, Simon P.
    Institute Cancer Research, England.
    Cox, Thomas R.
    University of Copenhagen, Denmark; University of New South Wales, Australia; University of New South Wales, Australia.
    Woods, Daniel
    Michelson Diagnost, England.
    Clowes, Peter
    Institute Cancer Research, England; Royal Marsden NHS Fdn Trust, England.
    De Luca, Ramona
    Institute Cancer Research, England; Institute Cancer Research, England; Royal Marsden NHS Fdn Trust, England; Sapienza University of Rome, Italy.
    Marinozzi, Franco
    Sapienza University of Rome, Italy.
    Fromageau, Jeremie
    Institute Cancer Research, England; Institute Cancer Research, England; Royal Marsden NHS Fdn Trust, England.
    Bamber, Jeffrey C.
    Institute Cancer Research, England; Institute Cancer Research, England; Royal Marsden NHS Fdn Trust, England.
    Multi-Channel Optical Coherence Elastography Using Relative and Absolute Shear-Wave Time of Flight2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 1, artikkel-id e0169664Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elastography, the imaging of elastic properties of soft tissues, is well developed for macroscopic clinical imaging of soft tissues and can provide useful information about various pathological processes which is complementary to that provided by the original modality. Scaling down of this technique should ply the field of cellular biology with valuable information with regard to elastic properties of cells and their environment. This paper evaluates the potential to develop such a tool by modifying a commercial optical coherence tomography (OCT) device to measure the speed of shear waves propagating in a three-dimensional (3D) medium. A needle, embedded in the gel, was excited to vibrate along its long axis and the displacement as a function of time and distance from the needle associated with the resulting shear waves was detected using four M-mode images acquired simultaneously using a commercial four-channel swept-source OCT system. Shear-wave time of arrival (TOA) was detected by tracking the axial OCT-speckle motion using cross-correlation methods. Shear-wave speed was then calculated from inter-channel differences of TOA for a single burst (the relative TOA method) and compared with the shear-wave speed determined from positional differences of TOA for a single channel over multiple bursts (the absolute TOA method). For homogeneous gels the relative method provided shear-wave speed with acceptable precision and accuracy when judged against the expected linear dependence of shear modulus on gelatine concentration (R-2 = 0.95) and ultimate resolution capabilities limited by 184 mu m inter-channel distance. This overall approach shows promise for its eventual provision as a research tool in cancer cell biology. Further work is required to optimize parameters such as vibration frequency, burst length and amplitude, and to assess the lateral and axial resolutions of this type of device as well as to create 3D elastograms.

  • 134.
    Enerbäck, Charlotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Univ Michigan, MI 48109 USA.
    Sandin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Lambert, S.
    Univ Michigan, MI 48109 USA.
    Zawistowski, M.
    Univ Michigan, MI 48109 USA.
    Stuart, P. E.
    Univ Michigan, MI 48109 USA.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Tsoi, L. C.
    Univ Michigan, MI 48109 USA.
    Nair, R. P.
    Univ Michigan, MI 48109 USA.
    Johnston, A.
    Univ Michigan, MI 48109 USA.
    Elder, J. T.
    Univ Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hlth Syst, MI USA.
    The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+and CD8+memory T-cells2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 7043Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. GWAS have consistently implicated TYK2 in psoriasis susceptibility. We performed an in-depth association analysis of TYK2 using GWAS and resequencing data. Strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256) were found. rs12720356 encoding I684S is predicted to be deleterious based on its location in the pseudokinase domain. We analyzed PBMCs from 29 individuals representing the haplotypes containing each of the significantly associated signals. STAT4 phosphorylation was evaluated by phospho-flow cytometry after CD3/CD28 activation of cells followed by IL-12 stimulation. Individuals carrying the protective I684S variant manifested significantly reduced p-STAT4 levels in CD4 + CD25 + CD45RO + (mean Stimulation Index (S.I.) 48.08, n = 10) and CD8 + CD25 + CD45RO + cells (S.I. 55.71, n = 10), compared to controls homozygous for the ancestral haplotype (S.I. 68.19, n = 10 (p = 0.002) and 76.76 n = 10 (p = 0.0008) respectively). Reduced p-STAT4 levels were also observed in skin-homing, cutaneous lymphocyte associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. No significant changes in p-STAT4 for the psoriasis-associated variant rs34536443 was found. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility.

