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  • 1.
    Aardal-Eriksson, Elisabeth
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Mobäck, Caroline
    Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Jakobsson, Sandra
    Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Germany.
    Hoffmann, Johannes J. M. L.
    Abbott GmbH and Co KG, Germany.
    Iron depletion in blood donors - Have extended erythrocyte and reticulocyte parameters diagnostic utility?2015In: Transfusion and apheresis science, ISSN 1473-0502, E-ISSN 1878-1683, Vol. 53, no 1, p. 76-81Article in journal (Refereed)
    Abstract [en]

    Background: Blood donation is associated with iron depletion, but donor iron status is not usually investigated, as such tests are cumbersome and costly. It would therefore be desirable to have simple, fast and inexpensive tests that give information on a donors risk of developing iron depletion. In a pilot study we investigated whether novel erythrocyte and reticulocyte parameters can serve this goal. Methods: In regular blood donors extended red cell parameters were measured using the Abbott CELL-DYN Sapphire hematology analyzer and conventional biochemical tests of iron status. Donors were compared with a regionally matched group of non-donating controls. Results: In the controls, the reference ranges of extended RBC parameters were well comparable to published data. Donors had significantly more microcytic RBC than controls (median 0.9 vs 0.6%), lower serum ferritin concentration (median 43 vs 91 mg/L) and higher soluble transferrin receptor/ferritin index (median 1.60 vs 1.27). Overall 18-28% of the donors were iron depleted. Moreover, 3.3% of donors had iron-restricted erythropoiesis. Microcytic RBC and reticulocyte mean cell hemoglobin content predicted iron depletion with 70% and 64% sensitivities and specificities of 72% and 78%, respectively. When combined these two parameters increased the sensitivity to 82%. Conclusions: Our results in Swedish blood donors confirm a high prevalence of iron depletion, despite iron supplementation used by about half of the donors. Microcytic RBC and MCHr appeared to be helpful in identifying iron-depleted donors, who might benefit from iron supplementation. We recommend larger prospective investigations in order to confirm and extend the findings of this pilot study. (C) 2015 Elsevier Ltd. All rights reserved.

  • 2.
    Ali Abdi, Abshir
    et al.
    East Africa University, Somalia.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Prevalence of common hereditary risk factors for thrombophilia in Somalia and identification of a novel Gln544Arg mutation in coagulation factor V2017In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 44, no 4, p. 536-543Article in journal (Refereed)
    Abstract [en]

    Thrombophilia, commonly manifested as venous thromboembolism (VTE), is a worldwide concern but little is known on its genetic epidemiology in many parts of the globe particularly in the developing countries. Here we employed TaqMan genotyping and pyrosequencing to evaluate the prevalence of known common nucleotide polymorphisms associated with thrombophilia in a Somali population in the Puntland region of Somalia. We also employed next generation sequencing (NGS) to investigate other genetic variants in a Somali patient with deep venous thrombosis (DVT). As expected, we found no existence of factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) in the Somali population. The G allele of ABO [261G/delG] polymorphism (rs8176719) was found at a frequency of 29%, similar to that observed in other African populations. We found the lowest so far reported frequency of MTHFR C677T (rs1801133) polymorphism in the Somali population (T allele frequency 1.5%). A novel and deleterious single nucleotide variation in exon 11 of coagulation factor V (c.1631A amp;gt; G) causing Gln544Arg exchange in factor V was identified in a 29 years old Somali female with DVT. The same patient was heterozygous to VKORC1 Asp36Tyr polymorphism (rs61742245) that predisposes to warfarin resistance. In conclusion, this study shows that common hereditary factors for thromboembolism found in Caucasians are either less frequent or absent in the Somali population-similar to the situation in other Africans. NGS is possibly a better choice to detect genetic risk variants for thrombosis in this ethnic group.

  • 3.
    Banch Clausen, Frederik
    et al.
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Barrett, Angela Natalie
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Akkok, Cigdem Akalin
    Oslo Univ Hosp, Norway.
    Armstrong-Fisher, Sylvia
    Scottish Natl Blood Transfus Serv, Scotland.
    Danielsson Bergstrom, Karolina
    Orebro Univ Hosp, Sweden.
    Trucco Boggione, Carolina
    Univ Nacl Rosario, Argentina.
    Sillhagen Baevre, Mette
    Oslo Univ Hosp, Norway.
    Choolani, Mahesh
    Natl Univ Singapore City, Singapore.
    Christiansen, Mette
    Aarhus Univ, Denmark.
    Cotorruelo, Carlos
    Univ Nacl Rosario, Argentina.
    Drnovsek, Tadeja Dovc
    Blood Transfus Ctr Slovenia, Slovenia.
    Finning, Kirstin
    NHS Blood and Transplant, England.
    Guz, Katarzyna
    Inst Hematol and Transfus Med, Poland.
    de Haas, Masja
    Sanquin Blood Supply Fdn, Netherlands.
    Haimila, Katri
    Finnish Red Cross Blood Serv, Finland.
    Halldorsdottir, Anna Margret
    Landspitali Univ Hosp, Iceland.
    Hellberg, Asa
    Lund Univ, Sweden.
    Henny, Christine
    Interreg Blood Transfus SRC, Switzerland.
    Holmertz, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Al Houghton, Jayne
    Royal Devon and Exeter NHS Fdn Trust, England.
    Hyland, Catherine
    Australian Red Cross Blood Serv, Australia.
    Jakobsen, Marianne Antonius
    Odense Univ Hosp, Denmark.
    Kvitland, Mona Andersen
    St Olavs Hosp, Norway.
    Lambert, Mark
    Natl Blood Ctr, Ireland.
    Legler, Tobias J.
    Georg August Univ, Germany.
    Liew, Yew-Wah
    Australian Red Cross Blood Serv, Australia.
    Muniz-Diaz, Eduardo
    Banc Sang and Teixits, Spain.
    Mortberg, Anette
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Niederhauser, Christoph
    Interreg Blood Transfus SRC, Switzerland.
    Nogues, Nuria
    Banc Sang and Teixits, Spain.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Olsson, Martin L.
    Lund Univ, Sweden; Lund Univ, Sweden.
    Orzinska, Agnieszka
    Inst Hematol and Transfus Med, Poland.
    Parks, Michael
    Nonacus Ltd, England.
    Rietkotter, Eva
    LADR GmbH MVZ Dr Kramer and Kollegen, Germany.
    Ryan, Helen
    Natl Blood Ctr, Ireland.
    Sachs, Ulrich J.
    Justus Liebig Univ, Germany.
    van der Schoot, Ellen
    Sanquin Res CLB, Netherlands.
    Silcock, Lee
    Nonacus Ltd, England.
    Steffensen, Rudi
    Aalborg Univ Hosp, Denmark.
    Sulin, Kati
    Finnish Red Cross Blood Serv, Finland.
    Sorensen, Anne Solling
    Naestved Hosp, Denmark.
    Tarrant, Sarah
    NHS Blood and Transplant, England.
    Thorlacius, Steinunn
    Landspitali Univ Hosp, Iceland.
    Wienzek-Lischka, Sandra
    Justus Liebig Univ, Germany.
    Wikman, Agneta
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Wulf-Johansson, Helle
    Naestved Hosp, Denmark.
    Zupan, Mojca
    Blood Transfus Ctr Slovenia, Slovenia.
    Dziegiel, Morten Hanefeld
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Noninvasive fetal RHD genotyping to guide targeted anti-D prophylaxis-an external quality assessment workshop2019In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 114, no 4, p. 386-393Article in journal (Refereed)
    Abstract [en]

    Background and Objectives Fetal RHD genotyping of cell-free fetal DNA from RhD-negative pregnant women can be used to guide targeted antenatal and postnatal anti-D prophylaxis for the prevention of RhD immunization. To assure the quality of clinical testing, we conducted an external quality assessment workshop with the participation of 28 laboratories. Materials and Methods Aliquots of pooled maternal plasma were sent to each laboratory. One sample was positive, and the second sample was negative for fetal RHD, verified by pre-workshop testing using quantitative real-time PCR (qPCR) analysis of RHD exons 4, 5, 7 and 10. Plasma samples were shipped at room temperature. A reporting scheme was supplied for data collection, including questions regarding the methodological setup, results and clinical recommendations. Different methodological approaches were used, all employing qPCR with a total of eight different combinations of RHD exon targets. The samples were tested blindly. Results Fetal RHD genotyping was performed with no false-negative and no false-positive results. One inconclusive result was reported for the RHD-positive sample, and four inconclusive results were reported for the RHD-negative sample. All clinical conclusions were satisfactory. Conclusion This external quality assessment workshop demonstrates that despite the different approaches taken to perform the clinical assays, fetal RHD genotyping is a reliable laboratory assay to guide targeted use of Rh prophylaxis in a clinical setting.

  • 4.
    Baudet, Anna
    et al.
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden; Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden .
    Ek, Fredrik
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Davidsson, Josef
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Soneji, Shamit
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Olsson, Roger
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Magnusson, Mattias
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Cammenga, Jörg
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden;Department of Chemical Biology and Therapeutics Lund University Lund Sweden .
    Juliusson, Gunnar
    Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden; Departments of Haematology Skanes University Hospital Lund University Lund Sweden.
    Small molecule screen identifies differentiation-promoting compounds targeting genetically diverse acute myeloid leukaemia2016In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 175, no 2, p. 342-346Article in journal (Other academic)
  • 5.
    Berlin, Gösta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Cherif, Honar
    Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden.
    Knutson, Folke
    Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden.
    Mattsson, Jonas
    Karolinska Universitetssjukhuset - Centrum för allogen stamcellstransplantation Stockholm, Sweden .
    Axdorph Nygell, Ulla
    Karolinska Universitetssjukhuset - Klinisk immunologi och transfusionsmedicin Stockholm, Sweden .
    Granulocyttransfusion bör övervägas vid neutropeni och allvarlig infektion [Granulocyte transfusion – when and how should it be used?]2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115, article id EXUUArticle, review/survey (Refereed)
    Abstract [en]

    There are no randomized controlled trials proving the clinical benefit of granulocyte transfusions. However, clinical experience and a number of case studies suggest that granulocyte transfusions may be life-saving in certain situations. In our opinion granulocyte transfusions should be considered for patients with profound neutropenia and severe, life-threatening infection not responding to antibiotic or antifungal therapy. Since the clinical effect seems to be dose-dependent, the granulocyte concentrate should contain a large number of cells, which usually means that the donor should be mobilized with steroids and G-CSF. Regular blood donors as well as relatives to the patient can be used for granulocyte donations with apheresis technique after information of the process. Granulocyte transfusion should be given daily as long as the indication remains. The clinical efficacy of the transfusions should be evaluated daily.

  • 6.
    Berlin, Gösta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Cherif, Honar
    Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden.
    Knutson, Folke
    Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden.
    Mattsson, Jonas
    Karolinska Universitetssjukhuset - Centrum för allogen stamcellstransplantation Stockholm, Sweden Karolinska Universitetssjukhuset - Centrum för allogen stamcellstransplantation Stockholm, Sweden.
    Axdorph Nygell, Ulla
    Karolinska Universitetssjukhuset - Klinisk immunologi och transfusionsmedicin Stockholm, Sweden Karolinska Universitetssjukhuset - Klinisk immunologi och transfusionsmedicin Stockholm, Sweden.
    Replik gällande granulocyttransfusion: Rekommendationerna är väl underbyggda2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115Article in journal (Refereed)
  • 7.
    Birgegard, Gunnar
    et al.
    Uppsala Univ, Sweden.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ahlstrand, Erik
    Orebro Univ, Sweden.
    Ejerblad, Elisabeth
    Uppsala Univ, Sweden.
    Enevold, Christian
    Copenhagen Univ Hosp, Denmark.
    Ghanima, Waleed
    Ostfold Hosp, Norway.
    Hasselbalch, Hans
    Zealand Univ Hosp, Denmark.
    Nielsen, Claus H.
    Zealand Univ Hosp, Denmark.
    Knutsen, Havar
    Ulleval Hosp, Norway.
    Pedersen, Ole B.
    Naestved Hosp, Denmark.
    Sorensen, Anders
    Copenhagen Univ Hosp, Denmark; Zealand Univ Hosp, Denmark.
    Andreasson, Bjorn
    NU Hosp Grp, Sweden.
    Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group2019In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 102, no 3, p. 235-240Article in journal (Refereed)
    Abstract [en]

    Objectives The study investigates the hypothesis that inflammation in myelofibrosis (MF) like in myeloma and lymphoma, may disturb iron distribution and contribute to anaemia. Methods A cross-sectional study of 80 MF and 23 ET patients was performed. Results About 35% of anaemic MF patients had functional iron deficiency (FID) with transferrin saturation amp;lt;20 and normal or elevated S-ferritin (amp;lt;500 mu g/L). In ET, FID was rare. In MF patients with FID, 70.6% were anaemic, vs 29.4% in patients without FID (P = 0.03). Hepcidin was significantly higher in MF patients with anaemia, including transfusion-dependent patients, 50.6 vs 24.4 mu g/L (P = 0.01). There was a significant negative correlation between Hb and inflammatory markers in all MF patients: IL-2, IL-6 and TNF-alpha, (P amp;lt; 0.01-0.03), LD (P = 0.004) and hepcidin (P = 0.03). These correlations were also seen in the subgroup of anaemic MF patients (Table ). Tsat correlated negatively with CRP (P amp;lt; 0.001). Symptom burden was heavier in MF patients with FID, and MPN-SAF quality of life scores correlated with IL-6 and CRP. Conclusions The inflammatory state of MF disturbs iron turnover, FID is common and contributes to anaemia development and impairment of QoL. Anaemic MF patients should be screened for FID.

