| 1. |
- Abrahamsson, Anna, et al.
(författare)
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Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study.
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 124:8, s. 1288-1295
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Tidskriftsartikel (refereegranskat)abstract
- There is consensus that young patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens, but optimal treatment of elderly patients as well for as patients with limited or indolent disease is not defined. Our aim was to evaluate and compare outcome in relation to prognostic factors and first-line treatment in patients with MCL in a population-based data set. Data were collected from the Swedish and Danish Lymphoma Registries from the period of 2000-2011. A total of 1389 patients were diagnosed with MCL. During this period, age-standardized incidence MCL increased, most prominently among males. Furthermore, male gender was associated with inferior overall survival (OS) in multivariate analysis (HR 1.36; p=0.002). Forty-three (3.6%) patients with stage I-II disease received radiotherapy with curative intent, showing a 3 year OS of 93%. Twenty-nine (2.4%) patients followed a watch-and-wait approach and showed a 3 year OS of 79.8%. Among patients receiving systemic treatment, rituximab (n=766; HR 0.66; p=0.001) and autologous stem cell transplant (ASCT) (n=273; HR 0.55; p=0.004) were independently associated with improved overall survival in multivariate analysis. Hence, by a population-based approach, we were able to provide novel data on prognostic factors and primary treatment of MCL, applicable to routine clinical practice.
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| 2. |
- Agar, Cetin, et al.
(författare)
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beta(2)-Glycoprotein I: a novel component of innate immunity
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 117:25, s. 6939-6947
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis is a systemic host response to invasive infection by bacteria. Despite treatment with antibiotics, current mortality rates are in the range of 20%-25%, which makes sepsis the most important cause of death in intensive care. Gram-negative bacteria are a prominent cause of sepsis. Lipopolysaccharide (LPS), one of the major constituents of the outer membrane of Gram-negative bacteria, plays a major role in activating the host's immune response by binding to monocytes and other cells. Several proteins are involved in neutralization and clearance of LPS from the bloodstream. Here, we provide evidence that beta(2)-glycoprotein I (beta(2)GPI) is a scavenger of LPS. In vitro, beta(2)GPI inhibited LPS-induced expression of tissue factor and IL-6 from monocytes and endothelial cells. Binding of beta(2)GPI to LPS caused a conformational change in beta(2)GPI that led to binding of the beta(2)GPI-LPS complex to monocytes and ultimately clearance of this complex. Furthermore, plasma levels of beta(2)GPI were inversely correlated with temperature rise and the response of inflammatory markers after a bolus injection of LPS in healthy individuals. Together, these observations provide evidence that beta(2)GPI is involved in the neutralization and clearance of LPS and identify beta(2)GPI as a component of innate immunity. (Blood. 2011;117(25):6939-6947)
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| 3. |
- Agar, Cetin, et al.
(författare)
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beta(2)-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 116:8, s. 1336-1343
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Tidskriftsartikel (refereegranskat)abstract
- The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that beta(2)-glycoprotein I (beta(2)GPI) is the major antigen for antiphospholipid antibodies. The autoantibodies recognize beta(2)GPI when bound to anionic surfaces and not in solution. We showed that beta(2)GPI can exist in at least 2 different conformations: a circular plasma conformation and an "activated" open conformation. We also showed that the closed, circular conformation is maintained by interaction between the first and fifth domain of beta(2)GPI. By changing pH and salt concentration, we were able to convert the conformation of beta(2)GPI from the closed to the open conformation and back. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables patient antibodies to bind and form an antibody-beta(2)GPI complex. We also demonstrate that the open conformation of beta(2)GPI prolonged the activated partial thromboplastin time when added to normal plasma, whereas the activated partial thromboplastin time is further prolonged by addition of anti-beta(2)GPI antibodies. The conformational change of beta(2)GPI, and the influence of the autoantibodies may have important consequences for our understanding of the antiphospholipid syndrome. (Blood. 2010; 116(8): 1336-1343)
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| 6. |
- Agathangelidis, Andreas, et al.
(författare)
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Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia : a molecular classification with implications for targeted therapies
- 2012
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:19, s. 4467-4475
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Tidskriftsartikel (refereegranskat)abstract
- Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1: 2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.
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| 7. |
- Aguilo, Francesca, et al.
(författare)
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Prdm16 is a physiologic regulator of hematopoietic stem cells.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 117:19
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Tidskriftsartikel (refereegranskat)abstract
- Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.
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| 8. |
- Ahnström, Josefin, et al.
(författare)
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Activated protein C cofactor function of protein S: a novel role for a gamma-carboxyglutamic acid residue
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 117:24, s. 6685-6693
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Tidskriftsartikel (refereegranskat)abstract
- Protein S has an important anticoagulant function by acting as a cofactor for activated protein C (APC). We recently reported that the EGF1 domain residue Asp95 is critical for APC cofactor function. In the present study, we examined whether additional interaction sites within the Gla domain of protein S might contribute to its APC cofactor function. We examined 4 residues, composing the previously reported "Face1" (N33S/P35T/E36A/Y39V) variant, as single point substitutions. Of these protein S variants, protein S E36A was found to be almost completely inactive using calibrated automated thrombography. In factor Va inactivation assays, protein S E36A had 89% reduced cofactor activity compared with wild-type protein S and was almost completely inactive in factor VIIIa inactivation; phospholipid binding was, however, normal. Glu36 lies outside the omega-loop that mediates Ca2+-dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is gamma-carboxylated. Our finding that Gla36 is important for APC cofactor function, but not for phospholipid binding, defines a novel function (other than Ca2+ coordination/phospholipid binding) for a Gla residue in vitamin K-dependent proteins. It also suggests that residues within the Gla and EGF1 domains of protein S act cooperatively for its APC cofactor function. (Blood. 2011;117(24):6685-6693)
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