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| 3. |
- Jamali, Elham, et al.
(författare)
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The significance of surface neutrophilic MPO expression level in NETosis and NETosis-associated coagulopathies in covid-19 infected patients
- 2022
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Ingår i: Blood Cells, Molecules & Diseases. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1079-9796 .- 1096-0961. ; 96
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Inflammatory response-induced coagulopathy is a common complication associated with severe form of covid-19 infection. Evidences suggest that neutrophil extracellular traps (NETs) play a significant role in triggering the immunothrombosis in this condition. We aimed to evaluate the diagnostic value of surface neutrophilic myeloperoxidase (MPO) as NETosis biomarker for predicting the risk of covid-19-associated coagulopathies.Methods: Covid-19 infection was assessed by real-time-PCR and plasma d-dimer levels were measured by ELFA. Based on the covid-19 infection and d-dimer level outcomes, patients were categorized into four groups. Any alteration in the serum level of IL-6, H3Cit and neutrophilic surface MPO were analyzed by CLIA, ELISA, and flow cytometry, respectively.Results: H3Cit variations and different d-dimer values confirmed the association between NETosis and coagu-lopathies. Findings showed that the expression of neutrophilic MPO reduced in cases with NETosis, which was correlated with increased levels of H3Cit. ANC/MPO ratio was signified as a valuable marker to discriminate the covid-19 and non covid-19-associated coagulopathies and could be considered as a prognostic factor due to its noteworthy correlation with serum IL-6 concentration.Conclusion: Declined levels of surface neutrophilic MPO in NETosis correlate with covid-19-associated coagu-lopathies and increased IL-6 levels, as a potential biomarker of covid-19 disease severity.
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| 5. |
- Lorenz, Fryderyk, et al.
(författare)
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Ferritinemia and serum inflammatory cytokines in Swedish adults with Gaucher disease type 1
- 2018
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Ingår i: Blood Cells, Molecules & Diseases. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1079-9796 .- 1096-0961. ; 68, s. 35-42
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Tidskriftsartikel (refereegranskat)abstract
- Background: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. Patients and methods: The study included 16 adults with GD1 aged 20-86 years. All but one patient carried at least one allele with the c.1226A > G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. Results: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-alpha was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-alpha concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1 beta, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-alpha level however, normalized in all treated patients, reaching the lowest values after 2 years of therapy and continued to be stable during the remaining 2 years of follow-up. Conclusions: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-alpha concentration in GD1.
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| 6. |
- Machaczka, Maciej, et al.
(författare)
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Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients
- 2018
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Ingår i: Blood Cells, Molecules & Diseases. - San Diego : Academic Press. - 1079-9796 .- 1096-0961. ; 68:S1, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1.METHODS: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken.RESULTS: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations.CONCLUSIONS: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD.
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| 7. |
- Matsson, H, et al.
(författare)
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Erythropoiesis in the Rps19 disrupted mouse: Analysis of erythropoietin response and biochemical markers for Diamond-Blackfan anemia.
- 2006
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Ingår i: Blood Cells Mol Dis. - : Elsevier BV. ; 36:2, s. 259-264
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Tidskriftsartikel (refereegranskat)abstract
- The human ribosomal protein S19 gene (RPS19) is mutated in approximately 20% of patients with Diamond-Blackfan anemia (DBA), a congenital disease with a specific defect in erythropoiesis. The clinical expression of DBA is highly variable, and subclinical phenotypes may be revealed by elevated erythrocyte deaminase (eADA) activity only. In mice, complete loss of Rps19 results in early embryonic lethality whereas Rps19+/− mice are viable and without major abnormalities including the hematopoietic system. We have performed a detailed analysis of the Rps19+/− mice. We estimated the Rps19 levels in hematopoietic tissues and we analyzed erythrocyte deaminase activity and globin isoforms which are used as markers for DBA. The effect of a disrupted Rps19 allele on a different genetic background was investigated as well as the response to erythropoietin (EPO). From our results, we argue that the loss of one Rps19 allele in mice is fully compensated for at the transcriptional level with preservation of erythropoiesis.
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| 9. |
- Niebuhr, Birte, et al.
(författare)
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Gatekeeper function of the RUNX1 transcription factor in acute leukemia
- 2008
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Ingår i: Blood Cells, Molecules & Diseases. - : Elsevier BV. - 1096-0961 .- 1079-9796. ; 40:2, s. 211-218
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Tidskriftsartikel (refereegranskat)abstract
- The RUNX1 gene encodes the alpha subunit of the core binding factor (CBF) and is a common target of genetic mutations in acute leukemia. We propose that RUNX1 is a gatekeeper gene, the disruption of which leads to the exodus of a subset of hematopoietic progenitors with increased self-renewal potential from the normal environmental controls of homeostasis. This pool of "escaped" cells is the target of secondary mutations, accumulating over time to induce the aggressive manifestation of acute leukemia. Evidence from patient and animal studies supports the concept that RUNX1 Mutations are the initiating event in different leukemia subtypes, but also suggests that diverse mechanisms are used to subvert RUNX1 function. One common result is the inhibition of differentiation-but its effect impinges on different lineages and stages of differentiation, depending on the mutation or fusion partner. A number of different approaches have led to the identification of secondary events that lead to the overt acute phase; however, the majority is unknown. Finally, the concept of the "leukemia stern cell" and its therapeutic importance is discussed in light of the RUNX1 gatekeeper function.