  • 135.
    Englund, Ulrika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Apoptosis is one type of programmed cell death, important during tissue development and to maintain the tissue homeostasis. Apoptosis comprises a complex network of internal signaling pathways, and an important part of this signaling network is the action of voltage‐gated ion channels. The aim of this thesis was to explore the role of ion channels and the role of intracellular metal ions during apoptosis in Xenopus laevis oocytes. The reasons for using these oocytes are that they are large, robust, easy to handle, and easy to study electrophysiologically. Apoptosis was induced either chemically by incubation of the oocytes in staurosporine (STS) or mechanically by centrifugation of the oocytes. Ion currents were measured by a two‐electrode voltage clamp technique, intracellular ion concentrations were measured either directly by in‐house developed K+‐selective microelectrodes or indirectly by the electrophysiological technique, and apoptosis was measured by caspase‐3 activation. Paper I describes that the intracellular K+ concentration was reduced by about 30 % during STS‐induced apoptosis. However, this reduction was prevented by excessive expression of exogenous ion channels. Despite the magnitude of the intracellular K+ concentration, either normal or reduced level, the oocytes displayed normal signs of apoptosis, suggesting that the intracellular K+ reduction was not required for the apoptotic process. Because the intracellular K+ concentration was not critical for apoptosis we searched for other ion fluxes by exploring the electrophysiological properties of X. laevis oocytes. Paper II, describes a non‐inactivating Na+ current activated at positive membrane voltages that was upregulated by a factor of five during STS‐induced apoptosis. By preventing influx of Na+, the apoptotic signaling network involving capsase‐3 was prevented. To molecularly identify this voltage‐gated Na channel, the X. tropicalis genome and conserved regions of the human SCNA genes were used as a map. Paper III, shows that the voltage‐gated Na channel corresponds to the SCN2A gene ortholog and that supression of this SCN2A ortholog using miRNA prevented cell death. In conclusion, this thesis work demonstrated that a voltage‐gated Na channel is critical for the apoptotic process in X. laevis oocytes by increasing the intracellular Na+ concentration.

    Delarbeid
    1. Intracellular potassium (K+) concentration decrease is not obligatory for apoptosis
    Åpne denne publikasjonen i ny fane eller vindu >>Intracellular potassium (K+) concentration decrease is not obligatory for apoptosis
    Vise andre…
    2011 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, nr 46, s. 39823-39828Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    K+ efflux is observed as an early event in the apoptotic process in various cell types. Loss of intracellular K+ and subsequent reduction in ionic strength is suggested to release the inhibition of proapoptotic caspases. In this work, a new K+-specific microelectrode was used to study possible alterations in intracellular K+ in Xenopus laevis oocytes during chemically induced apoptosis. The accuracy of the microelectrode to detect changes in intracellular K+ was verified with parallel electrophysiological measurements within the same cells. In concordance with previous studies on other cell types, apoptotic stimuli reduced the intracellular K+ concentration in Xenopus oocytes and increased caspase-3 activity. The reduction in intracellular K+ was prevented by dense expression of voltage-gated K (Kv) channels. Despite this, the caspase-3 activity was increased similarly in Kv channel expressing oocytes as in oocytes not expressing Kv channels. Thus, in Xenopus oocytes caspase-3 activity is not dependent on the intracellular concentration of K+.

