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  • 951. Zachariadis, Vasilios
    et al.
    Schoumans, Jacqueline
    Barbany, Gisela
    Heyman, Mats
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Bertil
    Nordenskjöld, Magnus
    Nordgren, Ann
    Homozygous deletions of CDKN2A are present in all dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukaemias and may be important for leukaemic transformation2012In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 159, no 4, p. 488-491Article in journal (Refereed)
  • 952.
    Zainuddin, Norafiza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Molecular Genetic Analysis in B-cell Lymphomas: A Focus on the p53 Pathway and p16INK4a2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

  • 953.
    Zainuddin, Norafiza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, Göran
    Department of Medical Biosciences, Pathology, Umeå University, Umeå.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Quantitative evaluation of p16INK4a promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 4, p. 438-443Article in journal (Refereed)
    Abstract [en]

    The p16INK4a tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16INK4a methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16INK4a methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16INK4a methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16INK4a methylation and patients’ clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16INK4a methylation on lymphoma-specific survival. Although >25% of p16INK4a methylation correlated with a better progression-free survival (P=0.048), the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16INK4a promoter methylation as a negative prognostic factor in DLBCL.

  • 954.
    Zaleska, J.
    et al.
    Med Univ Lublin, Dept Expt Hematooncol, Lublin, Poland..
    Skorka, K.
    Med Univ Lublin, Dept Expt Hematooncol, Lublin, Poland..
    Zajac, M.
    Med Univ Lublin, Dept Expt Hematooncol, Lublin, Poland..
    Karczmarczyk, A.
    Med Univ Lublin, Dept Expt Hematooncol, Lublin, Poland..
    Karp, M.
    Med Univ Lublin, Dept Expt Hematooncol, Lublin, Poland..
    Tomczak, W.
    Med Univ Lublin, Dept Hematooncol, Lublin, Poland.;Med Univ Lublin, BMT Unit, Lublin, Poland..
    Wlasiuk, P.
    Med Univ Lublin, Dept Expt Hematooncol, Lublin, Poland..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Giannopoulos, K.
    Med Univ Lublin, Dept Expt Hematooncol, Lublin, Poland.;Med Univ Lublin, Dept Hematooncol, Lublin, Poland.;Med Univ Lublin, BMT Unit, Lublin, Poland..
    SPECIFIC T-CELL IMMUNE RESPONSES AGAINST AUTOANTIGENS RECOGNIZED BY CHRONIC LYMPHOCYTIC LEUKEMIA CELLS2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 48-48Article in journal (Other academic)
  • 955.
    Zeller, Bernward
    et al.
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Mailbox 4950 Nydalen, N-0424 Oslo, Norway..
    Glosli, Heidi
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Mailbox 4950 Nydalen, N-0424 Oslo, Norway..
    Forestier, Erik
    Umea Univ Hosp, Dept Med Biosci, Genet, Umea, Sweden..
    Ha, Shau-Yin
    Queen Mary Hosp, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China.;HKPHOSG, Hong Kong, Hong Kong, Peoples R China..
    Jahnukainen, Kirsi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Cent Hosp, Helsinki, Finland..
    Jonsson, Olafur G.
    Landspitali Univ Hosp, Dept Paediat, Reykjavik, Iceland..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hasle, Henrik
    Aarhus Univ, Hosp Skejby, Dept Paediat, Aarhus, Denmark..
    Abrahamsson, Jonas
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden..
    Hyperleucocytosis in paediatric acute myeloid leukaemia: the challenge of white blood cell counts above 200 x 109/l. The NOPHO experience 1984-20142017In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 3, p. 448-456Article in journal (Refereed)
    Abstract [en]

    Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC > 200 x 10/l). Eighty-six patients (10%) had WBC 100-199 x 109/l and 57 (6%) had WBC >= 200 x 109/l. Patients with WBC >= 200 x 109/l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 x 109/l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.

  • 956.
    Zhao, Jingcheng
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Ryden, Jenny
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Wikman, Agneta
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Stanworth, Simon J.
    Univ Oxford, Radcliffe Dept Med, Oxford Univ Hosp NHS Fdn Trust, Transfus Med,NHS Blood & Transplant, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Univ Hosp NHS Fdn Trust, Dept Hematol, Oxford, England.;Oxford BRC Hematol Theme, Oxford, England..
    Hjalgrim, Henrik
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark.;Copenhagen Univ Hosp, Dept Hematol, Copenhagen, Denmark..
    Edgren, Gustaf
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Blood use in hematologic malignancies: a nationwide overview in Sweden between 2000 and 20102018In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 58, no 2, p. 390-401Article in journal (Refereed)
    Abstract [en]