  • 8.
    Bjerrum, Ole Weis
    et al.
    Rigshosp, Denmark.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ghanima, Waleed
    Univ Oslo, Norway; Univ Oslo, Norway.
    Kauppila, Marjut
    Turku Univ Hosp, Finland.
    Andersen, Christen Lykkegaard
    Rigshosp, Denmark; Roskilde Hosp, Denmark.
    Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 5, p. 475-478Article in journal (Refereed)
    Abstract [en]

    Background: Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs. Objectives: The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems. Results: The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients. Conclusions: The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector.

  • 9.
    Björnsson, Jon Mar
    et al.
    Lund University, Department of Molecular Medicine.
    Larsson, Nina
    Lund University, Department of Molecular Medicine.
    Brun, Ann C. M.
    Lund University, Department of Molecular Medicine.
    Andersson, Elisabet
    Lund University, Department of Molecular Medicine.
    Lundström, Patrik
    Lund University, Department of Molecular Medicine.
    Larsson, Jonas
    Lund University, Department of Molecular Medicine.
    Repetowska, Ewa
    Lund University, Department of Molecular Medicine.
    Ehinger, Mats
    Lund University, Department of Molecular Medicine.
    Humphries, R. Keith
    University of British Columbia, Department of Medicine.
    Karlsson, Stefan
    Lund University, Department of Molecular Medicine.
    Reduced proliferative capacity of hematopoietic stem cells deficient in hoxb3 and hoxb42003In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 23, no 11, p. 3872-3883Article in journal (Refereed)
    Abstract [en]

    Several homeobox transcription factors, such as HOXB3 and HOXB4, have been implicated in regulation of hematopoiesis. In support of this, studies show that overexpression of HOXB4 strongly enhances hematopoietic stem cell regeneration. Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment. Analysis of embryonic day 14.5 fetal livers revealed a significant reduction in the hematopoietic stem cell pool, suggesting that the reduction in cellularity observed postnatally is due to insufficient expansion during fetal development. Primitive Lin(-) Scal(+) c-kit(+) hematopoietic progenitors lacking Hoxb3 and Hoxb4 displayed impaired proliferative capacity in vitro. Similarly, in vivo repopulating studies of Hoxb3/Hoxb4-deficient hematopoietic cells resulted in lower repopulating capability compared to normal littermates. Since no defects in homing were observed, these results suggest a slower regeneration of mutant HSC. Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs. Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response.

  • 10.
    Blimark, Cecilie Hveding
    et al.
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden.
    Turesson, Ingemar
    Skåne University Hospital, Lund-Malmö, Sweden.
    Genell, Anna
    Western Sweden Hlth Care Reg, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Björkstrand, Bo
    Karolinska Inst, Sweden.
    Carlson, Kristina
    Uppsala Univ Hosp, Sweden.
    Forsberg, Karin
    Umeå Univ Hosp, Sweden.
    Juliusson, Gunnar
    Lund Univ, Sweden.
    Linder, Olle
    Örebro Univ Hosp, Sweden.
    Mellqvist, Ulf-Henrik
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden; Boras Hosp, Sweden.
    Nahi, Hareth
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kristinsson, Sigurdur Y.
    Karolinska Inst, Sweden; Univ Iceland, Iceland; Karolinska Univ Hosp, Sweden.
    Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 3, p. 506-513Article in journal (Refereed)
    Abstract [en]

    Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent real-world patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabi-ants per year. Among initially symptomatic patients (n= 3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (Pamp;lt;0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95% CI: 0.77-0.92; Pamp;lt;0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95% CI: 0.87-0.99; Pamp;lt;0.05). We report here on a near complete real-world population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period.

  • 11.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Bosè, Francesca
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy / Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Bianchi, Paola
    Haematology Unit 2, Unit of Physiopathology of Anaemia, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Reali, Eva
    Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Colzani, Maria Teresa
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Cantù, Ileana
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Barbarani, Gloria
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Witke, Walter
    Institut of Genetics, University of Bonn, Bonn, Germany.
    Spinardi, Laura
    Scientific Direction, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Ronchi, Antonella Ellena
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Defective Erythroid Maturation In Gelsolin Mutant Mice2012In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, no 7, p. 980-988Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: During late differentiation, erythroid cells undergo profound changes involving actin filament remodeling. One of the proteins controlling actin dynamics is gelsolin, a calcium-activated actin filament severing and capping protein. Gelsolin-null (Gsn(-/-)) mice generated in a C57BL/6 background are viable and fertile.1

    DESIGN AND METHODS: We analyzed the functional roles of gelsolin in erythropoiesis by: (i) evaluating gelsolin expression in murine fetal liver cells at different stages of erythroid differentiation (using reverse transcription polymerase chain reaction analysis and immunohistochemistry), and (ii) characterizing embryonic and adult erythropoiesis in Gsn(-/-) BALB/c mice (morphology and erythroid cultures).

    RESULTS: In the context of a BALB/c background, the Gsn(-/-) mutation causes embryonic death. Gsn(-/-) embryos show defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn(-/-) mice reaching adulthood fail to recover from phenylhydrazine-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays, E13.5 fetal liver Gsn(-/-) cells failed to undergo terminal maturation, a defect partially rescued by Cytochalasin D, and mimicked by administration of Jasplakinolide to the wild-type control samples.

    CONCLUSIONS: In BALB/c mice, gelsolin deficiency alters the equilibrium between erythrocyte actin polymerization and depolymerization, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn(-/-) mice lethality observed in mid-gestation.

  • 12.
    Carlstrom, Karl E.
    et al.
    Karolinska Inst, Sweden.
    Ewing, Ewoud
    Karolinska Inst, Sweden.
    Granqvist, Mathias
    Karolinska Inst, Sweden.
    Gyllenberg, Alexandra
    Karolinska Inst, Sweden.
    Aeinehband, Shahin
    Karolinska Inst, Sweden.
    Enoksson, Sara Lind
    Karolinska Univ Hosp, Sweden.
    Checa, Antonio
    Karolinska Inst, Sweden.
    Badam, Tejaswi
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering. Univ Skovde, Sweden.
    Huang, Jesse
    Karolinska Inst, Sweden.
    Gomez-Cabrero, David
    Univ Publ Nevarra UPNA, Spain.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Al Nimer, Faiez
    Karolinska Inst, Sweden.
    Wheelock, Craig E.
    Karolinska Inst, Sweden.
    Kockum, Ingrid
    Karolinska Inst, Sweden.
    Olsson, Tomas
    Karolinska Inst, Sweden.
    Jagodic, Maja
    Karolinska Inst, Sweden.
    Piehl, Fredrik
    Karolinska Inst, Sweden.
    Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 3081Article in journal (Refereed)
    Abstract [en]

    Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

  • 13.
    Czerw, Tomasz
    et al.
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Labopin, Myriam
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Schmid, Christoph
    University of Munich, Germany.
    Cornelissen, Jan J.
    Erasmus University, Netherlands.
    Chevallier, Patrice
    CHU Nantes, France.
    Blaise, Didier
    Institute J Paoli I Calmettes, France.
    Kuball, Juergen
    University of Medical Centre, Netherlands.
    Vigouroux, Stephane
    Hop Haut Leveque, France.
    Garban, Frederic
    Hop A Michallon, France.
    Lioure, Bruno
    Nouvel Hop Civil, France.
    Fegueux, Nathalie
    CHU Lapeyronie, France.
    Clement, Laurence
    Centre Hospital University of CHU Nancy, France.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Maertens, Johan
    University Hospital Gasthuisberg, Belgium.
    Guillerm, Gaelle
    CHU Morvan, France.
    Bordessoule, Dominique
    CHRU Limoges, France.
    Mohty, Mohamad
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Nagler, Arnon
    Hop St Antoine, France; Chaim Sheba Medical Centre, Israel.
    High CD3+and CD34+peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia - an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 19, p. 27255-27266Article in journal (Refereed)
    Abstract [en]

    Inconsistent results have been reported regarding the influence of graft composition on the incidence of graft versus host disease (GVHD), disease control and survival after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation (allo-PBSCT). These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning. The current retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose on the outcome of RIC allo-PBSCT in patients with acute myelogenous leukemia (AML) in first complete remission, allografted from HLA-matched unrelated donors (10 of 10 match). We included 203 adults. In univariate analysis, patients transplanted with the highest CD3+ and CD34+ doses (above the third quartile cut-off point values, amp;gt;347 x 10amp;lt;^amp;gt;6/kg and amp;gt;8.25 x 10amp;lt;^amp;gt;6/kg, respectively) had an increased incidence of grade III-IV acute (a) GVHD (20% vs. 6%, P = .003 and 18% vs. 7%, P = .02, respectively). There was no association between cellular composition of grafts and transplant-related mortality, AML relapse, incidence of chronic GVHD and survival. Neither engraftment itself nor the kinetics of engraftment were affected by the cell dose. In multivariate analysis, CD3+ and CD34+ doses were the only adverse predicting factors for grade III-IV aGVHD (HR = 3.6; 95% CI: 1.45-9.96, P = .006 and 2.65 (1.07-6.57), P = .04, respectively). These results suggest that careful assessing the CD3+ and CD34+ graft content and tailoring the cell dose infused may help in reducing severe acute GVHD risk without negative impact on the other transplantation outcomes.

  • 14.
    Edvardsson, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Finspång.
    Sund-Levander, Märtha
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Milberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Advanced Home Care in Norrköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Elevated levels of CRP and IL-8 are related to reduce survival time: 1-year follow-up measurements of different analytes in frail elderly nursing home residents2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 5, p. 288-292Article in journal (Refereed)
    Abstract [en]

    There are only few studies with specific focus on predictors of survival in nursing home residents (NHRs). The aim was to study whether 1-year changes in complete blood count (including hemoglobin, red blood cells, erythrocyte volume fraction, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cells count and platelet count), C-reactive protein and interleukin-1 beta (IL-1 beta), IL-1Ra, IL-6, IL-8 and IL-10, are associated with 8-year survival in elderly NHRs, aged amp;gt;= 80 years. Complete blood count, C-reactive protein and interleukins were measured at baseline, after 6 and 12 months from 167 NHRs aged 80-101 years, mean age 88 +/- 4.5 years, 75% of whom were women. Dates of death were collected from the National Death Register 8 years after baseline. Levels of hemoglobin, red blood cells and mean corpuscular hemoglobin concentration were lower after 1-year, but higher for mean corpuscular volume and IL-1 beta, compared to baseline or 6 month follow-up. In the Cox regression model with a time-dependent covariate, raised levels of C-reactive protein and IL-8 were associated with reduced survival time. Elevated levels of C-reactive protein and IL-8 during 1-year follow-up were related to reduce lengths of survival in elderly NHRs.

  • 15.
    Eketorp Sylvan, Sandra
    et al.
    Karolinska Inst, Sweden.
    Asklid, Anna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Johansson, Hemming
    Karolinska Inst, Sweden.
    Klintman, Jenny
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Bjellvi, Jenny
    Sahlgrens Univ Hosp, Sweden.
    Tolvgard, Staffan
    Ostersunds Hosp, Sweden.
    Kimby, Eva
    Karolinska Inst, Sweden.
    Norin, Stefan
    Karolinska Inst, Sweden.
    Andersson, Per-Ola
    South Alvsborg Hosp, Sweden.
    Karlsson, Claes
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Karlsson, Karin
    Skane Univ Hosp, Sweden.
    Lauri, Birgitta
    Sunderby Hosp, Sweden.
    Mattsson, Mattias
    Uppsala Univ Hosp, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Strandberg, Maria
    Sundsvall Hosp, Sweden.
    Osterborg, Anders
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hansson, Lotta
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    FFirst-line therapy in chronic lymphocytic leukemia: a Swedish nation-wide real-world study on 1053 consecutive patients treated between 2007 and 20132019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 4, p. 797-805Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate long-term outcome following first-line therapy in consecutive chronic lymphocytic leukemia (CLL) patients in a well-defined geographic area: Sweden. All patients diagnosed with CLL (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) treated first line (n=1053) and for those, an in-depth analysis was performed. End points were overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Median age was 71 years; 53% had Rai stage III-IV and 97% had performance status grade 0-2. Fluorescence in situ hybridization (FISH) was performed in 57% of patients: 15% had del(17p). Chlorambucil + prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine + rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine + rituximab 75%. Median PFS and OS was 24 and 58 months, respectively, both were significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, gender, age and geographical region (OS only). Chlorambucil-treated patients had a median PFS and OS of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil + rituximab in 2013. Infections amp;gt;= grade III were significantly associated with treatment; chlorambucil 19% versus fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first-line treated CLL patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified.

  • 16.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.