    sted, utgiver, år, opplag, sider
    American Society for Biochemistry and Molecular Biology, 2011
    Emneord
    Caspase-3 activation, Electrophysiology, Intracellular K+ concentrations, K+-selective microelectrode, Xenopus laevis oocytes
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-68853 (URN)10.1074/jbc.M111.262725 (DOI)000296925700016 ()
    Merknad
    Funding agencies|Swedish Research Council||Swedish Heart-Lung Foundation||Swedish Brain Foundation||County Council of Ostergotland, King Gustaf V and Queen Victorias Freemasons Foundation||Swedish Society for Medical Research||Tilgjengelig fra: 2011-06-08 Laget: 2011-06-08 Sist oppdatert: 2018-01-25bibliografisk kontrollert
    2. A Voltage Dependent Non-Inactivating Na+ Channel Activated during Apoptosis in Xenopus Oocytes
    Åpne denne publikasjonen i ny fane eller vindu >>A Voltage Dependent Non-Inactivating Na+ Channel Activated during Apoptosis in Xenopus Oocytes
    2014 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 2, s. 0088381-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Ion channels in the plasma membrane are important for the apoptotic process. Different types of voltage-gated ion channels are up-regulated early in the apoptotic process and block of these channels prevents or delays apoptosis. In the present investigation we examined whether ion channels are up-regulated in oocytes from the frog Xenopus laevis during apoptosis. The two-electrode voltage-clamp technique was used to record endogenous ion currents in the oocytes. During staurosporine-induced apoptosis a voltage-dependent Na+ current increased three-fold. This current was activated at voltages more positive than 0 mV (midpoint of the open-probability curve was +55 mV) and showed almost no sign of inactivation during a 1-s pulse. The current was resistant to the Na+-channel blockers tetrodotoxin (1 mM) and amiloride (10 mM), while the Ca2+-channel blocker verapamil (50 mM) in the bath solution completely blocked the current. The intracellular Na+ concentration increased in staurosporine-treated oocytes, but could be prevented by replacing extracellular Na+ whith either K+ or Choline(+). Prevention of this influx of Na+ also prevented the STS-induced up-regulation of the caspase-3 activity, suggesting that the intracellular Na+ increase is required to induce apoptosis. Taken together, we have found that a voltage dependent Na+ channel is up-regulated during apoptosis and that influx of Na+ is a crucial step in the apoptotic process in Xenopus oocytes.

    sted, utgiver, år, opplag, sider
    Public Library of Science, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-105899 (URN)10.1371/journal.pone.0088381 (DOI)000332396200017 ()
    Tilgjengelig fra: 2014-04-14 Laget: 2014-04-12 Sist oppdatert: 2018-01-25
    3. Inhibition of SCN2A ortholog upregulation in Xenopus laevis oocytes prevents cell death
    Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of SCN2A ortholog upregulation in Xenopus laevis oocytes prevents cell death
    2014 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Transport of ions across the cell membrane is essential for the regulation of cell death and tissue homeostasis, and alterations in the function of voltage-gated ion channels and of the intracellular ionic compositions interfere with these processes. Opening of K, Na , or Cl channels have been linked to the apoptotic process and in many cases, opening of these channels precede caspase-3 activation and are thus early events in the apoptotic process. Consistent with the role of these channels in apoptosis, inhibition of these channels prevents or delays the apoptotic process. However, the role of ion channels during apoptosis has been difficult to explore, mainly due to unspecific/non-selective ion channe blockers. In the present investigation, the molecular identity of a  voltage-gated Na channel in oocytes from Xenopus laevis, which is crucial for the apoptotic response to mechanical stress, was identified. Specific down regulation of SCN2A Na channel expression by miRNA prevented apoptosis, suggesting that Na+ influx is essential for apoptosis in Xenopus oocytes.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-111044 (URN)
    Tilgjengelig fra: 2014-10-06 Laget: 2014-10-06 Sist oppdatert: 2018-01-25bibliografisk kontrollert
  • 136.
    Englund, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Brask, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Inhibition of SCN2A ortholog upregulation in Xenopus laevis oocytes prevents cell death2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Transport of ions across the cell membrane is essential for the regulation of cell death and tissue homeostasis, and alterations in the function of voltage-gated ion channels and of the intracellular ionic compositions interfere with these processes. Opening of K, Na , or Cl channels have been linked to the apoptotic process and in many cases, opening of these channels precede caspase-3 activation and are thus early events in the apoptotic process. Consistent with the role of these channels in apoptosis, inhibition of these channels prevents or delays the apoptotic process. However, the role of ion channels during apoptosis has been difficult to explore, mainly due to unspecific/non-selective ion channe blockers. In the present investigation, the molecular identity of a  voltage-gated Na channel in oocytes from Xenopus laevis, which is crucial for the apoptotic response to mechanical stress, was identified. Specific down regulation of SCN2A Na channel expression by miRNA prevented apoptosis, suggesting that Na+ influx is essential for apoptosis in Xenopus oocytes.