    BACKGROUNDPatients with hematologic malignancies receive large numbers of blood transfusions, and transfusion practices for this patient group are increasingly being scrutinized by randomized controlled trials. However, no studies so far have presented current transfusion statistics on a population level for this patient group. STUDY DESIGN AND METHODSA retrospective descriptive study was conducted that was based on the Scandinavian Donations and Transfusions Database (SCANDAT2), which includes data on all blood donations and transfusions in Sweden and Denmark since the 1960s. Incident cases of hematologic malignancies were identified in the Swedish Cancer Register between 2000 and 2010. Cases were divided into nine patient groups based on diagnosis. RESULTSA total of 28,693 patients were included in the cohort. Overall, the transfusion pattern varied depending on diagnosis and age. Patients with aggressive and acute diagnoses generally received more transfusions with immediate decline in transfusion incidence after diagnosis, whereas chronic diagnoses generally maintained more stable, but lower, transfusion incidence. In general, patients with leukemia received more transfusions than patients with lymphoma, and patients with acute leukemia as well as patients that had undergone allogeneic stem cell transplantations received the most transfusions. Within 2 years after diagnosis, patients with acute myeloid leukemia diagnosed at ages 0 to 65 years received on average between 30 to 40 red blood cell transfusions and platelet transfusions, respectively, corresponding to direct material costs close to 200,000 SEK (23,809 USD). CONCLUSIONResults from this population-based overview of blood use in hematologic malignancies showed high variability depending on diagnosis and age.

  • 957.
    Zimdahl Kahlin, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Helander, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Mårtensson, Lars-Göran
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden2019In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 164, p. 263-272Article in journal (Refereed)
    Abstract [en]

    Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patients TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

  • 958. Zong, N. C.
    et al.
    Li, H.
    Lam, M. P. Y.
    Jimenez, R. C.
    Kim, C. S.
    Deng, N.
    Kim, A. K.
    Choi, J. H.
    Zelaya, I.
    Liem, D.
    Meyer, D.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fang, C.
    Lu, H. -J
    Xu, T.
    Weiss, J.
    Duan, H.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yates III, J. R.
    Apweiler, R.
    Ge, J.
    Hermjakob, H.
    Ping, P.
    Integration of cardiac proteome biology and medicine by a specialized knowledgebase2013In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 113, no 9, p. 1043-1053Article in journal (Refereed)
    Abstract [en]

    Rationale: Omics sciences enable a systems-level perspective in characterizing cardiovascular biology. Integration of diverse proteomics data via a computational strategy will catalyze the assembly of contextualized knowledge, foster discoveries through multidisciplinary investigations, and minimize unnecessary redundancy in research efforts. Objective: The goal of this project is to develop a consolidated cardiac proteome knowledgebase with novel bioinformatics pipeline and Web portals, thereby serving as a new resource to advance cardiovascular biology and medicine. Methods and results: We created Cardiac Organellar Protein Atlas Knowledgebase (COPaKB; www.HeartProteome.org), a centralized platform of high-quality cardiac proteomic data, bioinformatics tools, and relevant cardiovascular phenotypes. Currently, COPaKB features 8 organellar modules, comprising 4203 LC-MS/MS experiments from human, mouse, drosophila, and Caenorhabditis elegans, as well as expression images of 10 924 proteins in human myocardium. In addition, the Java-coded bioinformatics tools provided by COPaKB enable cardiovascular investigators in all disciplines to retrieve and analyze pertinent organellar protein properties of interest. Conclusions: COPaKB provides an innovative and interactive resource that connects research interests with the new biological discoveries in protein sciences. With an array of intuitive tools in this unified Web server, nonproteomics investigators can conveniently collaborate with proteomics specialists to dissect the molecular signatures of cardiovascular phenotypes.