    List of papers
    1. Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
    Open this publication in new window or tab >>Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
    2006 (English)In: Journal of Stem Cells, ISSN 1556-8539, Vol. 1, no 4, p. 247-257Article in journal (Refereed) Published
    Abstract [en]

    Self-renewal is a prerequisite for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow throughout adult life. Cytokines are mainly providing pro-survival signals of HSC, whereas low oxygen levels (hypoxia) were recently shown to influence self-renewal. In contrast, the effects on other progenitor cell types is not clear. In the present work, we have analyzed whether hypoxia has any effects on mouse multipotent progenitors. When bone marrow-derived Lin-Sca1+c-kit+ (LSK) cells were kept in hypoxic cultures (1% O2 ) for 4 days together with cytokines, the numbers of colony forming high-proliferative progenitors (HPP-CFC) and precursors for cobble-stone forming cells (CAFC) were increased compared to normoxic conditions. A similar effect was seen with pre-CFCmulti from unfractionated bone marrow, whereas more committed progenitors (CFU-GM) were expanded better in normoxia compared to hypoxia. The observed increase in numbers of primitive colony-forming progenitor cells was associated with maintenance of the c-kit/Sca-1 phenotype and a preferential expansion of immature  blast-like appearing cells. The results suggest that a major function of hypoxia is to regulate differentiation by increased self-renewal. Furthermore, in cultures of limited cytokine supply, survival of the stem cell-like cell line FDCP-mix was increased during hypoxia. Thus, hypoxia allows for better survival and self-renewal of multipotent progenitors and HSCs from adult bone marrow. Such culture conditions may have beneficial clinical implications for ex vivo purposes and may improve the yields of stem cells and early progenitors.

    Place, publisher, year, edition, pages
    Nova Science Publishers, Inc., 2006
    Keywords
    Hematopoiesis, Stem cells, Progenitor, Hypoxia, Survival, Self-renewal
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17713 (URN)
    Note

    Original Publication: Pernilla Eliasson, Richard Karlsson and Jan-Ingvar Jönsson, Hypoxia Expands Primitive Hematopoietic Progenitor Cellsfrom Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability, 2006, Journal of Stem Cells, (1), 4, 247-257. https://www.novapublishers.com/catalog/editorial.php?products_id=3730 Copyright: Nova Science Publishers https://www.novapublishers.com/

    Available from: 2009-04-16 Created: 2009-04-16 Last updated: 2018-05-29Bibliographically approved
    2. Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
    Open this publication in new window or tab >>Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
    Show others...
    2010 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 38, no 4, p. 301-310Article in journal (Refereed) Published
    Abstract [en]

    Objective. Recent evidence suggests that hematopoietic stem cells (HSCs) in the bone marrow (BM) are located in areas where the environment is hypoxic. Although previous studies have demonstrated positive effects by hypoxia, its role in HSC maintenance has not been fully elucidated, neither has the molecular mechanisms been delineated. Here, we have investigated the consequence of in vitro incubation of HSCs in hypoxia prior to transplantation and analyzed the role of hypoxia-inducible factor (HIF)-1 alpha. Materials and Methods. HSC and progenitor populations isolated from mouse BM were cultured in 20% or 1% O-2, and analyzed for effects on cell cycle, expression of cyclin-dependent kinase inhibitors genes, and reconstituting ability to lethally irradiated mice. The involvement of HIF-1 alpha was studied using methods of protein stabilization and gene silencing. Results. When long-term FLT3(-)CD34(-)Lin(-)Sca-1(+)c-Kit(+) (LSK) cells were cultured in hypoxia, cell numbers were significantly reduced in comparison to normoxia. This was due to a decrease in proliferation and more cells accumulating in G(0). Moreover, the proportion of HSCs with long-term engraftment potential was increased. Whereas expression of the cyclin-dependent kinase inhibitor genes p21(cip1), p27(Kip1), and p57(Kip2) increased in LSK cells by hypoxia, only p21(cip1) was upregulated in FLT3(-)CD34(-)LSK cells. We could demonstrate that expression of p27(KiP1) and p57(Kip2) was dependent of HIF-1 alpha. Surprisingly, overexpression of constitutively active HIF-1 alpha or treatment with the HIF stabilizer agent FG-4497 led to a reduction in HSC reconstituting ability. Conclusions. Our results imply that hypoxia, in part via HIF-1 alpha, maintains HSCs by decreasing proliferation and favoring quiescence.

    Place, publisher, year, edition, pages
    Elsevier, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54780 (URN)10.1016/j.exphem.2010.01.005 (DOI)000276054300005 ()
    Note

    Original Publication: Pernilla Eliasson, Matilda Rehn, Petter Hammar, Peter Larsson, Oksana Sirenko, Lee A Flippin, Jorg Cammenga and Jan-Ingvar Jönsson, Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture, 2010, EXPERIMENTAL HEMATOLOGY, (38), 4, 301-310. http://dx.doi.org/10.1016/j.exphem.2010.01.005 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/

    On the day of the defence date the title of this article was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.

    When finally published online the title of this article changed name to Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.

    Available from: 2010-04-09 Created: 2010-04-09 Last updated: 2017-12-12Bibliographically approved
    3. Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
    Open this publication in new window or tab >>Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.

    Keywords
    Hematopoiesis, Stem cells, Progenitor, Hypoxia, Hypoxia-inducible factor 1 alpha, oxidative stress, Puruvate dehydrogenase kinase 1
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-52941 (URN)
    Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2018-10-08
    4. BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.
    Open this publication in new window or tab >>BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.
    Show others...
    2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 10, p. 2302-2311Article in journal (Refereed) Published
    Abstract [en]

    Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.

     

