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  • 1. Berglund, S.
    et al.
    Magalhaes, I.
    Gaballa, A.
    Vanherberghen, Bruno
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. Karolinska Institutet, Sweden.
    Advances in umbilical cord blood cell therapy: the present and the future2017In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 17, no 6, p. 691-699Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Umbilical cord blood (UCB), previously seen as medical waste, is increasingly recognized as a valuable source of cells for therapeutic use. The best-known application is in hematopoietic stem cell transplantation (HSCT), where UCB has become an increasingly important graft source in the 28 years since the first umbilical cord blood transplantation (UCBT) was performed. Recently, UCB has been increasingly investigated as a putative source for adoptive cell therapy. Areas covered: This review covers the advances in umbilical cord blood transplantation (UCBT) to overcome the limitation regarding cellular dose, immunological naivety and additional cell doses such as DLI. It also provides an overview regarding the progress in adoptive cellular therapy using UCB. Expert opinion: UCB has been established as an important source of stem cells for HSCT. Successful strategies to overcome the limitations of UCBT, such as the limited cell numbers and naivety of the cells, are being developed, including novel methods to perform in vitro expansion of progenitor cells, and to improve their homing to the bone marrow. Promising early clinical trials of adoptive therapies with UCB cells, including non-immunological cells, are currently performed for viral infections, malignant diseases and in regenerative medicine.

  • 2. Bruzelius, M.
    et al.
    Bottai, M.
    Sabater-Lleal, M.
    Strawbridge, R. J.
    Bergendal, A.
    Silveira, A.
    Sundstrom, A.
    Kieler, H.
    Hamsten, A.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska University Hospital Solna, Sweden; Karolinska Institutet, Sweden .
    Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no 2, p. 219-227Article in journal (Refereed)
    Abstract [en]

    BackgroundFamily history of venous thromboembolism (VTE) has been suggested to be more useful in risk assessment than thrombophilia testing. ObjectivesWe investigated established genetic susceptibility variants for association with VTE and evaluated a genetic risk score in isolation and combined with known trigger factors, including family history of VTE. Patients/MethodA total of 18 single nucleotide polymorphisms (SNPs) selected from the literature were genotyped in 2835 women participating in a Swedish nationwide case-control study (the ThromboEmbolism Hormone Study [TEHS]). Association with VTE was assessed by odds ratios (ORs) with 95% confidence interval (CI) using logistic regression. Clinical and genetic predictors that contributed significantly to the fit of the logistic regression model were included in the prediction models. SNP-SNP interactions were investigated and incorporated into the models if found significant. Risk scores were evaluated by calculating the area under the receiver-operating characteristics curve (AUC). ResultsSeven SNPs (F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446) with four SNP-SNP interactions contributed to the genetic risk score for VTE, with an AUC of 0.66 (95% CI, 0.64-0.68). After adding clinical risk factors, which included family history of VTE, the AUC reached 0.84 (95% CI, 0.82-0.85). The goodness of fit of the genetic and combined scores improved when significant SNP-SNP interaction terms were included. ConclusionPrediction of VTE in high-risk individuals was more accurate when a combination of clinical and genetic predictors with SNP-SNP interactions was included in a risk score.

  • 3. Bruzelius, M.
    et al.
    Iglesias, Maria Jesus
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hong, Mun-Gwan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sanchez-Rivera, Laura
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gyorgy, B.
    Souto, J. C.
    Franberg, M.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Strawbridge, R. J.
    Holmström, M.
    Hamsten, A.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Silveira, A.
    Soria, J. M.
    Smadja, D. M.
    Butler, L. M.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Morange, P. -E
    Trégouët, D. -A
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    PDGFB, a new candidate plasma biomarker for venous thromboembolism: Results from the VEREMA affinity proteomics study2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. e59-e66Article in journal (Refereed)
    Abstract [en]

    There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish ¡°Venous Thromboembolism Biomarker Study,¡± using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor β (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (p ~ 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P 5 .002). PDGF was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.