  • 137.
    Englund, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Gertow, Jens
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    A Voltage Dependent Non-Inactivating Na+ Channel Activated during Apoptosis in Xenopus Oocytes2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 2, s. 0088381-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ion channels in the plasma membrane are important for the apoptotic process. Different types of voltage-gated ion channels are up-regulated early in the apoptotic process and block of these channels prevents or delays apoptosis. In the present investigation we examined whether ion channels are up-regulated in oocytes from the frog Xenopus laevis during apoptosis. The two-electrode voltage-clamp technique was used to record endogenous ion currents in the oocytes. During staurosporine-induced apoptosis a voltage-dependent Na+ current increased three-fold. This current was activated at voltages more positive than 0 mV (midpoint of the open-probability curve was +55 mV) and showed almost no sign of inactivation during a 1-s pulse. The current was resistant to the Na+-channel blockers tetrodotoxin (1 mM) and amiloride (10 mM), while the Ca2+-channel blocker verapamil (50 mM) in the bath solution completely blocked the current. The intracellular Na+ concentration increased in staurosporine-treated oocytes, but could be prevented by replacing extracellular Na+ whith either K+ or Choline(+). Prevention of this influx of Na+ also prevented the STS-induced up-regulation of the caspase-3 activity, suggesting that the intracellular Na+ increase is required to induce apoptosis. Taken together, we have found that a voltage dependent Na+ channel is up-regulated during apoptosis and that influx of Na+ is a crucial step in the apoptotic process in Xenopus oocytes.

  • 138.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Björk, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eskilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Vasilache, Ana-Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Elander, Louise
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-22013Inngår i: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 71, s. 124-129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

  • 139.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ruud, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eskilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Larsson, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Qian, Hong
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Vasilache, Ana Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Larsson, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiofysik. Linköpings universitet, Hälsouniversitetet.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells2012Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, nr 10, s. 4849-4861Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.

  • 140.
    Engström, Maria
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Karlsson, Thomas
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Landtblom, Anne-Marie
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Craig, Arthur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Barrow Neurol Institute, AZ 85013 USA.
    Evidence of conjoint activation of the anterior insular and cingulate cortices during effortful tasks2015Inngår i: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 8, nr 1071Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ability to perform effortful tasks is a topic that has received considerable interest in the research of higher functions of the human brain. Neuroimaging studies show that the anterior insular and the anterior cingulate cortices are involved in a multitude of cognitive tasks that require mental effort. In this study, we investigated brain responses to effort using cognitive tasks with task-difficulty modulations and functional magnetic resonance imaging (fMRI). We hypothesized that effortful performance involves modulation of activation in the anterior insular and the anterior cingulate cortices, and that the modulation correlates with individual performance levels. Healthy participants performed tasks probing verbal working memory capacity using the reading span task, and visual perception speed using the inspection time task. In the fMRI analysis, we focused on identifying effort-related brain activation. The results showed that working memory and inspection time performances were directly related. The bilateral anterior insular and anterior cingulate cortices showed significantly increased activation during each task with common portions that were active across both tasks. We observed increased brain activation in the right anterior insula and the anterior cingulate cortex in participants with low working memory performance. In line with the reported results, we suggest that activation in the anterior insular and cingulate cortices is consistent with the neural efficiency hypothesis (Neubauer).

  • 141.
    Ericsson, Maria
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Henriksen, Rie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Bélteky, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Sundman, Ann-Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Shionoya, Kiseko
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Long-Term and Transgenerational Effects of Stress Experienced during Different Life Phases in Chickens (Gallus gallus)2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 4, artikkel-id e0153879Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stress in animals causes not only immediate reactions, but may affect their biology for long periods, even across generations. Particular interest has been paid to perinatal stress, but also adolescence has been shown to be a sensitive period in mammals. So far, no systematic study has been performed of the relative importance of stress encountered during different life phases. In this study, groups of chickens were exposed to a six-day period of repeated stress during three different life phases: early (two weeks), early puberty (eight weeks) and late puberty (17 weeks), and the effects were compared to an unstressed control group. The short-term effects were assessed by behaviour, and the long-term and transgenerational effects were determined by effects on behavior and corticosterone secretion, as well as on hypothalamic gene expression. Short-term effects were strongest in the two week group and the eight week group, whereas long-term and transgenerational effects were detected in all three stress groups. However, stress at different ages affected different aspects of the biology of the chickens, and it was not possible to determine a particularly sensitive life phase. The results show that stress during puberty appears to be at least equally critical as the previously studied early life phase. These findings may have important implications for animal welfare in egg production, since laying hens are often exposed to stress during the three periods pinpointed here.