    Place, publisher, year, edition, pages
    Washington, D.C: The American Society of Hematology, 2009
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-52728 (URN)10.1182/blood-2008-07-167023 (DOI)
    Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2018-01-12
  • 17.
    Engert, Andreas
    et al.
    University of Cologne, Germany.
    Balduini, Carlo
    IRCCS Policlin San Matteo Fdn, Italy.
    Brand, Anneke
    Leids University, Netherlands.
    Coiffier, Bertrand
    University of Lyon 1, France.
    Cordonnier, Catherine
    Hop University of Henri Mondor, France.
    Doehner, Hartmut
    University of Klinikum Ulm, Germany.
    Duyvene de Wit, Thom
    European Hematol Assoc, Netherlands.
    Eichinger, Sabine
    Medical University of Wien, Austria.
    Fibbe, Willem
    Leids University, Netherlands.
    Green, Tony
    Cambridge Institute Medical Research, England.
    de Haas, Fleur
    European Hematol Assoc, Netherlands.
    Iolascon, Achille
    University of Naples Federico II, Italy.
    Jaffredo, Thierry
    University of Paris 06, France.
    Rodeghiero, Francesco
    Osped San Bortolo, Italy.
    Salles, Gilles
    University of Lyon, France.
    Jacob Schuringa, Jan
    University of Groningen, Netherlands.
    Andre, Marc
    Catholic University of Louvain, Belgium.
    Andre-Schmutz, Isabelle
    University of Paris 05, France.
    Bacigalupo, Andrea
    Osped San Martino Genova, Italy.
    Bochud, Pierre-Yves
    University of Lausanne, Switzerland.
    den Boer, Monique
    Erasmus MC, Netherlands.
    Bonini, Chiara
    University of Milan, Italy.
    Camaschella, Clara
    San Raffaele Institute, Italy.
    Cant, Andrew
    Great North Childrens Hospital, England.
    Domenica Cappellini, Maria
    University of Milan, Italy.
    Cazzola, Mario
    University of Pavia, Italy.
    Lo Celso, Cristina
    Imperial Coll London, England.
    Dimopoulos, Meletios
    University of Athens, Greece.
    Douay, Luc
    University of Paris 06, France.
    Dzierzak, Elaine
    University of Edinburgh, Scotland.
    Einsele, Hermann
    University of Wurzburg, Germany.
    Ferreri, Andres
    Ist Science San Raffaele, Italy.
    De Franceschi, Lucia
    University of Verona, Italy.
    Gaulard, Philippe
    Hop Henri Mondor, France.
    Gottgens, Berthold
    University of Cambridge, England.
    Greinacher, Andreas
    University of Medical Greifswald, Germany; Ernst Moritz Arndt University of Greifswald, Germany.
    Gresele, Paolo
    University of Perugia, Italy.
    Gribben, John
    Queen Mary University of London, England.
    de Haan, Gerald
    University of Groningen, Netherlands.
    Hansen, John-Bjarne
    University of Tromso, Norway.
    Hochhaus, Andreas
    University of Klinikum Jena, Germany.
    Kadir, Rezan
    Royal Free Hospital, England.
    Kaveri, Srini
    Institute National Sante and Rech Med, France.
    Kouskoff, Valerie
    University of Manchester, England.
    Kuehne, Thomas
    University of Kinderspital Beider Basel, Switzerland.
    Kyrle, Paul
    Medical University of Wien, Austria.
    Ljungman, Per
    Karolinska Institute, Sweden.
    Maschmeyer, Georg
    Klinikum Ernst Von Bergmann, Germany.
    Mendez-Ferrer, Simon
    University of Cambridge, England.
    Milsom, Michael
    Deutsch Krebsforschungszentrum Neuenheimer Feld, Germany.
    Mummery, Christine
    Leids University, Netherlands.
    Ossenkoppele, Gert
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Pecci, Alessandro
    University of Pavia, Italy.
    Peyvandi, Flora
    University of Milan, Italy.
    Philipsen, Sjaak
    Erasmus MC, Netherlands.
    Reitsma, Pieter
    Leids University, Netherlands.
    Maria Ribera, Jose
    Institute Catala Oncol, Spain.
    Risitano, Antonio
    University of Naples Federico II, Italy.
    Rivella, Stefano
    Weill Medical Coll, NY USA.
    Ruf, Wolfram
    Johannes Gutenberg University of Mainz, Germany.
    Schroeder, Timm
    Swiss Federal Institute Technology, Switzerland.
    Scully, Marie
    University of Coll London Hospital, England.
    Socie, Gerard
    Hop St Louis, France.
    Staal, Frank
    Leids University, Netherlands.
    Stanworth, Simon
    John Radcliffe Hospital, England.
    Stauder, Reinhard
    Medical University of Innsbruck, Austria.
    Stilgenbauer, Stephan
    University of Klinikum Ulm, Germany.
    Tamary, Hannah
    Schneider Childrens Medical Centre Israel, Israel.
    Theilgaard-Monch, Kim
    University of Copenhagen, Denmark.
    Lay Thein, Swee
    Kings Coll London, England.
    Tilly, Herve
    University of Rouen, France.
    Trneny, Marek
    Charles University of Prague, Czech Republic.
    Vainchenker, William
    Institute Gustave Roussy, France.
    Maria Vannucchi, Alessandro
    University of Florence, Italy.
    Viscoli, Claudio
    University of Genoa, Italy.
    Vrielink, Hans
    Sanquin Research, Netherlands.
    Zaaijer, Hans
    Sanquin Research, Netherlands.
    Zanella, Alberto
    Osped Maggiore Policlin, Italy.
    Zolla, Lello
    University of Tuscia, Italy.
    Jan Zwaginga, Jaap
    Leids University, Netherlands.
    Aguilar Martinez, Patricia
    Hop St Eloi, France.
    van den Akker, Emile
    Sanquin Research, Netherlands.
    Allard, Shubha
    Barts Health NHS Trust and NHS Blood and Transplant, England.
    Anagnou, Nicholas
    University of Athens, Greece.
    Andolfo, Immacolata
    University of Naples Federico II, Italy.
    Andrau, Jean-Christophe
    Institute Genet Molecular Montpellier, France.
    Angelucci, Emanuele
    Osp A Businco, Italy.
    Anstee, David
    NHSBT Blood Centre, England.
    Aurer, Igor
    University of Zagreb, Croatia.
    Avet-Loiseau, Herve
    Centre Hospital University of Toulouse, France.
    Aydinok, Yesim
    Ege University, Turkey.
    Bakchoul, Tamam
    University of Medical Greifswald, Germany.
    Balduini, Alessandra
    IRCCS Policlin San Matteo Fdn, Italy.
    Barcellini, Wilma
    Osped Maggiore Policlin, Italy.
    Baruch, Dominique
    University of Paris 05, France.
    Baruchel, Andre
    Hop University of Robert Dabre, France.
    Bayry, Jagadeesh
    Institute National Sante and Rech Med, France.
    Bento, Celeste
    Centre Hospital and University of Coimbra, Portugal.
    van den Berg, Anke
    University of Groningen, Netherlands.
    Bernardi, Rosa
    Ist Science San Raffaele, Italy.
    Bianchi, Paola
    Osped Maggiore Policlin, Italy.
    Bigas, Anna
    Institute Hospital del Mar Investgac Med, Spain.
    Biondi, Andrea
    University of Milano Bicocca, Italy.
    Bohonek, Milos
    Central Mil Hospital, Czech Republic.
    Bonnet, Dominique
    Francis Crick Institute, England.
    Borchmann, Peter
    University Hospital Cologne Int, Germany.
    Borregaard, Niels
    University of Copenhagen, Denmark.
    Braekkan, Sigrid
    University of Tromso, Norway.
    van den Brink, Marcel
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Brodin, Ellen
    University of Sykehuset Nordic Norge, Norway.
    Bullinger, Lars
    University of Klin Ulm, Germany.
    Buske, Christian
    University of Klinikum Ulm, Germany.
    Butzeck, Barbara
    European Federat Assoc Patients Haemochromatosis, France.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Campo, Elias
    University of Barcelona, Spain.
    Carbone, Antonino
    Centre Riferimento Oncol, Italy.
    Cervantes, Francisco
    University of Barcelona, Spain.
    Cesaro, Simone
    Policlin GB Rossi, Italy.
    Charbord, Pierre
    University of Paris 06, France.
    Claas, Frans
    Leids University, Netherlands.
    Cohen, Hannah
    Imperial Coll London, England.
    Conard, Jacqueline
    Hop Hotel Dieu, France.
    Coppo, Paul
    Hop St Antoine, France.
    Vives Corrons, Joan-Lluis
    University of Barcelona, Spain.
    da Costa, Lydie
    Hop Robert Debre, France.
    Davi, Frederic
    University of Paris 06, France.
    Delwel, Ruud
    Erasmus MC, Netherlands.
    Dianzani, Irma
    University of Turin, Italy.
    Domanovic, Dragoslav
    European Centre Disease Prevent and Control, Sweden.
    Donnelly, Peter
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Dovc Drnovsek, Tadeja
    Zavod RS Transfuzijsko Med, Slovenia.
    Dreyling, Martin
    University of Munich, Germany.
    Du, Ming-Qing
    University of Cambridge, England.
    Dufour, Carlo
    Ist Giannina Gaslini, Italy.
    Durand, Charles
    University of Paris 06, France.
    Efremov, Dimitar
    Int Centre Genet Engn and Biotechnol, Italy.
    Eleftheriou, Androulla
    Thalassaemia Int Fed, Cyprus.
    Elion, Jacques
    University of Paris Diderot, France.
    Emonts, Marieke
    Great North Childrens Hospital, England.
    Engelhardt, Monika
    University of Klinikum Freiburg, Germany.
    Ezine, Sophie
    University of Paris 05, France.
    Falkenburg, Fred
    Leids University, Netherlands.
    Favier, Remi
    Hop Enfants A Trousseau, France.
    Federico, Massimo
    University of Modena and Reggio Emilia, Italy.
    Fenaux, Pierre
    Hop St Louis, France.
    Fitzgibbon, Jude
    Queen Mary University of London, England.
    Flygare, Johan
    Lund University, Sweden.
    Foa, Robin
    University of Roma La Sapienza, Italy.
    Forrester, Lesley
    University of Edinburgh, Scotland.
    Galacteros, Frederic
    Hop University of Henri Mondor, France.
    Garagiola, Isabella
    University of Milan, Italy.
    Gardiner, Chris
    University of Oxford, England.
    Garraud, Olivier
    University of St Etienne, France.
    van Geet, Christel
    Katholieke University of Leuven, Belgium.
    Geiger, Hartmut
    University of Klinikum Ulm, Germany.
    Geissler, Jan
    CML Advocates Network, Switzerland.
    Germing, Ulrich
    University of Klinikum Dusseldorf, Germany.
    Ghevaert, Cedric
    University of Cambridge, England.
    Girelli, Domenico
    Institute Cochin, France.
    Godeau, Bertrand
    Hop University of Henri Mondor, France.
    Goekbuget, Nicola
    University of Klinikum Frankfurt, Germany.
    Goldschmidt, Hartmut
    University of Klinikum Heidelberg, Germany.
    Goodeve, Anne
    University of Sheffield, England.
    Graf, Thomas
    Centre Genom Regulat, Spain.
    Graziadei, Giovanna
    University of Milan, Italy.
    Griesshammer, Martin
    Muhlenkreisklin, Germany.
    Gruel, Yves
    Hop Trousseau, France.
    Guilhot, Francois
    University of Poitiers, France.
    von Gunten, Stephan
    University of Bern, Switzerland.
    Gyssens, Inge
    University of Hasselt, Belgium.
    Halter, Jorg
    University of Spital Basel, Switzerland.
    Harrison, Claire
    Guys and St Thomas, England.
    Harteveld, Cornelis
    Leids University, Netherlands.
    Hellstrom-Lindberg, Eva
    Karolinska Institute, Sweden.
    Hermine, Olivier
    University of Paris 05, France.
    Higgs, Douglas
    University of Oxford, England.
    Hillmen, Peter
    University of Leeds, England.
    Hirsch, Hans
    University of Basel, Switzerland.
    Hoskin, Peter
    Mt Vernon Hospital, England.
    Huls, Gerwin
    University of Groningen, Netherlands.
    Inati, Adlette
    Lebanese American University, Lebanon.
    Johnson, Peter
    University of Southampton, England.
    Kattamis, Antonis
    University of Athens, Greece.
    Kiefel, Volker
    University of Medical Rostock, Germany.
    Kleanthous, Marina
    Cyprus School Molecular Med, Cyprus.
    Klump, Hannes
    University of Klinikum Essen, Germany.
    Krause, Daniela
    Georg Speyer Haus Institute Tumorbiol and Expt Therapy, Germany.
    Kremer Hovinga, Johanna
    University of Bern, Switzerland.
    Lacaud, Georges
    University of Manchester, England.
    Lacroix-Desmazes, Sebastien
    Institute National Sante and Rech Med, France.
    Landman-Parker, Judith
    Hop Armand Trousseau, France.
    LeGouill, Steven
    University of Nantes, France.
    Lenz, Georg
    University of Klinikum Munster, Germany.
    von Lilienfeld-Toal, Marie
    University of Klinikum Jena, Germany.
    von Lindern, Marieke
    Sanquin Research, Netherlands.
    Lopez-Guillermo, Armando
    Hospital Clin Barcelona, Spain.
    Lopriore, Enrico
    Leiden University of Medical Centre, Netherlands.
    Lozano, Miguel
    University of Barcelona, Spain.
    MacIntyre, Elizabeth
    University of Paris 05, France.
    Makris, Michael
    Royal Hallamshire Hospital, England; University of Sheffield, England.
    Mannhalter, Christine
    Medical University of Wien, Austria.
    Martens, Joost
    Radboud University of Nijmegen, Netherlands.
    Mathas, Stephan
    Charite University of Medical Berlin, Germany.
    Matzdorff, Axel
    Caritasclin Saarbrucken, Germany.
    Medvinsky, Alexander
    University of Edinburgh, Scotland.
    Menendez, Pablo
    University of Barcelona, Spain.
    Rita Migliaccio, Anna
    Mt Sinai Hospital, NY 10029 USA.
    Miharada, Kenichi
    Lund University, Sweden.
    Mikulska, Malgorzata
    University of Genoa, Italy.
    Minard, Veronique
    Institute Gustave Roussy, France.
    Montalban, Carlos
    MD Anderson Cancer Centre Madrid, Spain.
    de Montalembert, Mariane
    Necker Enfants Malades University Hospital, France.
    Montserrat, Emili
    Hospital Clin Barcelona, Spain.
    Morange, Pierre-Emmanuel
    Aix Marseille University, France.
    Mountford, Joanne
    University of Glasgow, Scotland.
    Muckenthaler, Martina
    University of Klinikum Heidelberg, Germany.
    Mueller-Tidow, Carsten
    University of Klinikum Halle, Germany.
    Mumford, Andrew
    University of Bristol, England.
    Nadel, Bertrand
    University of Mediterranee, France.
    Navarro, Jose-Tomas
    Institute Catala Oncol, Spain.
    el Nemer, Wassim
    INSERM, France.
    Noizat-Pirenne, France
    Etab Francais Sang, France.
    OMahony, Brian
    European Haemophilia Consortium, Belgium.
    Oldenburg, Johannes
    University of Klinikum Bonn, Germany.
    Olsson, Martin
    Lund University, Sweden.
    Oostendorp, Robert
    Technical University of Munich, Germany.
    Palumbo, Antonio
    University of Turin, Italy.
    Passamonti, Francesco
    Osp Circolo and Fdn Macchi, Italy.
    Patient, Roger
    University of Oxford, England.
    Peffault de Latour, Regis
    NIH, MD 20892 USA.
    Pflumio, Francoise
    Institute Rech Radiobiol Cellulaire and Molecular IRCM, France.
    Pierelli, Luca
    University of Roma La Sapienza, Italy.
    Piga, Antonio
    University of Turin, Italy.
    Pollard, Debra
    Royal Free Hospital, England.
    Raaijmakers, Marc
    Erasmus MC, Netherlands.
    Radford, John
    University of Manchester, England.
    Rambach, Ralf
    DLH, Germany.
    Koneti Rao, A.
    Temple University of School Med, PA USA.
    Raslova, Hana
    University of Paris Sud, France.
    Rebulla, Paolo
    Ops Maggiore, Italy.
    Rees, David
    Kings Coll Hospital London, England.
    Ribrag, Vincent
    Institute Gustave Roussy, France.
    Rijneveld, Anita
    Erasmus MC, Netherlands.
    Rinalducci, Sara
    University of Tuscia, Italy.
    Robak, Tadeusz
    University of Medical Lodz, Poland.
    Roberts, Irene
    University of Oxford, England.
    Rodrigues, Charlene
    Great North Childrens Hospital, England.
    Rosendaal, Frits
    Leids University, Netherlands.
    Rosenwald, Andreas
    University of Wurzburg, Germany.
    Rule, Simon
    Derriford Hospital, England.
    Russo, Roberta
    University of Naples Federico II, Italy.
    Saglio, Guiseppe
    University of Turin, Italy.
    Sanchez, Mayka
    IJC, Spain.
    Scharf, Ruediger E.
    University of Dusseldorf, Germany.
    Schlenke, Peter
    Medical University of Graz, Austria.
    Semple, John
    St Michaels Hospital, Canada.
    Sierra, Jorge
    Hospital Santa Creu I Sant Pau, Spain.
    So-Osman, Cynthia
    Sanquin Research, Netherlands.
    Manuel Soria, Jose
    Hospital Santa Creu I Sant Pau, Spain.
    Stamatopoulos, Kostas
    Institute Appl Bioscience, Greece.
    Stegmayr, Bernd
    Umeå University, Sweden.
    Stunnenberg, Henk
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Swinkels, Dorine
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Pedro Taborda Barata, Joao
    University of Lisbon, Portugal.
    Taghon, Tom
    University of Ghent, Belgium.
    Taher, Ali
    Amer University of Beirut Medical Centre, Lebanon.
    Terpos, Evangelos
    National and Kapodistrian University of Athes, Greece.
    Daniel Tissot, Jean
    University of Lausanne, Switzerland.
    Touw, Ivo
    Erasmus MC, Netherlands.
    Toye, Ash
    University of Bristol, England.
    Trappe, Ralf
    Charite University of Medical Berlin, Germany.
    Unal, Sule
    Hacettepe University, Turkey.
    Vaulont, Sophie
    Institute Cochin, France.
    Viprakasit, Vip
    Mahidol University, Thailand.
    Vitolo, Umberto
    University of Turin, Italy.
    van Wijk, Richard
    University of Medical Centre Utrecht, Netherlands.
    Wojtowicz, Agnieszka
    CHU Vaudois, Switzerland.
    Zeerleder, Sacha
    Sanquin Research, Netherlands.
    Zieger, Barbara
    University of Klinikum Freiburg, Germany.
    The European Hematology Association Roadmap for European Hematology Research: a consensus document2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, p. 115-208Article in journal (Refereed)
    Abstract [en]

    The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

  • 18.
    Eriksson, Mia
    et al.
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Peña-Martínez, Pablo
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Ramakrishnan, Ramprasad
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Chapellier, Marion
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Högberg, Carl
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Glowacki, Gabriella
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Orsmark-Pietras, Christina
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Velasco-Hernández, Talía
    Department of Molecular Hematology, Lund University, Lund, Sweden.
    Lazarevic, Vladimir Lj
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Juliusson, Gunnar
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Mulloy, James C
    Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
    Richter, Johan
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Fioretos, Thoas
    Department of Clinical Genetics, Lund, Sweden.
    Ebert, Benjamin L.
    Division of Hematology, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA.
    Järås, Marcus
    Department of Clinical Genetics, Lund, Sweden.
    Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NF?B-dependent differentiation of AML cells2017In: Blood advances, ISSN 2473-9529, Vol. 1, no 23, p. 2046-2057Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NF?B-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NF?B, thus revealing a new putative strategy for therapeutically targeting AML cells.

  • 19.
    Friesen, C.
    et al.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Herr, I.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Los, Marek Jan
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Debatin, K. M.
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Drug induced cytotoxicity in leukemia cells involves the CD95 (APO-1/FAS) pathway of apoptosis1996In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 93, p. 367-367Article in journal (Refereed)
  • 20.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Fomichov, Victoria
    Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Juliusson, G.
    Lund University, Sweden; Lund University, Sweden.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Frequent and long-term follow-up of health-related quality of life following allogeneic haematopoietic stem cell transplantation2015In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 24, no 6, p. 898-910Article in journal (Refereed)
    Abstract [en]

    Health-related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n=18) or reduced intensity conditioning (RIC, n=76). HRQL was assessed with the EORTC QLQ C-30 during the inpatient period as well as during the following 3years, i.e. at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1year for HRQL to return to the baseline level. The only function that improved significantly 3years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease experienced reduced HRQL. These results provide a clinically useful overview of patients HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow-ups during the first year after HSCT to improve preventive or supportive interventions.