  • 4. Bruzelius, Maria
    et al.
    Strawbridge, Rona J.
    Tregouet, David-Alexandre
    Wiggins, Kerri L.
    Gertow, Karl
    Sabater-Lleal, Maria
    Ohrvik, John
    Bergendal, Annica
    Silveira, Angela
    Sundstrom, Anders
    Kieler, Helle
    Syvanen, Ann-Christine
    Smith, Nicholas L.
    Morange, Pierre-Emmanuel
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Coagulation Unit, Hematology Centre; Atherosclerosis Research Unit, Centre for Molecular Medicine Karolinska University Hospital Solna, Sweden.
    Hamsten, Anders
    Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 426-432Article in journal (Refereed)
    Abstract [en]

    Introduction: We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case-control study (n = 2753) from Sweden. Materials and Methods: 39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression. Results: Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181). Conclusions: It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.

  • 5. Eissler, N.
    et al.
    Mao, Y.
    Brodin, D.
    Reuterswärd, Philippa
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Svahn Andersson, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Johnsen, J. I.
    Kiessling, R.
    Kogner, P.
    Combination Therapy of Anti-PD-1 Antibody and CSF-1R Inhibitor Reverses Induction of Suppressive Myeloid Cells and Controls Spontaneous Neuroblastoma Progression2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, p. S28-S28Article in journal (Refereed)
  • 6. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjörn
    Nahi, Hareth
    Hermanson, Monica
    Rosenquist, Richard
    Höglund, Martin
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Gréen, Henrik
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lotfi, Kourosh
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5 '-nucleotidase2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed)
    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 2451C> T rs532545), 50-nucleotidase (cN-II 7A> G rs10883841), and deoxycytidine kinase (DCK 30UTR 948T> C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P< 0.001 and 5 vs. 23 months, P50.015, 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, P50.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML.

  • 7. Gaballa, A.
    et al.
    Norberg, A.
    Stikvoort, A.
    Mattsson, J.
    Sundberg, B.
    Uzunel, M.
    Remberger, M.
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics. Karolinska Institutet, Sverige.
    Assessment of TREC, KREC and telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for telomere homeostasis in young recipients2018In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 53, no 1, p. 69-77Article in journal (Refereed)
    Abstract [en]

    Reconstitution of the adaptive immune system following allogeneic hematopoietic stem cell transplantation is crucial for beneficial outcome and is affected by several factors, such as GvHD and graft source. The impact of these factors on immune reconstitution has been thoroughly investigated during the early phase after transplantation. However, little is known about their long-term effect. Similarly, leukocyte telomere length (TL) shortening has been reported shortly after transplantation. Nevertheless, whether TL shortening continues in long-term aspect is still unsettled. Here, we assessed T-cell receptor excision circle (TREC), kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post transplantation (median 17 years). Our analysis showed that, recipients who received bone marrow (BM) as the graft source have higher levels of both TREC and KREC. Also, chronic GvHD affected TREC levels and TL but not KREC levels. Finally, we show that recipient's TL was longer than respective donors in a group of young age recipients with high KREC levels. Our results suggest that BM can be beneficial for long-term adaptive immune recovery. We also present supporting evidence for recipient telomere homeostasis, especially in young age recipients, rather than telomere shortening.

  • 8. Ivert, Torbjorn
    et al.
    Dalen, Magnus
    Ander, Charlotte
    Stalesen, Ragnhild
    Näsman, Per
    KTH, School of Architecture and the Built Environment (ABE), Transport Science, Transport Planning, Economics and Engineering.
    Lordkipanidze, Marie
    Hjemdahl, Paul
    Platelet function one and three months after coronary bypass surgery in relation to once or twice daily dosing of acetylsalicylic acid2017In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 149, p. 64-69Article in journal (Refereed)
    Abstract [en]

    Introduction: Current guidelines recommend acetylsalicylic acid (ASA) treatment after coronary artery bypass grafting (CABG) to reduce thrombotic vein graft occlusion. The optimal dosage of ASA is not known. Materials and methods: Forty-two patients undergoing elective CABG were randomized to receive either ASA 75 mg or 160 mg once daily (OD) or 75 mg twice daily (BID) after the operation. Platelet function testing was performed before, and one and three months after the operation. Results: White blood cell counts increased during the initial postoperative days whereas platelet countswere initially slightly reduced after the operation but increased after one month without any major changes of mean platelet volumes. Serum thromboxane B-2 was more effectively suppressed at one and three months after the operation with ASA 75 mg BID or 160 mg OD than with 75 mg OD (p < 0.001). ASA 75 mg BID and 160 mg OD were equally effective. Adenosine diphosphate stimulated platelet aggregation in whole blood (Multiplate (R)) was increased one and three months after the operation, and this was counteracted by ASA 75 mg BID but not by 75 or 160 mg OD. Arachidonic acid-induced aggregation was more effectively inhibited by 75 mg BID or 160 mg OD compared to 75 mg OD at three months. Conclusions: Less effective inhibition of platelet activation was obtained with ASA 75 mg OD than with ASA 160mg OD or 75mg BID up to three months after CABG. Especially the latter dose is of interest for further studies of efficacy and clinical outcomes after CABG.