  • 142.
    Eriksson, D.
    et al.
    Karolinska Institute, Sweden; Metab and Diabet Karolinska University Hospital, Sweden.
    Bianchi, M.
    Uppsala University, Sweden.
    Landegren, N.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Nordin, J.
    Uppsala University, Sweden.
    Dalin, F.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Mathioudaki, A.
    Uppsala University, Sweden.
    Eriksson, G. N.
    Karolinska Institute, Sweden.
    Hultin-Rosenberg, L.
    Uppsala University, Sweden.
    Dahlqvist, J.
    Uppsala University, Sweden.
    Zetterqvist, H.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Karlsson, A.
    Uppsala University, Sweden.
    Hallgren, A.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Farias, F. H. G.
    Uppsala University, Sweden.
    Muren, E.
    Uppsala University, Sweden.
    Ahlgren, K. M.
    Uppsala University, Sweden.
    Lobell, A.
    Uppsala University, Sweden.
    Andersson, G.
    Swedish University of Agriculture Science, Sweden.
    Tandre, K.
    Uppsala University, Sweden.
    Dahlqvist, S. R.
    Umeå University, Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Rönnblom, L.
    Uppsala University, Sweden.
    Hulting, A. -L.
    Karolinska Institute, Sweden.
    Wahlberg Topp, Jeanette
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Endokrinmedicinska kliniken.
    Ekwall, O.
    University of Gothenburg, Sweden.
    Dahlqvist, P.
    Umeå University, Sweden.
    Meadows, J. R. S.
    Uppsala University, Sweden.
    Bensing, S.
    Metab and Diabet Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Lindblad-Toh, K.
    Uppsala University, Sweden; Broad Institute MIT and Harvard, MA USA.
    Kampe, O.
    Karolinska Institute, Sweden; Metab and Diabet Karolinska University Hospital, Sweden; Uppsala University, Sweden.
    Pielberg, G. R.
    Uppsala University, Sweden.
    Extended exome sequencing identifies BACH2 as a novel major risk locus for Addisons disease2016Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, nr 6, s. 595-608Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addisons disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addisons disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addisons disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addisons disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addisons disease, we have identified BACH2 as a major risk locus in Addisons disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

  • 143.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Landegren, Nils
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Dalin, Frida
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Skov, Jakob
    Karolinska Inst, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala Univ, Sweden.
    Mathioudaki, Argyri
    Uppsala Univ, Sweden.
    Nordin, Jessika
    Uppsala Univ, Sweden.
    Hallgren, Asa
    Karolinska Inst, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Sweden.
    Tandre, Karolina
    Uppsala Univ, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Hulting, Anna-Lena
    Not Found:[Eriksson, Daniel; Landegren, Nils; Dalin, Frida; Hallgren, Asa; Kampe, Olle] Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; [Eriksson, Daniel; Bensing, Sophie; Kampe, Olle] Karolinska Univ Hosp, Dept Endocrinol Metab and Diabet, Stockholm, Sweden; [Bianchi, Matteo; Hultin-Rosenberg, Lina; Mathioudaki, Argyri; Nordin, Jessika; Meadows, Jennifer R. S.; Lindblad-Toh, Kerstin; Pielberg, Gerli Rosengren] Uppsala Univ, Dept Med Biochem and Microbiol, Sci Life Lab, Uppsala, Sweden; [Landegren, Nils; Dalin, Frida; Tandre, Karolina; Ronnblom, Lars] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden; [Skov, Jakob; Bensing, Sophie] Karolinska Inst, Dept Mol Med and Surg, Stockholm, Sweden; [Andersson, Goran] Swedish Univ Agr Sci, Dept Anim Breeding and Genet, Uppsala, Sweden; [Dahlqvist, Solbritt Rantapaa; Dahlqvist, Per] Umea Univ, Dept Publ Hlth and Clin Med, Umea, Sweden; [Soderkvist, Peter; Wahlberg, Jeanette] Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Endocrinol, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol and Inflammat Res, Gothenburg, Sweden; [Lindblad-Toh, Kerstin] Broad Inst MIT and Harvard, Cambridge, MA USA; [Kampe, Olle] KG Jebsen Ctr Autoimmune Dis, Bergen, Norway;.
    Wahlberg, Jeanette
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Endokrinmedicinska kliniken.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Meadows, Jennifer R. S.
    Uppsala Univ, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT and Harvard, MA USA.
    Bensing, Sophie
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala Univ, Sweden.
    Kampe, Olle
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; KG Jebsen Ctr Autoimmune Dis, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addisons disease in Sweden2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 8395Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Autoimmune Addisons disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