  • 21.
    Fulda, S.
    et al.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Friesen, C.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Benedict, M.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Nunez, G.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Peter, M. E.
    UNIV ULM, CHILDRENS HOSP, ULM, GERMANY .
    Debatin, K. M.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    CD95 (APO-1/Fas)- and p53-independent apoptosis by betulinic acid involves mitochondrial alterations and activation of caspases.1997In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 90, no 10, p. 2207-2207Article in journal (Refereed)
  • 22.
    Gregers, Jannie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. University of Copenhagen Hospital, Denmark.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. KTH Royal Institute Technology, Sweden; National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Christensen, I. J.
    Rigshosp, Denmark.
    Dalhoff, K.
    Bispebjerg Hospital, Denmark.
    Schroeder, H.
    University Hospital Skejby, Denmark.
    Carlsen, N.
    Odense University Hospital, Denmark.
    Rosthoej, S.
    University Hospital Aalborg, Denmark.
    Lausen, B.
    University of Copenhagen, Denmark.
    Schmiegelow, K.
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia2015In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, no 4, p. 372-379Article in journal (Refereed)
    Abstract [en]

    The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P = 0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P = 0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P = 0.01/P less than 0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT ( P = 0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G greater than A may be a new possible predictive marker for outcome in childhood ALL.

  • 23.
    Hedbrant, Johan
    et al.
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering.
    Bjorne, Assar
    Specialisttandvården, Lasarettet Ystad.
    Ny mätmetod för käkmuskulaturen kan finna orsaken till tinnitus: Slutrapport Nutek 92-119041997Report (Other academic)
    Abstract [sv]

    Tinnitus är en åkomma som i lindrigare eller allvarligare former drabbar 17% av västvärldens befolkning. Ca 85 000 svenskar har tinnitus på invalidiserande nivå. Förutom mänskligt lidande orsakar tinnitus samhällskostnader på ca 1.5 miljard kr årligen. Orsaken är till största delen okänd.

    Vissa tecken tyder på ett samband mellan tinnitus och funktionsstörning i en käkmuskel. Några olika icke–invasiva metoder för mätning av muskelstörning i M Pterygoideus Lateralis har utvärderas. Två av dessa är intressanta för fortsatta studier.

    Termografi användes för att diagnosticera muskelstörningar på ytligt liggande muskler. Vi såg åtskilliga varma områden på ytliga käk– och nackmuskler på de patienter som hade käkledsstörningar, samt möjligen tecken på onormal värme från M Pterygoideus Lateralis. Mätförhållandena var dock ej ideala.

    En metod att mäta EMG med adaptiv noise cancelling provades. EMG från en ryggmuskel, stört av en “EKG–signal” från hjärtat användes. Metoden fungerade bra. Fortsatt metodutveckling på t.ex. ryggmuskler borde göras.

  • 24.
    Hellberg, Sandra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Köpsén, Mattias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kockum, Ingrid
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Olsson, Tomas
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Håkansson, Irene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

  • 25.
    Hjorth-Hansen, H.
    et al.
    St Olavs Hospital, Norway; Norwegian University of Science and Technology NTNU, Norway.
    Stentoft, J.
    Aarhus University Hospital, Denmark.
    Richter, J.
    Skåne University Hospital, Sweden.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Hoeglund, M.
    University of Uppsala Hospital, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Gjertsen, B. T.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Gruber, F. X.
    University Hospital North Norway, Norway.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Eriksson, K. M.
    Sunderbysjukhuset, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Lubking, A.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Vestergaard, H.
    Odense University Hospital, Denmark.
    Udby, L.
    Roskilde Hospital, Denmark.
    Bjerrum, O. W.
    University of Copenhagen Hospital, Denmark.
    Persson, I.
    Uppsala University, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden; University of Helsinki, Finland.
    Olsson-Stromberg, U.
    University of Uppsala Hospital, Sweden.
    Safety and efficacy of the combination of pegylated interferon-alpha 2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 9, p. 1853-1860Article in journal (Refereed)
    Abstract [en]

    Dasatinib (DAS) and interferon-a have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-alpha 2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 mu g/week and it increased to 25 mu g/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR4 was achieved by 46% and MR4.5 by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS +/- PegIFN is warranted.

  • 26.
    Ilander, M.
    et al.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Olsson-Stromberg, U.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden.
    Schlums, H.
    Karolinska Institute, Sweden.
    Guilhot, J.
    CHU Poitiers, France.
    Bruck, O.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Lahteenmaki, H.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Kasanen, T.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Soderlund, S.
    Uppsala University Hospital, Sweden.
    Hoglund, M.
    Uppsala University Hospital, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Sjalander, A.
    Umeå University, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Lubking, A.
    Skåne University Hospital, Sweden.
    Holm, E.
    Skåne University Hospital, Sweden.
    Bjoreman, M.
    University Hospital, Sweden.
    Lehmann, S.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden; Karolinska University Hospital, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden.
    Ohm, L.
    Karolinska University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Majeed, W.
    Stavanger University Hospital, Norway.
    Ehrencrona, H.
    Skåne University Hospital, Sweden.
    Koskela, S.
    Finnish Red Cross Blood Serv, Finland.
    Saussele, S.
    Heidelberg University, Germany.
    Mahon, F-X
    University of Bordeaux Segalen, France.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Hjorth-Hansen, H.
    St Olavs University Hospital, Norway.
    Bryceson, Y. T.
    Karolinska Institute, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Finland; University of Helsinki, Finland.
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 5, p. 1108-1116Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naive CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-alpha/IFN-gamma cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.

  • 27.
    Jaako, P.
    et al.
    Lund University, Sweden.
    Ugale, A.
    Lund University, Sweden.
    Wahlestedt, M.
    Lund University, Sweden.
    Velasco-Hernandez, T.
    Lund University, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lindström, M. S.
    Karolinska Institute, Sweden.
    Bryder, D.
    Lund University, Sweden.
    Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 1, p. 213-221Article in journal (Refereed)
    Abstract [en]

    Mutations resulting in constitutive activation of signaling pathways that regulate ribosome biogenesis are among the most common genetic events in acute myeloid leukemia (AML). However, whether ribosome biogenesis presents as a therapeutic target to treat AML remains unexplored. Perturbations in ribosome biogenesis trigger the 5S ribonucleoprotein particle (RNP)-Mdm2-p53 ribosomal stress pathway, and induction of this pathway has been shown to have therapeutic efficacy in Myc-driven lymphoma. In the current study we address the physiological and therapeutic role of the 5S RNP-Mdm2-p53 pathway in AML. By utilizing mice that have defective ribosome biogenesis due to downregulation of ribosomal protein S19 (Rps19), we demonstrate that induction of the 5S RNP-Mdm2-p53 pathway significantly delays the initiation of AML. However, even a severe Rps19 deficiency that normally results in acute bone marrow failure has no consistent efficacy on already established disease. Finally, by using mice that harbor a mutation in the Mdm2 gene disrupting its binding to 5S RNP, we show that loss of the 5S RNP-Mdm2-p53 pathway is dispensable for development of AML. Our study suggests that induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway holds limited potential as a single-agent therapy in the treatment of AML.

  • 28.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Khan, Muhammad Suleman
    COMSATS Institute of Information Technology, Abbottabad, Pakistan.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nahi, Hareth
    Karolinska University Hospital and Karolinska Institutet, Huddinge, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Association of CYP2B6 Genotype with Survival and Progression Free Survival in Cyclophosphamide Treated Multiple Myeloma2012In: Journal of Cancer Therapy, ISSN 2151-1934, E-ISSN 2151-1942, Vol. 3, no 1, p. 20-27Article in journal (Refereed)
    Abstract [en]

    Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST en-zymes are involved in detoxification. Polymorphisms of these enzymes may affect enzyme expression and function as well as treatment outcome. The aim of this study was to investigate the impact of the CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 SNP Ile105Val, and GSTM1 and GSTT1 null variants, on the outcome for cyclophosphamide treated MM patients, in order to find markers of value for individualised therapy. Methods: We used allele specific PCR and Pyrosequencing to investigate the impact of CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 Ile105Val, and GSTM1 and GSTT1 variants, on the outcome for 26 cyclophosphamide treated multiple myeloma patients. Results and Major Conclusion:

    The CYP2B6 785G carriers had significantly shorter progression free survival (p = 0.048*) and overall survival (p = 0.037*) with 785G/G patients having the worst outcome compared to patients carrying the wild type. A shorter progression free survival was also indicated in patients carrying both CYP2B6 516T & 785G (p = 0.068). These results indicate a predictive role of CYP2B6 SNPs, particularly A785G, in cyclophosphamide treatment.

  • 29.
    Jakobsen, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Prognostic markers in acute myeloid leukemia: A candidate gene approach2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The standard treatment of acute myeloid leukemia (AML) consists of induction chemotherapy, most commonly daunorubicin together with the nucleoside analogue cytarabine (Ara-C), followed by consolidation chemotherapy and in selected cases allogenic stem cell transplantation (allo-SCT). Despite a high initial response rate, a considerable proportion of all AML cases eventually suffer from relapse and the five-year overall survival rate in patients >60 years is only around 15%. Based on cytogenetic analysis, patients are divided into low risk, intermediate risk, and high-risk groups. While low risk patients have a high chance of reaching and remaining in remission after standard induction therapy, high-risk patients are likely to suffer from relapse and should be scheduled for allo-SCT when first complete remission is reached. The intermediate risk group consists of normal karyotype (NK) patients and those with karyotypes of uncertain clinical relevance, but the outcomes are heterogeneous. In NKAML patients, risk classification has improved with the addition of molecular markers including FLT3 internal tandem duplications (ITD) and mutations of NPM1 and CEBPA. Despite this development, there is a group of patients lacking reliable prognostic markers and in some cases the outcomes predicted do not match the outcomes observed, highlighting the need for additional markers. ABCB1 encodes a transporter protein responsible for the extrusion of cytotoxic compounds, including daunorubicin, over the cell membrane, and is a known resistance mechanism. Ara-C is subject to both activating and inactivating metabolic enzymes including DCK (activating), CDA and cN-II (inactivating). ABCB1, DCK, CDA and cN-II are all polymorphic, and SNPs affecting enzyme function and/or activity have potential as prognostic markers. In addition, recurrent IDH1/2 mutations lead to the expression of an enzyme with neomorphic activity associated with epigenetic alterations and disturbed differentiation. Mutations as well as a SNP in codon 105 of IDH1 have prognostic implications in AML, although the effects of different IDH mutations have been unclear. The aim of this thesis was to investigate SNPs in ABCB1 and genes associated with Ara-C metabolism, mutations in IDH1/2 and the IDH1 SNP, and their associations with treatment response and survival in AML. We show that the 1236C>T and 2677G>T SNPs in ABCB1 influence in vitro sensitivity towards AML drugs, with corresponding effects on NK-AML patient survival. These survival differences were seen mainly in patients lacking FLT3-ITD, further adding to the risk stratification. In contrast, the CDA SNPs 79A>C and -451C>T appear to influence survival mainly in FLT3-ITD positive cases. In conclusion, the above-mentioned SNPs have the potential to add important information to risk classifications especially in NK-AML patients with the ambiguous FLT3-ITD-/NPM1- or FLT3-ITD+/NPM1+ genotypes. In addition, we have shown that IDH2 R140 mutation is associated with impaired survival in AML, and that the IDH1 codon 105 SNP appears to confer a worse outcome in a subset of intermediate risk patients without FLT3-ITD. With the introduction of next generation sequencing into clinical diagnostics, IDH mutations may not only provide prognostic information but also guide the selection of patients for new drugs targeting the variant enzyme. Our results indicate that in addition to leukemia-specific mutations, constitutional SNPs may prove useful for further individualizing care-taking and should be considered when implementing these new techniques.

    List of papers
    1. Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype
    Open this publication in new window or tab >>Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype
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    2012 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 12, no 2, p. 111-118Article in journal (Refereed) Published
    Abstract [en]

    Overexpression of the multi-drug transporter P-glycoprotein, encoded by the ABCB1 gene, is a clinically relevant problem in acute myeloid leukemia (AML). Polymorphisms in ABCB1 might contribute to cancer risk and therapeutic response. We therefore investigated the influence of polymorphisms G1199A, C1236T, G2677T/A and C3435T on cancer susceptibility, in vitro cytotoxicity and overall survival in 100 de novo AML patients with normal karyotype. Patients with 1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes (P = 0.03 and P = 0.02, respectively). Both these genotypes were significant factors for survival in multivariate analysis, along with age, NPM1 and FLT3 mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 2677T/T patients were significantly more susceptible to mitoxantrone (P 0.02), and tended to be more susceptible to etoposide and daunorubicin (P = 0.07-0.09), but not to cytarabine. No significant difference in allele frequencies was found between patients and healthy volunteers (n = 400).