  • 9. Kremer, A. N.
    et al.
    van der Griendt, J. C.
    van der Meijden, E. D.
    Honders, M. W.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Falkenburg, J. H. F.
    Griffioen, M.
    Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation2014In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 2, p. 365-369Article in journal (Refereed)
    Abstract [en]

    It is well known that allo-reactive T cells play a crucial role in graft-versus-leukemia and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (alloSCT). Allo-reactive CD4+ T cells can mediate direct cytolysis, but may also stimulate production of IgG antibodies as helper cells. Immune complexes may subsequently be processed and presented by professional antigen presenting cells and stimulate induction of specific CD8+ T cells. As such, proteins targeted in coordinated T- and B-cell responses may represent a class of immunodominant antigens in clinical responses after alloSCT. We previously identified LB-PTK2B-1T as HLA class II restricted polymorphic antigen in a patient treated with donor lymphocyte infusion for relapsed chronic myeloid leukemia after HLA-matched alloSCT. Since PTK2B has also been described as antibody target, we here investigated whether a coordinated T- and B-cell response against PTK2B was induced. Patient serum before and after alloSCT and donor lymphocyte infusion (DLI) was screened for antibodies, and we indeed observed development of a humoral immune response against PTK2B. Antibodies against PTK2B were only found after DLI and, in contrast to the CD4+ T cells, recognized a monomorphic region of the protein. To our knowledge, this is the first description of a coordinated allo-reactive CD4+ T-cell and auto-reactive antibody response against an autosomal antigen.

  • 10. Lindberg, Eva Hellstrom
    et al.
    Almeida, Antonio
    Enoksson, Fredrik
    KTH, School of Computer Science and Communication (CSC), Media Technology and Interaction Design, MID.
    de Wit, Thom Duyvene
    Strivens, Janet
    Naeve, Ambjörn
    KTH, School of Computer Science and Communication (CSC), Media Technology and Interaction Design, MID.
    Toh, Cheng-Hock
    Survey of professional competence in hematology in Europe2014In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 3, p. 404-408Article in journal (Refereed)
  • 11. Liwing, Johan
    et al.
    Uttervall, Katarina
    Lund, Johan
    Aldrin, Anders
    Blimark, Cecilie
    Carlson, Kristina
    Enestig, Jon
    Flogegård, Max
    Forsberg, Karin
    Gruber, Astrid
    Kviele, Helene Haglöf
    Johansson, Peter
    Lauri, Birgitta
    Mellqvist, Ulf-Henrik
    Swedin, Agneta
    Svensson, Magnus
    Näsman, Per
    KTH, School of Architecture and the Built Environment (ABE), Transport Science, Transport and Location Analysis. KTH, School of Architecture and the Built Environment (ABE), Centres, Centre for Transport Studies, CTS.
    Alici, Evren
    Gahrton, Gösta
    Aschan, Johan
    Nahi, Hareth
    Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population2014In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 164, no 5, p. 684-693Article in journal (Refereed)
    Abstract [en]

    The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2.8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4.9 years) compared to conventional treatment (2.3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6.9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

  • 12. Ljungqvist, Maria
    et al.
    Holmstrom, Margareta
    Kieler, Helle
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska University Hospital, Sweden.
    Larfars, Gerd
    Cardiovascular disease and mortality after a first episode of venous thromboembolism in young and middle-aged women2016In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 138, p. 80-85Article in journal (Refereed)
    Abstract [en]