  • 959.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tissue factor/FVIIA transactivates the IGF-1R in prostate cancer cells via inhibition of caveolin-12015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 707-707, article id PO552-TUEArticle in journal (Other academic)
  • 960.
    Ångström-Brännström, C.
    et al.
    Umea Univ, Dept Nursing, Umea, Sweden..
    Engvall, Gunn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Mullaney, T.
    Umea Univ, Umea Inst Design, Umea, Sweden..
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wickart-Johansson, G.
    Karolinska Univ Hosp, Dept Oncol Radiumhemmet, Stockholm, Sweden..
    Svärd, A. M.
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Nyholm, T.
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Lindh, J.
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Lindh, V.
    Umea Univ, Dept Nursing, Umea, Sweden..
    Facilitating Radiotherapy for Children: Technique, Design and Professional Care in Synergy, a Multicenter Intervention Study2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, p. S213-S213Article in journal (Refereed)
  • 961.
    Åström, Maria
    Dpt of medicine and laboratory medicine, Örebro University Hospital, Örebro, Sweden.
    Clinical cases: Presentation, diagnosis, treatment and follow-up: Case 2 - Chuvash polycythemia2015In: Congenital Erythrocytosis and Hereditary Thrombocytosis: Clinical presentation, diagnosis, treatment and follow-up. A practical guide with clinical cases. / [ed] Sylvie Hermouet, Portugal: European cooperation in science and technology , 2015Chapter in book (Other academic)
  • 962.
    Åström, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Undersökningar av X-bunden trombocytopeni med talassemi (XLTT) och jämförelser med andra former av myelofibros2010In: Oss hematologer emellan, Vol. 4, no 22, p. 39-40Article in journal (Other academic)
  • 963.
    Åström, Maria
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hahn-Strömberg, Victoria
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Zetterberg, Eva
    Departments of Medicine and Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Vedin, Inger
    Departments of Medicine and Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Merup, Mats
    Departments of Medicine and Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Palmblad, Jan
    Departments of Medicine and Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden .
    X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis2015In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 90, no 3, p. E44-E48Article in journal (Refereed)
    Abstract [en]

    X-linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β-thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild-moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis.

  • 964.
    Ölje, Elin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Metodjämförelse mellan DiffMaster Octavia och CellaVision DM1200 avseende differentialräkning av leukocyter: en viktig analys inom vården2016Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Leukocytes, white blood cells, are cells of the immune system. They are produced and derived from hematopoietic stem cells in the bone marrow. Leukocytes can be divided into neutrophils, lymphocytes, monocytes, eosinophils and basophils. To determine the numbers of leukocytes in blood the leukocyte particle concentration (B-LPK) can be analyzed by cell counters. When B-LPK is elevated or lowered a differential count of leukocytes (B-Diff) is performed to see in which cell systems the change exists. The manual analysis involves peripheral blood smears stained with a cytochemical color, May-Grünwald Giemsa. The smear examined in an automatic microscopically system that counts, photographs and pre-classify leukocytes by its appearance. DiffMaster Octavia and CellaVision DM1200 are two variants of such instruments from the same manufacturer (CellaVision AB, Lund, Sweden). The aim of the study was to do a comparison between these instruments by analyzing 60 samples consisting venous blood in EDTA-tubes. The samples were collected randomly from patients (32 men and 28 women) between 19-95 years old. The results from two-sided paired t-test showed no significant difference between the differential count of neutrophils, lymphocytes and monocytes. The correlation was 0,95, 0,91 and 0,68. However, there was a significant difference between the instruments differential count of eosinophils and basophils, the correlation was 0,91 and 0,20. When counting only 200 cells a profit of 2 % distinguish up to 1-5 %. Abnormalities in leukocytes which represents only a few percent in blood can therefore be very large. Method comparison showed that both instruments give the same results and are considered equivalent in analysis of manual B-Diff.

  • 965.
    Österroos, Albin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kashif, Muhammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Blom, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Combination screening in vitro identifies synergistically acting KP372-1 and cytarabine against acute myeloid leukemia2016In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 118, p. 40-49Article in journal (Refereed)
    Abstract [en]

    Cytogenetic lesions often alter kinase signaling in acute myeloid leukemia (AML) and the addition of kinase inhibitors to the treatment arsenal is of interest. We have screened a kinase inhibitor library and performed combination testing to find promising drug-combinations for synergistic killing of AML cells. Cytotoxicity of 160 compounds in the library InhibitorSelect (TM) 384-Well Protein Kinase Inhibitor I was measured using the fluorometric microculture cytotoxicity assay (FMCA) in three AML cell lines. The 15 most potent substances were evaluated for dose-response. The 6 most cytotoxic compounds underwent combination synergy analysis based on the FMCA readouts after either simultaneous or sequential drug addition in AML cell lines. The 4 combinations showing the highest level of synergy were evaluated in 5 primary AML samples. Synergistic calculations were performed using the combination interaction analysis package COMBIA, written in R, using the Bliss independence model. Based on obtained results, an iterative combination search was performed using the therapeutic algorithmic combinatorial screen (TACS) algorithm. Of 160 substances, cell survival was <= 50% at <0.5 mu M for Cdk/Crk inhibitor, KP372-1, synthetic fascaplysin, herbimycin A, PDGF receptor tyrosine kinase inhibitor IV and reference-drug cytarabine. KP372-1, synthetic fascaplysin or herbimycin A obtained synergy when combined with cytarabine in AML cell lines MV4-11 and HL-60. KP372-1 added 24 h before cytarabine gave similar results in patient cells. The iterative search gave further improved synergy between cytarabine and KP372-1. In conclusion, our in vitro studies suggest that combining KP372-1 and cytarabine is a potent and synergistic drug combination in AML.

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