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2012
    Keywords
    ABCB1, acute myeloid leukemia, single-nucleotide polymorphisms, anthracyclines
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-76805 (URN)10.1038/tpj.2010.79 (DOI)000302133700004 ()
    Note

    Funding Agencies|Swedish Cancer Society||Swedish Research Council-Medicine||Cancer Society in Stockholm||Karolinska Institutet||County Council in Ostergotland||

    Available from: 2012-04-20 Created: 2012-04-20 Last updated: 2018-12-19Bibliographically approved
    2. Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase
    Open this publication in new window or tab >>Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase
    Show others...
    2013 (English)In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed) Published
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and −451C>T rs532545), 5′-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3′UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and −451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-98699 (URN)10.1002/ajh.23549 (DOI)000327224000125 ()23873772 (PubMedID)
    Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2018-12-19
    3. Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype
    Open this publication in new window or tab >>Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype
    Show others...
    2014 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, no 5, p. 671-680Article in journal (Refereed) Published
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199Ggreater thanA, 1236Cgreater thanT, 2677Ggreater thanT/A and 3435Cgreater thanT, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236Cgreater thanT and 2677Ggreater thanT may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

    Place, publisher, year, edition, pages
    Wiley, 2014
    Keywords
    acute myeloid leukaemia; ABCB1; single nucleotide polymorphism; anthracyclines; FLT3
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-112996 (URN)10.1111/bjh.13097 (DOI)000345222100009 ()25155901 (PubMedID)
    Note

    Funding Agencies|Swedish Cancer Society; County Council of Ostergotland; AFA Insurance; Stockholm Cancer Society; Karolinska Institutet; Swedish Research Council

    Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2019-01-10
    4. Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
    Open this publication in new window or tab >>Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
    Show others...
    2014 (English)In: Biomarker Research, ISSN 2050-7771, Vol. 2, no 18Article in journal (Refereed) Published
    Abstract [en]

    The isocitrate dehydrogenase (IDH1/IDH2) genes are frequently mutated and reported to associate with poor prognosis in acute myeloid leukemia (AML). We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP  105C>T (rs11554137) in 207 unselected de novo AML patients. IDH1 codon 132 mutations were present in 7.7%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 10.1% and 2.9%, respectively. The SNP 105C>T was present in 10.1% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p=0.009) was observed in the intermediate risk patient group with cytogenetically normal karyotype (CN-AML). Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative CN-AML, (p=0.007). Our results indicate that IDH2 mutations and the IDH1 SNP 105C>T variant may represent a new subgroup for risk stratification and may indicate new treatment options.

    Keywords
    AML, IDH1, IDH2, SNP, prognostic markers
    National Category
    Clinical Medicine Medical Genetics
    Identifiers
    urn:nbn:se:liu:diva-104949 (URN)10.1186/2050-7771-2-18 (DOI)
    Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2018-12-19Bibliographically approved
  • 30.
    Kozlowski, Piotr
    et al.
    Örebro University, Sweden.
    Lennmyr, Emma
    Uppsala University, Sweden.
    Ahlberg, Lucia
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Bernell, Per
    Karolinska Institute, Sweden.
    Hulegardh, Erik
    Sahlgrens University Hospital, Sweden.
    Karbach, Holger
    University Hospital Umeå, Sweden.
    Karlsson, Karin
    Skåne University Hospital, Sweden.
    Tomaszewska-Toporska, Beata
    Skåne University Hospital, Sweden.
    Åström, Maria
    Örebro University, Sweden.
    Hallbook, Helene
    Uppsala University, Sweden.
    Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden2017In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 99, no 2, p. 141-149Article in journal (Refereed)
    Abstract [en]

    ObjectivesOlder/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials. MethodsUsing Swedish national leukemia registries, we investigated disease/patient characteristics, treatment choices, outcome, and the impact of an age-adapted protocol (introduced in 2009) in this population-based study of patients aged 55-85years, diagnosed with ALL 2005-2012. ResultsOf 174 patients, 82% had B-phenotype, 11% Burkitt leukemia (excluded), and 7% T-phenotype. Philadelphia chromosome positivity (Ph+) occurred in 35%. Of the 155 B- and T-ALL patients, 80% were treated with intensive protocols, and 20% with a palliative approach. Higher age and WHO performance status 2 influenced the choice of palliation. Intensive, palliative, and both approaches resulted in complete remission rate 83/16/70% and 3-year overall survival (OS) 32/3/26%. The age-adapted protocol did not improve outcome. With intensive treatment, platelet count 35x10(9)/L and age 75years were adverse prognostic factors for OS, Ph+ was not. Male sex was an adverse prognostic factor in the 55-64 year age-group. ConclusionsWe report a high frequency of Ph+ in older/elderly patients, with no evidence of poorer outcome compared to Ph-negative disease. Overall prognosis for elderly patients with ALL remains dismal, despite the use of age-adapted treatment.

  • 31.
    Kreutzman, Anna
    et al.
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Yadav, Bhagwan
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Brummendorf, Tim H.
    Univ Klinikum RWTH Aachen, Germany.
    Gjertsen, Bjorn Tore
    Univ Bergen, Norway; Univ Bergen, Norway.
    Hee, Moon Lee
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Janssen, Jeroen
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    Kasanen, Tiina
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Koskenvesa, Perttu
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Markevarn, Berit
    Umea Univ Hosp, Sweden.
    Olsson-Stromberg, Ulla
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Stentoft, Jesper
    Aarhus Univ Hosp, Denmark.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Soderlund, Stina
    Uppsala Univ Hosp, Sweden.
    Udby, Lene
    Zealand Univ Hosp, Denmark.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Norway; Norwegian Univ Sci and Technol NTNU, Norway.
    Mustjoki, Satu
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line2019In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 9, article id e1638210Article in journal (Refereed)
    Abstract [en]

    Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naive and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.

  • 32.
    Landberg, Niklas
    et al.
    Lund University, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Rissler, Marianne
    Lund University, Sweden.
    Billstrom, Rolf
    Central Hospital Skovde, Sweden.
    Agerstam, Helena
    Lund University, Sweden.
    Primary cells in BCR/FGFR1-positive 8p11 myeloproliferative syndrome are sensitive to dovitinib, ponatinib, and dasatinib2017In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 99, no 5, p. 442-448Article in journal (Refereed)
    Abstract [en]

    ObjectivesTranslocations involving the fibroblast growth factor receptor 1 (FGFR1) gene are associated with the 8p11 myeloproliferative syndrome (EMS), a rare neoplasm that following a usually short chronic phase progresses into acute myeloid or lymphoid leukemia. The treatment commonly involves chemotherapy and, if possible, allogeneic stem cell transplantation which is the only therapeutic option for long-term survival. Given the aggressive course of EMS, we here evaluated tyrosine kinase inhibitors as treatment options to delay disease progression. MethodsWe described a new case of EMS and used chromosome analyses, PCR, and sequencing to investigate the underlying genetic aberrations. The sensitivity to several tyrosine kinase inhibitors was tested in vitro on the EMS cell line KG1 and on primary cells from the newly diagnosed EMS patient. ResultsA translocation involving chromosomes 8 and 22 was detected, and a BCR/FGFR1 fusion gene was confirmed and characterized by sequencing. KG1 cells and primary EMS cells displayed distinct sensitivity to dovitinib, ponatinib, and dasatinib as compared to normal bone marrow control cells. ConclusionsThese results suggest that treatment with tyrosine kinase inhibitors may be beneficial for patients with EMS during the search for a suitable stem cell donor and for those not eligible for transplantation.

  • 33.
    Lazarevic, V.
    et al.
    Skåne University Hospital, Sweden Lund University, Sweden .
    Horstedt, A-S
    Skåne University Hospital, Sweden .
    Johansson, B.
    University of and Regional Labs Regional Skåne, Sweden Lund University, Sweden .
    Antunovic, Petar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Billstrom, R.
    Central Hospital Skovde, Sweden .
    Derolf, A.
    Karolinska University Hospital, Sweden Karolinska University Hospital, Sweden .
    Hulegardh, E.
    Sahlgrens University Hospital, Sweden .
    Lehmann, S.
    Karolinska University Hospital, Sweden Karolinska University Hospital, Sweden .
    Mollgard, L.
    Sahlgrens University Hospital, Sweden .
    Nilsson, C.
    Karolinska University Hospital, Sweden Karolinska University Hospital, Sweden .
    Peterson, S.
    Skåne University Hospital, Sweden .
    Stockelberg, D.
    Sahlgrens University Hospital, Sweden .
    Uggla, B.
    Örebro University Hospital, Sweden .
    Wennstrom, L.
    Sahlgrens University Hospital, Sweden .
    Wahlin, A.
    Umeå University, Sweden .
    Hoglund, M.
    Academic Hospital, Sweden .
    Juliusson, G.
    Skåne University Hospital, Sweden Lund University, Sweden .
    Incidence and prognostic significance of karyotypic subgroups in older patients with acute myeloid leukemia: the Swedish population-based experience2014In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 4, no e188Article in journal (Refereed)
    Abstract [en]

    The Swedish population-based acute myeloid leukemia registry contains data from 3251 patients (excluding acute promyelocytic leukemia) diagnosed between 1997 and 2006. Informative cytogenetic data from 1893 patients were retrospectively added, including 1054 patients aged between 60 and 79 years. Clonal abnormalities were found in 57% of the informative karyotypes. Karyotypic patterns differed by age: t(8; 21), inv(16) and t(11q23) were more common in younger patients, whereas loss of 5q, 7q and 17p, monosomal karyotype (MK) and complex karyotypes were more common in older patients. Loss of 5q, 7q and 17p often occurred together within MK. Patients with greater than= 5 chromosome abnormalities had worse overall survival than those with fewer abnormalities or normal karyotype in all age groups. Loss of 5q, 7q and/or 17p had, in contrast to MK, a further negative impact on survival. Multivariable Cox regression analyses on risk factors in patients less than80 years with cytogenetic abnormalities and intensive treatment revealed that age and performance status had the most significant impact on survival (both Pless than0.001), followed by sex (P = 0.0135) and a karyotype including - 7/del(7q) (P = 0.048).

  • 34.
    Lazarevic, Vladimir Lj
    et al.
    Skane Univ Hosp, Sweden.
    Bredberg, Anders
    Lund Univ, Sweden.
    Lorenz, Fryderyk
    Norrland Univ Hosp, Sweden.
    Ohlander, Emma
    Sundsvall Hosp, Sweden.
    Antunovic, Petar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden.
    Derolf, Asa
    Karolinska Univ Hosp, Sweden.
    Hoglund, Martin
    Acad Hosp, Sweden.
    Juliusson, Gunnar
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Acute myeloid leukemia in very old patients2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 12, p. E578-E580Article in journal (Other academic)
    Abstract [en]

    n/a

  • 35.
    Lazarevic, Vladimir
    et al.
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Rosso, Aldana
    Skåne University Hospital, Sweden.
    Juliusson, Gunnar
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Antunovic, Petar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Rangert-Derolf, Asa
    Karolinska University Hospital, Sweden.
    Lehmann, Soren
    Karolinska University Hospital, Sweden.
    Mollgard, Lars
    Sahlgrens University Hospital, Sweden.
    Uggla, Bertil
    Örebro University Hospital, Sweden.
    Wennstrom, Lovisa
    Sahlgrens University Hospital, Sweden.
    Wahlin, Anders
    Umeå University, Sweden.
    Hoglund, Martin
    Academic Hospital, Sweden.
    Johansson, Bertil
    University of and Regional Labs Regional Skåne, Sweden; Lund University, Sweden.
    Prognostic significance of high hyperdiploid and triploid/tetraploid adult acute myeloid leukemia2015In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 90, no 9, p. 800-805Article in journal (Refereed)
    Abstract [en]

    To ascertain the clinical implications of high hyperdiploid (HH; 49-65 chromosomes) and triploid/tetraploid (TT; greater than65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n=50)/TT (n=18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P=0.042) and less often had de novo AML (63% vs. 79%; P=0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P=0.082), whereas OS was significantly longer (median 1.6 years; P=0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P=0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P=0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers greater than65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.Am. J. Hematol. 90:800-805, 2015. (c) 2015 Wiley Periodicals, Inc.

  • 36.
    Lennmyr, Emma
    et al.
    Uppsala Univ, Sweden.
    Karlsson, Karin
    Skane Univ Hosp, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Garelius, Hege
    Sahlgrens Univ Hosp, Sweden.
    Hulegardh, Erik
    Sahlgrens Univ Hosp, Sweden.
    Izarra, Antonio S.
    Univ Hosp Umea, Sweden.
    Joelsson, Joel
    Karolinska Inst, Sweden.
    Kozlowski, Piotr
    Orebro Univ, Sweden.
    Moicean, Andreea
    Cent Hosp Skovde, Sweden.
    Tomaszewska-Toporska, Beata
    Skane Univ Hosp, Sweden.
    Lubking, Anna
    Skane Univ Hosp, Sweden.
    Hallbook, Helene
    Uppsala Univ, Sweden.
    Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry2019In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 103, no 2, p. 88-98Article in journal (Refereed)
    Abstract [en]

    Objectives As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care. Methods We used the population-based Swedish ALL Registry to evaluate characteristics, treatment and long-term outcome in 933 patients with diagnosis between 1997 and 2015. Results The median age was 53 years. The frequency of Philadelphia (Ph)-positive leukaemia was 34% of examined B-ALL with a peak incidence at 50-59 years. Five-year overall survival (OS) improved between 1997-2006 and 2007-2015; in patients 18-45 years from 50% (95% CI 43-57) to 65% (95% CI 58-72), 46-65 years from 25% (95% CI 18-32) to 46% (95% CI 37-55) and amp;gt;65 years from 7% (95% CI 2.6-11) to 11% (95% CI 5.9-16) (P amp;lt; 0.05). Men with Ph-neg B-ALL 46-65 years had inferior OS compared with women (P amp;lt; 0.01). Standardised mortality ratio was 5.7 (95% CI 5.0-6.3) for patients who survived 5 years from diagnosis. In multivariable analysis, Ph-positive disease was not associated with impaired prognosis but with lower risk of death in 2007-2015. Conclusions In a population-based cohort, OS has improved in adult ALL, especially for Ph-positive disease but for middle-aged men with Ph-negative B-ALL outcome was poor. Cure without late toxicity or relapse is still desired.