    Background: Patients with a history of venous thromboembolism (VTE) seem to have an increased risk of arterial cardiovascular disease (CVD). Objectives: To evaluate the risk of CVD and overall mortality after a first episode of VTE in women and to assess common risk factors for VTE and CVD. Patients/methods: We performed a cohort study inviting 1433 women with a previous VTE (exposed) and 1402 women without VTE (unexposed). The cohort was derived from TEHS, a Swedish population-based case-control study on risk factors for VTE in women age 18-64 years. The women were recruited in 2002-2009. During 2011 information on CVD and mortality was obtained from a questionnaire and from the Swedish Patient Register and the Cause of Death Register. Hazard ratios (HR) for CVD and their 95% confidence intervals (CI) were calculated using Cox regression. In multivariate analyses we adjusted for age, smoking, diabetes mellitus, hypertension and body mass index. Results: 2108 (75%) women (mean age 47 +/- 13 years) accepted participation. During the total follow up of 11,920 person years 35 (3.2%, 95% CI 0.7-2.1) among the exposed and 14 (1.4%, 95% CI 0.2-4.3) among the unexposed had any CVD event. The adjusted HR for CVD was 2.0 (95% CI 1.1-3.9) the adjusted HR for mortality was 2.3 (95% CI 1.2-4.6) Conclusion: Women with a previous VTE had a two-fold increased risk of CVD and overall mortality. Adjusting for cardiovascular risk factors only modestly changed the estimates.

  • 13.
    Lundin, Karin E.
    et al.
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, Novum, SE-14186 Stockholm, Sweden..
    Wang, Qing
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, Novum, SE-14186 Stockholm, Sweden..
    Hamasy, Abdulrahman
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, Novum, SE-14186 Stockholm, Sweden.;Hawler Med Univ, Coll Pharm, Dept Clin Anal, Erbil, Kurdistan Regio, Iraq..
    Marits, Per
    Karolinska Univ Hosp, Dept Clin Immunol, SE-14186 Stockholm, Sweden..
    Uzunel, Mehmet
    Karolinska Univ Hosp, Dept Clin Immunol, SE-14186 Stockholm, Sweden..
    Wirta, Valtteri
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wikstrom, Ann-Charlotte
    Karolinska Univ Hosp, Dept Clin Immunol, SE-14186 Stockholm, Sweden..
    Fasth, Anders
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, SE-41685 Gothenburg, Sweden..
    Ekwall, Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, SE-41685 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, SE-41685 Gothenburg, Sweden..
    Smith, C. I. Edvard
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, Novum, SE-14186 Stockholm, Sweden..
    Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report2018In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 18, article id 285Article in journal (Refereed)
    Abstract [en]

    Background: A novel immunodeficiency, frequently accompanied by high serum-IgE, and caused by mutations in the PGM3 gene was described in 2014. To date there are no unique phenotype characteristics for PGM3 deficiency. PGM3 encodes a carbohydrate-modifying enzyme, phosphoglucomutase 3. Null-mutations are quite likely lethal, and to date only missense mutations or small deletions have been reported. Such mutations frequently cause a combination of reduced enzyme activity and protein instability, complicating determination of the enzyme level needed for survival. Here we present the first patient with a homozygous splice-modifying mutation in the PGM3 gene. An A > G substitution at position c.871 +3 (transcript NM_001199917) is causing a deletion of exon 7 in the majority of PGM3 transcripts. In addition, this case further increases the clinical phenotypes of immunodeficiency caused by PGM3 mutations. Case presentation: We describe the symptoms of a 3-year-old girl who was severely growth retarded, had vascular malformations, extensive eczema, multiple food-allergies, and was prone to infections. Unlike the majority of reported PGM3 deficient patients she lacked skeletal dysplasia and had normal neurocognitive development. In addition to the high serum-IgE, she displayed altered T cell numbers with reduced naive CD4(+) and CD8(+) T-cells, increased number of activated effector memory CD8(+) T cells and aberrant T-cell functions. The patient was homozygous for a new hypomorphic, splice-modifying mutation in the PGM3 gene, causing severely reduced mRNA levels. In the patient's cells, we observed 5% intact mRNA and approximately 11% of the protein levels seen in healthy controls. Treatment with allogeneic hematopoietic stem cell therapy was planned, but unfortunately the clinical condition deteriorated with multi-organ failure, which led to her death at 3 years of age. Conclusions: There is still no specific phenotype identified that distinguishes immunodeficiency caused by PGM3 mutations from other forms of immunodeficiency. The patient described here yields new information on the phenotypic variability among these patients. In addition, since all the synthesized protein is wild-type, it is possible for the first time to estimate the enzyme activity in vivo. The results suggest that1/10 of the normal PGM3 level is sufficient for survival but that it is insufficient for accurate carbohydrate processing.