  • 144.
    Eriksson, Ida
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bornefall, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Villamil Giraldo, Ana Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Impact of high cholesterol in a Parkinsons disease model: Prevention of lysosomal leakage versus stimulation of alpha-synuclein aggregation2017Inngår i: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 96, nr 2, s. 99-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Parkinsons disease is characterized by accumulation of intraneuronal cytoplasmic inclusions, Lewy bodies, which mainly consist of aggregated alpha-synuclein. Controversies exist as to whether high blood cholesterol is a risk factor for the development of the disease and whether statin treatment could have a protective effect. Using a model system of BE(2)-M17 neuroblastoma cells treated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), we found that MPP+-induced cell death was accompanied by cholesterol accumulation in a lysosomal-like pattern in pre-apoptotic cells. To study the effects of lysosomal cholesterol accumulation, we increased lysosomal cholesterol through pre-treatment with U18666A and found delayed leakage of lysosomal contents into the cytosol, which reduced cell death. This suggests that increased lysosomal cholesterol is a stress response mechanism to protect lysosomal membrane integrity in response to early apoptotic stress. However, high cholesterol also stimulated the accumulation of alpha-synuclein. Treatment with the cholesterol-lowering drug lovastatin reduced MPP+-induced cell death by inhibiting the production of reactive oxygen species, but did not prevent lysosomal cholesterol increase nor affect alpha-synuclein accumulation. Our study indicates a dual role of high cholesterol in Parkinsons disease, in which it acts both as a protector against lysosomal membrane permeabilization and as a stimulator of alpha-synuclein accumulation. (C) 2017 Elsevier GmbH. All rights reserved.

  • 145.
    Eriksson, Ida
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Öllinger, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Analysis of Lysosomal pH by Flow Cytometry Using FITC-Dextran Loaded Cells2017Inngår i: Lysosomes: Methods and Protocols / [ed] Karin Öllinger;Hanna Appelqvist, Humana Press, 2017, Vol. 1594, s. 179-189Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    The acidic environment of the lysosomal lumen provides an optimal milieu for the acid hydrolases and is also essential for fusion/fission of endo-lysosomal compartments and sorting of cargo. Evidence suggests that maintaining lysosomal acidity is essential to avoid disease. In this chapter, we describe a protocol for analyzing the lysosomal pH in cultured cells using the fluorescent probe fluorescein isothiocyanate (FITC)-dextran together with a dual-emission ratiometric technique suitable for flow cytometry. Fluorescence-labeled dextran is endocytosed and accumulated in the lysosomal compartment. FITC shows a pH-dependent variation in fluorescence when analyzed at maximum emission wavelength and no variation when analyzing at the isosbestic point, thereby the ratio can be used to determine the lysosomal pH. A standard curve is obtained by equilibrating intralysosomal pH with extracellular pH using the ionophore nigericin. The protocol also includes information regarding procedures to induce lysosomal alkalinization and lysosomal membrane permeabilization.

  • 146.
    Eriksson, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jacobs, Claudia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    A patient with Phenotype of Adult-onset Still Disease, But a Genotype Typical of Cryopyrin-associated Periodic Fever Syndrome2013Inngår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 40, nr 9, s. 1632-1633Artikkel i tidsskrift (Annet vitenskapelig)
  • 147.
    Erlandsson, Per
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ytors Fysik och Kemi. Linköpings universitet, Tekniska fakulteten.
    Åström, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Påhlsson, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Robinson, Nathaniel D
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Determination of Fucose Concentration in a Lectin-Based Displacement Microfluidic Assay2019Inngår i: Applied Biochemistry and Biotechnology, ISSN 0273-2289, E-ISSN 1559-0291, Vol. 188, nr 3, s. 868-877Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We compare three different methods to quantify the monosaccharide fucose in solutions using the displacement of a large glycoprotein, lactoferrin. Two microfluidic analysis methods, namely fluorescence detection of (labeled) lactoferrin as it is displaced by unlabeled fucose and the displacement of (unlabeled) lactoferrin in SPR, provide fast responses and continuous data during the experiment, theoretically providing significant information regarding the interaction kinetics between the saccharide groups and binding sites. For comparison, we also performed a static displacement ELISA. The stationary binding site in all cases was immobilized S2-AAL, a monovalent polypeptide based on Aleuria aurantia lectin. Although all three assays showed a similar dynamic range, the microfluidic assays with fluorescent or SPR detection show an advantage in short analysis times. Furthermore, the microfluidic displacement assays provide a possibility to develop a one-step analytical platform.