  • 37.
    Likus, Wirginia
    et al.
    Medical University of Silesia, Poland.
    Siemianowicz, Krzysztof
    Medical University of Silesia, Poland.
    Markowski, Jaroslaw
    Medical University of Silesia, Poland.
    Wiaderkiewicz, Jan
    Medical University of Silesia, Poland; George Washington University, DC USA.
    Kostrzab-Zdebel, Anna
    Medical University of Silesia, Poland.
    Jura-Szoltys, Edyta
    Medical University of Silesia, Poland.
    Dziubdziela, Wlodzimierz
    Outpatient Clin Treatment Chron Pain, Poland.
    Wiaderkiewicz, Ryszard
    Medical University of Silesia, Poland.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Pomeranian Medical University, Poland.
    Bacterial Infections and Osteoclastogenesis Regulators in Men and Women with Cholesteatoma2016In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 64, no 3, p. 241-247Article, review/survey (Refereed)
    Abstract [en]

    One of the most distinct features of middle ear cholesteatoma is bone destruction. Aetiology of cholesteatoma is thought to be multifactorial. Endotoxins produced by bacteria are thought to initiate the inflammation process in the middle ear leading to cholesteatoma. There are physiological differences in bone metabolism between men and women. The aim of our study was the immunohistochemical evaluation of the contents of two key components of the OPG/RANK/RANKL triad-RANKL and OPG in cholesteatoma, to analyse if there are any differences between the sexes and to evaluate the bacteria species isolated from cholesteatoma just before surgical treatment and to evaluate their plausible influence on the expression of OPG and RANKL in cholesteatoma. Twenty-one adult patients with acquired cholesteatoma who underwent surgery were analysed. There were no statistically significant differences in the expression of both regulators of osteoclastogenesis between the sexes. In 38.1 % patients cholesteatoma was not infected, whereas in 61.9 % patients various bacterial infections or mycosis were found. The most frequently isolated species was Pseudomonas aeruginosa (14.29 % infections) followed by Staphylococcus aureus (9.52 % infections). There were no statistically significant differences in expression of both OPG and RANKL between uninfected and infected cholesteatomas.

  • 38.
    Lj Lazarevic, Vladimir
    et al.
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Rosso, Aldana
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Juliusson, Gunnar
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Antunovic, Petar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Rangert Derolf, Åsa
    Karolinska University Hospital, Sweden.
    Deneberg, Stefan
    Karolinska University Hospital, Sweden.
    Mollgård, Lars
    Sahlgrens University Hospital, Sweden.
    Uggla, Bertil
    Örebro University Hospital, Sweden.
    Wennstrom, Lovisa
    Sahlgrens University Hospital, Sweden.
    Wahlin, Anders
    Umeå University, Sweden.
    Höglund, Martin
    Academic Hospital, Sweden.
    Lehmann, Sören
    Academic Hospital, Sweden.
    Johansson, Bertil
    University of and Regional Labs Regional Skåne, Sweden; Lund University, Sweden.
    Incidence and prognostic significance of isolated trisomies in adult acute myeloid leukemia: A population-based study from the Swedish AML registry2017In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 5, p. 493-500Article in journal (Refereed)
    Abstract [en]

    Objectives and MethodsTo ascertain the incidence/clinical implications of isolated autosomal trisomies in adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. ResultsOf the 3179 cytogenetically informative AMLs diagnosed January 1997-May 2015, 246 (7.7%) had isolated trisomies. The frequency increased by age (2.4% at age 18-60years vs. 23% at amp;gt;60years; Pamp;lt;.0001); the median age was 69years. The five most common were +8 (4.0%), +13 (0.9%), +11 (0.8%), +21 (0.7%), and +4 (0.5%). Age and gender, types of AML and treatment, and complete remission and early death rates did not differ between the single trisomy and the intermediate risk (IR) groups or among cases with isolated gains of chromosomes 4, 8, 11, 13, or 21. The overall survival (OS) was similar in the single trisomy (median 1.6years) and IR groups (1.7years; P=.251). The OS differed among the most frequent isolated trisomies; the median OS was 2.5years for +4, 1.9years for +21, 1.5years for +8, 1.1years for +11, and 0.8years for +13 (P=.013). ConclusionAML with single trisomies, with the exception of +13, should be grouped as IR.

  • 39.
    Los, Marek Jan
    et al.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Herr, I.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Friesen, C.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Fulda, S.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Schulze-Osthoff, K.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Debatin, K. M.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases)1997In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 90, no 8, p. 3118-3129Article in journal (Refereed)
    Abstract [en]

    The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system, After drug treatment, a strong increase of caspase activity was found that preceded cell death, Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin, The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis, Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells. (C) 1997 by The American Society of Hematology.

  • 40.
    Lundin, Anna-Carin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tendinosis in Trigger Finger2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it.

    We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology.

    Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis.

    Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis.

    We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups.

    In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.

    List of papers
    1. Trigger finger and tendinosis
    Open this publication in new window or tab >>Trigger finger and tendinosis
    2012 (English)In: Journal of Hand Surgery, European Volume, ISSN 1753-1934, E-ISSN 2043-6289, Vol. 37, no 3, p. 233-236Article in journal (Refereed) Published
    Abstract [en]

    The pathogenesis of trigger finger has generally been ascribed to primary changes in the pulley. Histological examination of the affected tendons has rarely been done. We studied biopsies from tendons of trigger fingers from 29 patients and compared these to biopsies from six intact tendons. We used a modified Movin score, which describes the tendinosis of the Achilles tendon. Trigger finger tendons had a high score (14.2; SD, 2.2) consistent with tendinosis, while the controls were almost normal (2.5; SD, 1.9). This suggests that the tendon is also affected, and that trigger finger is a form of tendinosis.

    Place, publisher, year, edition, pages
    Sage Publications, 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-76086 (URN)10.1177/1753193411421853 (DOI)000300994100007 ()21987275 (PubMedID)
    Available from: 2012-03-26 Created: 2012-03-26 Last updated: 2017-12-07Bibliographically approved
    2. Trigger finger, tendinosis, and intratendinous gene expression
    Open this publication in new window or tab >>Trigger finger, tendinosis, and intratendinous gene expression
    2014 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 24, no 2, p. 363-368Article in journal (Refereed) Published
    Abstract [en]

    The pathogenesis of trigger finger has generally been ascribed to primary changes in the first annular ligament. In contrast, we recently found histological changes in the tendons, similar to the findings in Achilles tendinosis or tendinopathy. We therefore hypothesized that trigger finger tendons would show differences in gene expression in comparison to normal tendons in a pattern similar to what is published for Achilles tendinosis. We performed quantitative real-time polymerase chain reaction on biopsies from finger flexor tendons, 13 trigger fingers and 13 apparently healthy control tendons, to assess the expression of 10 genes which have been described to be differently expressed in tendinosis (collagen type 1a1, collagen 3a1, MMP-2, MMP-3, ADAMTS-5, TIMP-3, aggrecan, biglycan, decorin, and versican). In trigger finger tendons, collagen types 1a1 and 3a1, aggrecan and biglycan were all up-regulated, and MMP-3and TIMP-3 were down-regulated. These changes were statistically significant and have been previously described for Achilles tendinosis. The remaining four genes were not significantly altered. The changes in gene expression support the hypothesis that trigger finger is a form of tendinosis. Because trigger finger is a common condition, often treated surgically, it could provide opportunities for clinical research on tendinosis.

    Place, publisher, year, edition, pages
    Wiley, 2014
    Keywords
    tendinopathy; tendinosis; stenosing tendovaginitis; tendovaginitis stenosans; quantitative real-time PCR; qPCR
    National Category
    Orthopaedics Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-106131 (URN)10.1111/j.1600-0838.2012.01514.x (DOI)000332982700018 ()
    Available from: 2014-04-25 Created: 2014-04-24 Last updated: 2018-01-11
  • 41.
    Lübking, Anna
    et al.
    Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
    Vosberg, Sebastian
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany .
    Konstandin, Nicola
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
    Dufour, Annika
    Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
    Graf, Alexander
    Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
    Krebs, Stefan
    Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
    Blum, Helmut
    Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Weber, Axel
    Institut für Humangenetik, Universitätsklinikum Giessen und Marburg/Standort Giessen, Germany.
    Lenhoff, Stig
    Institut für Humangenetik, Universitätsklinikum Giessen und Marburg/Standort Giessen, Germany.
    Ehinger, Mats
    Department of Pathology, Skåne University Hospital, Lund, Sweden.
    Spiekermann, Karsten
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany .
    Greif, Philip
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany .
    Cammenga, Jörg
    Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden; Department of Molecular Medicine and Gene Therapy, Lund University, BMC A12, Lund, Sweden.
    Young woman with mild bone marrow dysplasia, GATA2 and ASXL1 mutation treated with allogeneic hematopoietic stem cell transplantation2015In: Leukemia Research Reports, ISSN 2213-0489, Vol. 4, no 2, p. 72-75Article in journal (Refereed)
    Abstract [en]

    Heterozygous mutations in GATA2 underlie different syndromes, previously described as monocytopenia and mycobacterial avium complex infection (MonoMAC); dendritic cell, monocytes, B- and NK lymphocytes deficiency (DCML); lymphedema, deafness and myelodysplasia (Emberger syndrome) and familiar myelodysplastic syndrome/acute myeloid leukemia (MDS / AML). Onset and severity of clinical symptoms vary and preceding cytopenias are not always present. We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to GATA2 mutation. Exome sequencing revealed a somatic ASXL1 mutation and the patient underwent allogeneic stem cell transplantation successfully. © 2015.

  • 42.
    Macwan, Ankit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ntzouni, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Orebro Univ, Sweden.
    Gibbins, Jonathan M.
    Univ Reading, England.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 7Article in journal (Refereed)
    Abstract [en]

    As platelet activation is an irreversible and potentially harmful event, platelet stimulatory signaling must be tightly regulated to ensure the filtering-out of inconsequential fluctuations of agonist concentrations in the vascular milieu. Herein, we show that platelet activation via G protein-coupled receptors is gradient-dependent, i.e., determined not only by agonist concentrations per se but also by how rapidly concentrations change over time. We demonstrate that gradient-dependent inhibition is a common feature of all major platelet stimulatory G protein-coupled receptors, while platelet activation via the non-G protein-coupled receptor glycoprotein VI is strictly concentration-dependent. By systematically characterizing the effects of variations in temporal agonist concentration gradients on different aspects of platelet activation, we demonstrate that gradient-dependent inhibition of protease-activated receptors exhibits different kinetics, with platelet activation occurring at lower agonist gradients for protease-activated receptor 4 than for protease-activated receptor 1, but shares a characteristic bimodal effect distribution, as gradient-dependent inhibition increases over a narrow range of gradients, below which aggregation and granule secretion is effectively shut off. In contrast, the effects of gradient-dependent inhibition on platelet activation via adenosine diphosphate and thromboxane receptors increase incrementally over a large range of gradients. Furthermore, depending on the affected activation pathway, gradient-dependent inhibition results in different degrees of refractoriness to subsequent autologous agonist stimulation. Mechanistically, our study identifies an important role for the cyclic adenosine monophosphate-dependent pathway in gradient-dependent inhibition. Together, our findings suggest that gradient-dependent inhibition may represent a new general mechanism for hemostatic regulation in platelets.

  • 43.
    Milovanovic, Micha
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Hallert, Claes
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Järemo, Petter
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Platelet Density Distribution in Essential Thrombocythemia2010In: Pathophysiology of Haemostasis and Thrombosis, ISSN 1424-8832, E-ISSN 1424-8840, Vol. 37, no 1, p. 35-42Article in journal (Refereed)
    Abstract [en]

    Essential thrombocythemia (ET) is characterized by high platelet counts and a slightly increased bleeding risk. Why severe hemorrhage does not occur more frequently is not known. Variations of platelet density (kg/l) depend mainly on cell organelle content in that high-density platelets contain more alpha and dense granules. This study compares ET patients (n = 2) and healthy volunteers (n = 2) with respect to platelet density subpopulations. A linear Percoll gradient containing prostaglandin E(1) was employed to separate platelets according to density. The platelet population was subsequently divided by density into 16 or 17 subpopulations. Determination of platelet counts was carried out. In each density fraction, platelet in vivo activity, i.e. platelet-bound fibrinogen, was measured using a flow cytometer. To further characterize platelet subpopulations, we determined intracellular concentrations of CD40 ligand (CD40L) and P-selectin in all fractions. Patients and controls demonstrated similar density distributions, i.e. 1 density peak. High-density platelets had more surface-bound fibrinogen in conjunction with signs of platelet release reactions, i.e. with few exceptions they contained less CD40L and P-selectin. Peak density platelets showed less surface-bound fibrinogen. These platelets contained less CD40L and P-selectin than nearby denser populations. The light platelets had more surface-bound fibrinogen than peak platelets together with elevated concentrations of CD40L. In ET, the malignant platelet production could exist together with platelets originating from normal megakaryocytes. It is also possible that clonal megakaryocytes produce platelets covering the entire density span. The 'normal' density distribution offers a tenable explanation as to why serious bleedings do not occur more frequently.