  • 14.
    Mardinoglu, Adil
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Boren, Jan
    AUP1 (Ancient Ubiquitous Protein 1): A Molecular Link Between Hepatic Lipid Mobilization and VLDL Secretion2017In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 37, no 4, p. 609-610Article in journal (Refereed)
  • 15. Nahi, Hareth
    et al.
    Liwing, Johan
    Uttervall, Katarina
    Andreasson, Johan
    Gruber, Astrid
    Näsman, Per
    KTH, School of Architecture and the Built Environment (ABE), Transport Science, Transport and Location Analysis.
    Aschan, Johan
    Follow-up of Real Life Treated Multiple Myeloma Patients: Response, Disease Progression and Overall Survival2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 21, p. 1683-1683Article in journal (Other academic)
  • 16. Nilsson, B
    et al.
    Andersson, A
    Johansson, Mikael
    KTH, School of Electrical Engineering (EES), Automatic Control.
    Fioretos, T
    Cross-platform classification in microarray-based leukemia diagnostics2006In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 91, no 6, p. 821-824Article in journal (Refereed)
    Abstract [en]

    Gene expression profiling is a powerful technique for classifying hematologic malignancies. Its clinical use is, however, currently hindered by the need to collect large sets of expression profiles at each diagnostic facility. To overcome this limitation, we introduced cross-platform classification, allowing classifier construction using pre-existing microarray datasets. As proof-of-principle, we performed cross-platform classification of acute myeloid leukemia and childhood acute lymphoblastic leukemia using expression data from four different facilities. We show that cross-platform classification of these disorders is achievable, and, strikingly, that the diagnostic accuracy can be retained. We conclude that cross-platform classification constitutes an effective and convenient way to implement microarray diagnostics.

  • 17.
    Radestad, Emelie
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Sundin, Mikael
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Pediat, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Hematol Immunol HSCT Sect, Stockholm, Sweden..
    Torlen, Johan
    Karolinska Univ Hosp, Cell Therapy & Allogene Stem Cell Transplantat, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Thunberg, Sara
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ljungman, Per
    Karolinska Univ Hosp, Cell Therapy & Allogene Stem Cell Transplantat, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Watz, Emma
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Mattsson, Jonas
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 189Article in journal (Refereed)
    Abstract [en]

    Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of alpha beta T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The alpha beta T-cell depleted cell products were characterized by flow cytometry. The median log depletion of alpha beta T-cells was -4.3 and the median yield of gamma delta T-cells was 73.5%. The median CD34+ cell dose was 4.4 x 10(6)/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of alpha beta T-cell depleted products as stem cell boosters with encouraging results.

  • 18. Schriefl, A. J.
    et al.
    Collins, M. J.
    Pierce, D. M.
    Holzapfel, Gerhard A.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Niklason, L. E.
    Humphrey, J. D.
    Remodeling of Intramural Thrombus and Collagen in an Ang-II Infusion ApoE-/- Model of Dissecting Aortic Aneurysms2012In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 130, no 3, p. E139-E146Article in journal (Refereed)
    Abstract [en]

    Fibrillar collagen endows the normal aortic wall with significant stiffness and strength and similarly plays important roles in many disease processes. For example, because of the marked loss of elastic fibers and functional smooth cells in aortic aneurysms, collagen plays a particularly important role in controlling the dilatation of these lesions and governing their rupture potential. Recent findings suggest further that collagen remodeling may also be fundamental to the intramural healing of arterial or aneurysmal dissections. To explore this possibility further, we identified and correlated regions of intramural thrombus and newly synthesized fibrillar collagen in a well-established mouse model of dissecting aortic aneurysms. Our findings suggest that intramural thrombus that is isolated from free-flowing blood creates a permissive environment for the synthesis of fibrillar collagen that, albeit initially less dense and organized, could protect that region of the dissected wall from subsequent expansion of the dissection or rupture. Moreover, alpha-smooth muscle actin positive cells appeared to be responsible for the newly produced collagen, which co-localized with significant production of glycosaminoglycans.