  • 148.
    Eskilsson, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mirrasekhian, Elahe
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Dufour, Sylvie
    Institute Curie, France.
    Schwaninger, Markus
    Medical University of Lubeck, Germany.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis2014Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, nr 48, s. 15957-15961Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Herewegenerated mice with deletion of themembranebound IL-6 receptor alpha (IL-6R alpha) onneural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6R alpha on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6R alpha in the brain endothelium plays an important role. Hence deletion of IL-6R alpha on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R alpha on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines.

  • 149.
    Eskilsson, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tachikawa, M.
    Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan, Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of of Toyama, Toyama, Japan; Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan .
    Hosoya, K.-I.
    Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of of Toyama, Toyama, Japan.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Distribution of microsomal prostaglandin E synthase-1 in the mouse brain2014Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 522, nr 14, s. 3229-3244Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies in rats have demonstrated that microsomal prostaglandin E synthase-1 (mPGES-1) is induced in brain vascular cells that also express inducible cyclooxygenase-2, suggesting that such cells are the source of the increased PGE2 levels that are seen in the brain following peripheral immune stimulation, and that are associated with sickness responses such as fever, anorexia, and stress hormone release. However, while most of what is known about the functional role of mPGES-1 for these centrally evoked symptoms is based on studies on genetically modified mice, the cellular localization of mPGES-1 in the mouse brain has not been thoroughly determined. Here, using a newly developed antibody that specifically recognizes mouse mPGES-1 and dual-labeling for cell-specific markers, we report that mPGES-1 is constitutively expressed in the mouse brain, being present not only in brain endothelial cells, but also in several other cell types and structures, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. Regional differences were seen with particularly prominent labeling in autonomic relay structures such as the area postrema, the subfornical organ, the paraventricular hypothalamic nucleus, the arcuate nucleus, and the preoptic area. Following immune stimulation, mPGES-1 in brain endothelial cells, but not in other mPGES-1-positive cells, was coexpressed with cyclooxygenase-2, whereas there was no coexpression between mPGES-1 and cyclooxygenase-1. These data imply a widespread synthesis of PGE2 or other mPGES-1-dependent products in the mouse brain that may be related to inflammation-induced sickness symptom as well as other functions, such as blood flow regulation.

  • 150.
    Fagerholm, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Ong, Jeb A.
    Maisonneuve Rosemont Hospital, Montreal, Canada .
    Merrett, Kimberley
    Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM. Ottawa Hospital Research Institute, Canada.
    Jackson, W. Bruce
    Ottawa Hospital Research Institute, Canada .
    Polarek, James W.
    FibroGen Inc, San Francisco, CA, USA.
    Suuronen, Erik J.
    University of Ottawa Heart Institute, Canada .
    Liu, Yuwen
    CooperVision Inc, Pleasanton, CA, USA.
    Brunette, Isabelle
    Maisonneuve Rosemont Hospital, Montreal, Canada .
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold2014Inngår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, nr 8, s. 2420-2427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We developed cell-free implants, comprising carbodiimide crosslinked recombinant human collagen (RHC), to enable corneal regeneration by endogenous cell recruitment, to address the worldwide shortage of donor corneas. Patients were grafted with RHC implants. Over four years, the regenerated neo-corneas were stably integrated without rejection, without the long immunosuppression regime needed by donor cornea patients. There was no recruitment of inflammatory dendritic cells into the implant area, whereas, even with immunosuppression, donor cornea recipients showed dendritic cell migration into the central cornea and a rejection episode was observed. Regeneration as evidenced by continued nerve and stromal cell repopulation occurred over the four years to approximate the micro-architecture of healthy corneas. Histopathology of a regenerated, clear cornea from a regrafted patient showed normal corneal architecture. Donor human cornea grafted eyes had abnormally tortuous nerves and stromal cell death was found. Implanted patients had a 4-year average corrected visual acuity of 20/54 and gained more than 5 Snellen lines of vision on an eye chart. The visual acuity can be improved with more robust materials for better shape retention. Nevertheless, these RHC implants can achieve stable regeneration and therefore, represent a potentially safe alternative to donor organ transplantation.

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