     

  • 44.
    Mulligan, Stephen P.
    et al.
    Royal N Shore Hospital, Australia.
    -Karlsson, Karin
    Department of Hematology, Skåne University Hospital, Lund , Sweden.
    Stromberg, Mats
    Karolinska University Hospital, Sweden.
    Jonsson, Viggo
    National Hospital, Denmark.
    Gill, Devinder
    Princess Alexandra Hospital, Australia.
    Hammerstrom, Jens
    St Olavs University Hospital, Norway.
    Hertzberg, Mark
    Westmead Hospital, Australia.
    McLennan, Roger
    Ballarat Base Hospital, Australia.
    Uggla, Bertil
    University Hospital Örebro, Sweden.
    Norman, John
    Royal Adelaide Hospital, Australia.
    Wallvik, Jonas
    Department Med, Sweden.
    Sundstrom, Gunnel
    Norrlands University Hospital, Sweden.
    Johansson, Hemming
    Karolinska Institute, Sweden.
    Brandberg, Yvonne
    Karolinska Institute, Sweden.
    Liliemark, Jan
    Karolinska University Hospital, Sweden; Swedish Council Health Technology Assessment, Sweden.
    Juliusson, Gunnar
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Department of Hematology, Sk å ne University Hospital, Lund, Sweden.
    Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 12, p. 2769-2777Article in journal (Refereed)
    Abstract [en]

    We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

  • 45.
    Mörtzell Henriksson, M.
    et al.
    Nephrol, Umeå, Sweden.
    Newman, E.
    Bone Marrow Transplant and Apheresis, New South Wales, Australia.
    Witt, V.
    St. Anna, Vienna, Austria.
    Derfler, K.
    AKH, Vienna, Austria.
    Leitner, G.
    AKH, Vienna, Austria.
    Eloot, S.
    Gent, Belgium.
    Dhondt, A.
    Gent, Belgium.
    Deeren, D.
    Roeselar, Belgium.
    Rock, G.
    Canada.
    Ptak, J.
    Frydek-Mistek, Czech Republic.
    Blaha, M.
    Hradec Kralove, Czech Republic.
    Lanska, M.
    Hradec Kralove, Czech Republic.
    Gasova, Z.
    Prague, Czech Republic.
    Hrdlickova, R.
    Ostrava, Czech Republic.
    Ramlow, W.
    Rostock, Germany.
    Prophet, H.
    Rostock, Germany.
    Liumbruno, G.
    Livorno, Italy.
    Mori, E.
    Livorno, Italy.
    Griskevicius, A.
    Vilnius, Lithuania.
    Audzijoniene, J.
    Vilnius, Lithuania.
    Vrielink, H.
    Amsterdam, The Netherlands.
    Rombout, S.
    Maastricht, The Netherlands.
    Aandahl, A.
    Oslo, Norway.
    Sikole, A.
    Skopje, Macedonia.
    Tomaz, J.
    Coimbra, Portugal.
    Lalic, K.
    Belgrade, Serbia.
    Mazic, S.
    Zagreb, Croatia.
    Strineholm, V.
    Orebro, Sweden.
    Brink, B.
    Huddinge, Sweden.
    Berlin, Gösta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dykes, J.
    Lund, Sweden.
    Toss, F.
    BC, Umeå, Sweden.
    Axelsson, C.G.
    BC, Umeå, Sweden.
    Stegmayr, B.
    Nephrol, Umeå, Sweden.
    Nilsson, T.
    Nephrol, Uppsala, Sweden.
    Norda, R.
    BC, Uppsala, Sweden.
    Knutson, F.
    BC, Uppsala, Sweden.
    Ramsauer, B.
    Nephrol., Skövde, Sweden.
    Wahlström,, A.
    Nephrol., Karlstad, Sweden.
    Adverse events in apheresis: An update of the WAA registry data2016In: Transfusion and apheresis science, ISSN 1473-0502, E-ISSN 1878-1683, Vol. 54, no 1, p. 14p. 2-15Article, review/survey (Refereed)
    Abstract [en]

    Apheresis with different procedures and devices are used for a variety of indications that may have different adverse events (AEs). The aim of this study was to clarify the extent and possible reasons of various side effects based on data from a multinational registry. The WAA-apheresis registry data focus on adverse events in a total of 50846 procedures in 7142 patients (42% women). AEs were graded as mild, moderate (need for medication), severe (interruption due to the AE) or death (due to AE). More AEs occurred during the first procedures versus subsequent (8.4 and 5.5%, respectively). AEs were mild in 2.4% (due to access 54%, device 7%, hypotension 15%, tingling 8%), moderate in 3% (tingling 58%, urticaria 15%, hypotension 10%, nausea 3%), and severe in 0.4% of procedures (syncope/hypotension 32%, urticaria 17%, chills/fever 8%, arrhythmia/asystole 4.5%, nausea/vomiting 4%). Hypotension was most common if albumin was used as the replacement fluid, and urticaria when plasma was used. Arrhythmia occurred to similar extents when using plasma or albumin as replacement. In 64% of procedures with bronchospasm, plasma was part of the replacement fluid used. Severe AEs are rare. Although most reactions are mild and moderate, several side effects may be critical for the patient. We present side effects in relation to the procedures and suggest that safety is increased by regular vital sign measurements, cardiac monitoring and by having emergency equipment nearby.

  • 46.
    Nagata, Yasunobu
    et al.
    Cleveland Clin, OH 44106 USA.
    Narumi, Satoshi
    Natl Res Inst Child Hlth and Dev, Japan.
    Guan, Yihong
    Cleveland Clin, OH 44106 USA.
    Przychodzen, Bartlomiej P.
    Cleveland Clin, OH 44106 USA.
    Hirsch, Cassandra M.
    Cleveland Clin, OH 44106 USA.
    Makishima, Hideki
    Kyoto Univ, Japan.
    Shima, Hirohito
    Natl Res Inst Child Hlth and Dev, Japan.
    Aly, Mai
    Cleveland Clin, OH 44106 USA; Assiut Univ, Egypt.
    Pastor, Victor
    Univ Freiburg, Germany.
    Kuzmanovic, Teodora
    Cleveland Clin, OH 44106 USA.
    Radivoyevitch, Tomas
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    Adema, Vera
    Cleveland Clin, OH 44106 USA.
    Awada, Hassan
    Cleveland Clin, OH 44106 USA.
    Yoshida, Kenichi
    Kyoto Univ, Japan.
    Li, Samuel
    Case Western Reserve Univ, OH 44106 USA.
    Sole, Francesc
    Univ Autonoma Barcelona, Spain.
    Hanna, Rabi
    Cleveland Clin, OH 44106 USA.
    Jha, Babal K.
    Cleveland Clin, OH 44106 USA.
    LaFramboise, Thomas
    Case Western Reserve Univ, OH 44106 USA.
    Ogawa, Seishi
    Kyoto Univ, Japan.
    Sekeres, Mikkael A.
    Cleveland Clin, OH 44106 USA.
    Wlodarski, Marcin W.
    Univ Freiburg, Germany.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Maciejewski, Jaroslaw P.
    Cleveland Clin, OH 44106 USA.
    Letter: Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132, no 21, p. 2309-2313Article in journal (Other academic)
    Abstract [en]

    n/a

  • 47.
    Nahi, Hareth
    et al.
    Karolinska Institute, Sweden.
    Genell, Anna
    Regional Cancer Centre West, Sweden.
    Walinder, Goran
    Karolinska Institute, Sweden.
    Uttervall, Katarina
    Karolinska Institute, Sweden.
    Juliusson, Gunnar
    Lund University, Sweden.
    Karin, Forsberg
    Umeå University Hospital, Sweden.
    Hansson, Markus
    Lund University, Sweden.
    Svensson, Ronald
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Linder, Olle
    Örebro University Hospital, Sweden.
    Carlson, Kristina
    Uppsala University Hospital, Sweden.
    Bjorkstrand, Bo
    Karolinska Institute, Sweden.
    Kristinsson, Sigurdur Y.
    Karolinska Institute, Sweden.
    Henrik Mellqvist, Ulf
    South Elvsborg Hospital, Sweden.
    Blimark, Cecilie
    Sahlgrens University Hospital, Sweden.
    Turesson, Ingemar
    Skåne University Hospital, Sweden.
    Incidence, characteristics, and outcome of solitary plasmacytoma and plasma cell leukemia. Population-based data from the Swedish Myeloma Register2017In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 99, no 3, p. 216-222Article in journal (Refereed)
    Abstract [en]

    Solitary plasmacytoma (SP) and plasma cell leukemia (PCL) are uncommon (3-6%) types of plasma cell disease. The risk of progression to symptomatic multiple myeloma (MM) is probably important for the outcome of SP. PCL is rare and has a dismal outcome. In this study, we report on incidence and survival in PCL/SP, and progression to MM in SP, using the prospective observational Swedish Multiple Myeloma Register designed to document all newly diagnosed plasma cell diseases in Sweden since 2008. Both solitary bone plasmacytoma (SBP) (n=124) and extramedullary plasmacytoma (EMP) (n=67) have better overall survival (OS) than MM (n=3549). Progression to MM was higher in SBP than in EMP (35% and 7% at 2years, respectively), but this did not translate into better survival in EMP. In spite of treatment developments, the OS of primary PCL is still dismal (median of 11months, 0% at 5years). Hence, there is a great need for diagnostic and treatment guidelines as well as prospective studies addressing the role for alternative treatment options, such as allogeneic stem cell transplantation and monoclonal antibodies in the treatment of PCL.

  • 48.
    Norin, Stefan
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bjorkstrand, Bo
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Rommel, Franz
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Timberg, Lars
    Kristianstad Central Hospital, Sweden.
    Andersson, Per-Ola
    Sahlgrens University Hospital, Sweden.
    Haggstrom, Johan
    Kalmar Hospital, Sweden.
    Aldrin, Anders
    Visby Hospital, Sweden.
    Hansson, Lotta
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Severe infusion-related reactions are uncommon in rituximab-treated CLL patients in clinical practice: Results from a Swedish national observational study2015In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 39, no 1, p. 33-37Article in journal (Refereed)
    Abstract [en]

    There have been concerns about serious infusion-related adverse drug reactions (ADR) with rituximabin chronic lymphocytic leukemia (CLL). We therefore conducted an observational trial in which CLL patients planned for rituximab-containing therapy were eligible. Ninety-six patients from 19 centers were enrolled. The most common regimen was rituximab, fludarabine and cyclophosphamide. Fifty-six patients experienced ADR during rituximab infusion. Reactions greater than= grade 3 occurred in five patients and no cases of tumor lysis syndrome were recorded. Despite a high number of circulating tumor cells few severe ADR were noted. Thus, rituximab containing regimens can be considered safe for CLL patients in general practice.

  • 49.
    Olsson, Linda
    et al.
    Lund University, Sweden; Department Clin Genet, Sweden.
    Zettermark, Sofia
    Lund University, Sweden.
    Biloglav, Andrea
    Lund University, Sweden.
    Castor, Anders
    Skåne University Hospital, Sweden.
    Behrendtz, Mikael
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Forestier, Erik
    Umeå University, Sweden.
    Paulsson, Kajsa
    Lund University, Sweden.
    Johansson, Bertil
    Lund University, Sweden; Department Clin Genet, Sweden.
    The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes2016In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, no 2, p. 292-301Article in journal (Refereed)
    Abstract [en]

    Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFBMYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed amp;gt;= 1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML.

  • 50.
    Osman, Abdimajid
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hitzler, Walter E.
    Johannes Gutenberg Univ Mainz, Germany.
    Provost, Patrick
    CHUL, Canada; Univ Laval, Canada.
    The platelets perspective to pathogen reduction technologies2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 2, p. 140-147Article, review/survey (Refereed)
    Abstract [en]

    A wide variety of clinical conditions, associated with low circulating platelet counts, require platelet transfusion in order to normalize hemostatic function. Although single-donor apheresis platelets bear the lowest risk of transfusion-transmitted infections, pathogen reduction technologies (PRT) are being implemented worldwide to reduce this risk further through inactivation of known, emergent and as yet to be discovered nucleic acid-based pathogens. Human blood platelets are now known to harbor a diverse transcriptome, important to their function and comprised of amp;gt;5000 protein-coding messenger RNAs and different classes of non-coding RNAs, including microRNAs. Our appreciation of the nucleic acid-dependent functions of platelets is likely to increase. On the other hand, the side effects of PRT on platelet function are underappreciated. Recent evidences suggest that PRT may compromise platelets responsiveness to agonists, and induce platelet activation. For instance, platelets have the propensity to release proinflammatory microparticles (MPs) upon activation, and the possibility that PRT may enhance the production of platelet MPs in platelet concentrates (PCs) appears likely. With this in mind, it would be timely and appropriate to investigate other means to inactivate pathogens more specifically, or to modify the currently available PRT so to better preserve the platelet function and improve the safety of PCs; platelets perspective to PRT deserves to be considered.

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