  • 19.
    Sohlberg, Ebba
    et al.
    Karolinska Inst, CIM, Stockholm, Sweden..
    Haroun-Izquierdo, Alvaro
    Ctr Infect Med, Dept Med, Huddinge, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Bjorklund, Andreas T.
    Karolinska Univ Hosp, Karolinska Inst, Sollentuna, Sweden..
    Cooley, Sarah
    Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Box 736 UMHC, Minneapolis, MN 55455 USA..
    Wiiger, Merete Thune
    Oslo Univ Hosp, Dept Canc Immunol, Oslo, Norway..
    Goodridge, Peter
    Oslo Univ Hosp, Oslo, Norway..
    Hoel, Hanna Julie
    Oslo Univ Hosp, Oslo, Norway..
    Pfefferle, Aline
    Karolinska Inst, Stockholm, Sweden..
    Chrobook, Michael
    Karolinska Inst, Dept Med Huddinge, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Kremer, Veronika
    Karolinska Inst, Ctr Infectous Med, Stockholm, Sweden..
    Hellström-Lindberg, Eva
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Ask, Eivind Heggernes
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway..
    Pontus, Blomberg
    Karolinska Univ Hosp, Vecura, Stockholm, Sweden..
    Valamehr, Bahram
    Fate Therapeut Inc, San Diego, CA USA..
    Guldevall, Karolin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    van Ooijen, Hanna
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Alici, Evren
    Karolinska Inst, Stockholm, Sweden..
    Ljunggren, Hans-Gustaf
    Karolinska Inst, CIM, Stockholm, Sweden..
    Miller, Jeffrey S.
    Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA..
    Malmberg, Karl-Johan
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway..
    Efficient Scale-up and Pre-Clinical Evaluation of NKG2C+Adaptive NK Cell Expansion for Therapy Against High-Risk AML/MDS2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal (Other academic)
  • 20. Törlén, J.
    et al.
    Gaballa, A.
    Remberger, M.
    Mörk, L. -M
    Sundberg, B.
    Mattsson, J.
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation2019In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 25, no 6, p. 1260-1268Article in journal (Refereed)
    Abstract [en]

    Lymphocyte reconstitution is pivotal for successful long-term outcome after allogeneic hematopoietic stem cell transplantation (HSCT), and conditioning regimen and post-transplantation immunosuppression are risk factors for prolonged immunodeficiency. Nevertheless, the effects of different immunosuppressive protocols on lymphocyte output and replicative capacity have not been investigated. Here we assessed T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and T cell telomere length (TL) as proxy markers for immune reconstitution in patients in a prospective randomized trial comparing graft-versus-host disease (GVHD) prophylaxis after transplantation (cyclosporine/methotrexate versus tacrolimus/sirolimus; n = 200). Results showed that medians of TREC, KREC, and TL were not significantly different between the prophylaxis groups at any assessment time point during follow-up (24 months), but the kinetics of TREC, KREC, and TL were significantly influenced by other transplantation-related factors. Older recipient age, the use of antithymocyte globulin before graft infusion, and use of peripheral blood stem cell grafts were associated with lower TREC levels, whereas acute GVHD transiently affected KREC levels. Patients with lymphocyte excision circle levels above the median at ≤6 months post-transplantation had reduced transplantation-related mortality and superior 5-year overall survival (P <.05). We noticed significant T cell telomere shortening in the patient population as a whole during follow-up. Our results suggest that lymphocyte reconstitution after transplantation is not altered by different immunosuppressive protocols. This study has been registered at ClinicalTrials.gov (identifier: NCT00993343). 

  • 21. van der Griendt, Judith C.
    et al.
    van der Meijden, Edith D.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics.
    Falkenburg, J. H. Frederik
    Griffioen, Marieke
    High Throughput Screening for Antibody Responses Against H-Y Antigens and Their X-Variants in Allogeneic Hematopoeietic Stem Cell Transplantation2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 21, p. 1749-1750Article in journal (Other academic)
  • 22.
    Vanherberghen, Bruno
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Olofsson, Per E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forslund, Elin
    Sternberg-Simon, Michal
    Khorshidi, Mohammad Ali
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Pacouret, Simon
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Guldevall, Karolin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Enqvist, Monika
    Malmberg, Karl-Johan
    Mehr, Ramit
    Önfelt, Bjorn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Classification of human natural killer cells based on migration behavior and cytotoxic response2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 8, p. 1326-1334Article in journal (Refereed)
    Abstract [en]

    Despite intense scrutiny of the molecular interactions between natural killer (NK) and target cells, few studies have been devoted to dissection of the basic functional heterogeneity in individual NK cell behavior. Using a microchip-based, time-lapse imaging approach allowing the entire contact history of each NK cell to be recorded, in the present study, we were able to quantify how the cytotoxic response varied between individual NK cells. Strikingly, approximately half of the NK cells did not kill any target cells at all, whereas a minority of NK cells was responsible for a majority of the target cell deaths. These dynamic cytotoxicity data allowed categorization of NK cells into 5 distinct classes. A small but particularly active subclass of NK cells killed several target cells in a consecutive fashion. These "serial killers" delivered their lytic hits faster and induced faster target cell death than other NK cells. Fast, necrotic target cell death was correlated with the amount of perforin released by the NK cells. Our data are consistent with a model in which a small fraction of NK cells drives tumor elimination and inflammation.

  • 23.
    Wang, T.
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Remberger, M.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat CAST, Huddinge, Sweden..
    Nygell, U. Axdorph
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Haematol, Huddinge, Sweden..
    Sundin, M.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Björklund, A.
    Karolinska Univ Hosp, Dept Haematol, Huddinge, Sweden..
    Mattsson, J.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat CAST, Huddinge, Sweden..
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.
    Watz, E.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Change of apheresis device decreased the incidence of severe acute graft-versus-host disease among patients after allogeneic stem cell transplantation with sibling donors2018In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 58, no 6, p. 1442-1451Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The composition of the graft used for allogeneic hematopoietic stem cell transplantation (HSCT) is important for the treatment outcome. Different apheresis devices may yield significant differences in peripheral blood stem cell graft cellular composition. We compared stem cell grafts produced by Cobe Spectra (Cobe) and Spectra Optia (Optia) with use of the mononuclear cell (MNC) protocol, and evaluated clinical outcome parameters such as graft-versus-host disease (GvHD), transplant-related mortality (TRM), relapse, and overall survival.

    STUDY DESIGN AND METHODS: During 5 years, 31 Cobe Spectra and 40 Spectra Optia grafts were analyzed for CD34, CD3, CD4, CD8, CD19, and CD56 cell content. Clinical outcome parameters were correlated and compared between the two patient groups using different apheresis devices.

    RESULTS: Optia grafts contained fewer lymphocytes compared to Cobe (p<0.001). Optia grafts had a significantly lower incidence of acute GvHD Grades II through IV (Cobe 45% vs. Optia 23%; p=0.039) and TRM (16% vs. 2.5%; p<0.05) but higher chronic GvHD (32% vs. 67%; p=0.005) compared to Cobe grafts. Finally, the multivariate analysis showed a significant correlation among the different apheresis devices and both acute GvHD II through IV and severe chronic GvHD. The multivariate analysis also showed a significant correlation between the CD3+ cell dose and the incidence of severe acute GvHD.

    CONCLUSION: Optia-obtained grafts yielded a lower acute GvHD Grades II-IV and TRM risk, but had no impact on relapse or overall survival in this study. Understanding and further improvement of peripheral blood stem cell (PBSC) apheresis techniques may be used in the future to personalize HSCT by, for example, fine-tuning the GvHD incidence.

  • 24. Wild, F.
    et al.
    Scott, P.
    Karjalainen, J.
    Helin, K.
    Lind-Kohvakka, S.
    Naeve, Ambjörn
    KTH, School of Computer Science and Communication (CSC), Media Technology and Interaction Design, MID.
    An augmented reality job performance aid for kinaesthetic learning in manufacturing work places2014In: Lecture Notes in Computer Science, ISSN 0302-9743, E-ISSN 1611-3349, Vol. 8719 LNCS, p. 470-475Article in journal (Refereed)
    Abstract [en]

    Manufacturing - as the name already suggests - is an area where novel ’learning by doing’ approaches can help tackle the skills gap this industry is currently facing at large. Within this contribution, we apply human-centred design methodology to help overcome two significant ’teething problems’ for augmented reality. We propose five use cases for the application of learning technology on- and off-the-job and we show how these use cases can be implemented in an augmented reality based job performance aid, which we subsequently test on a real life story board in the furniture industry.

  • 25. 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.

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