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| 11. |
- Schuster, Jens, et al.
(författare)
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Ribosomal protein S19 binds to its own mRNA with reduced affinity in Diamond-Blackfan anemia
- 2010
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Ingår i: Blood Cells, Molecules & Diseases. - : Elsevier. - 1079-9796 .- 1096-0961. ; 45:1, s. 23-28
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Tidskriftsartikel (refereegranskat)abstract
- Heterozygous mutations in the ribosomal protein S19 (RPS19) gene are associated with Diamond-Blackfan anemia (DBA). The mechanism by which RPS19 mediates anemia are still unclear, as well as the regulation of RPS19 expression. We show herein that RPS19 binds specifically to the 5' untranslated region of its own mRNA with an equilibrium binding constant (K(D)) of 4.1+/-1.9 nM. We investigated the mRNA binding properties of two mutant RPS19 proteins (W52R and R62W) identified in DBA patients. We observed a significant increase in K(D) for both proteins (16.1+/-2.1 and 14.5+/-4.9 nM, respectively), indicating a reduced RNA binding capability (p<0.05). We suggest that the binding of RPS19 to its mRNA has a regulatory function and hypothesize that the weaker RNA binding of mutant rRPS19 may have implications for the pathophysiological mechanisms in DBA.
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| 13. |
- Tricoci, Pierluigi, et al.
(författare)
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Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome : Analysis from the TRACER trial
- 2018
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Ingår i: Blood Cells, Molecules & Diseases. - : Elsevier BV. - 1079-9796 .- 1096-0961. ; 72, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P= 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is similar to 65%.
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| 14. |
- Vikberg, Ann-Louise, 1979-, et al.
(författare)
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Differential tissue specific expression of Kif23 alternative transcripts in mice with the human mutation causing congenital dyserythropoietic anemia type III
- 2020
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Ingår i: Blood Cells, Molecules & Diseases. - : Elsevier. - 1079-9796 .- 1096-0961. ; 85
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Tidskriftsartikel (refereegranskat)abstract
- Kinesin Family Member 23 (KIF23), a cell cycle regulator, has a key task in cytokinesis. KIF23 over-expression in cancer has been associated with tumor growth, progression, and poor prognosis, indicating a potential to be a cancer biomarker. A mutation in KIF23 (c.2747C > G, p.P916R) was shown to cause congenital dyserythropoietic anemia, type III (CDA III). To-date, fifteen KIF23 transcripts have been annotated, but their expression is poorly investigated. We hypothesized that tissue specific expression of a particular transcript can be critical for CDA III phenotype. In this study, we quantified expression of alternative Kif23 transcripts in a mouse model with human KIF23 mutation and investigated its association with a regulator of alternative splicing, serine/arginine-rich splicing factor 3 (Srsf3). We confirmed presence of an additional exon 8 in both human and mouse KIF23 transcripts. A transcript lacking exons 17 and 18 was ubiquitously expressed in mice while other isoforms were common in human tissues however in bone marrow of knock-in mice a transcript without exon 18 was prevalent as it was in bone marrow of a CDA III patient. We conclude that the possibility that the tissue specific expression of KIF23 alternative transcripts influence the CDA III phenotype cannot be neglected.
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| 15. |
- Fischer, Kathelijn, et al.
(författare)
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Primary prophylaxis in haemophilia care : Guideline update 2016
- 2017
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Ingår i: Blood Cells, Molecules, and Diseases. - : Elsevier BV. - 1079-9796. ; 67, s. 81-85
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Tidskriftsartikel (refereegranskat)abstract
- This paper reviews the current status on recommendations or guidelines for primary prophylaxis based on recent published papers from organizations or group of experts as well as some original key papers. A rather uniform view exists that prophylaxis should be initiated at an early age before or after no more than a single joint bleed and, if possible, preferably be continued for life. The dose and dose frequency of prophylaxis is dependent on the goal of treatment, bleeding phenotype, compliance, venous access and economic resources in the health care system and should be tailored individually based on clinical outcome and pharmacokinetics. For children, the effectiveness of prophylaxis is more dependent on maintaining minimum trough levels than in adults. Novel extended half-life products are being introduced, which should not affect the decision on when to start prophylaxis nor the initial dose, but which may be helpful for patients with difficult venous access and which may enable higher trough levels of factor VIII.
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| 18. |
- Lin, Xiao Ping, et al.
(författare)
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Human small intestinal epithelial cells constitutively express the key elements for antigen processing and the production of exosomes.
- 2005
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Ingår i: Blood cells, molecules & diseases. - : Elsevier BV. - 1079-9796. ; 35:2, s. 122-8
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Tidskriftsartikel (refereegranskat)abstract
- In humans, the small intestinal epithelial cells (IEC) have a high constitutive expression of MHC class II (MHC II), and contains lysosomes. The IEC also contains MHC II rich multivesicular compartments and has been shown to produce exosomes. This suggests a role for the IEC in antigen processing and presentation either directly or indirectly by the production of exosomes. However, the presence and localisation in the IEC of other key molecules involved in this process has not been studied previously. In the present work, we have investigated small intestinal biopsies from healthy adults and the HT29 IEC cell line with monoclonal antibodies against molecules involved in the antigen processing/presenting systems and molecules typically found on exosomes derived from professional APCs and IECs. Immunohistology was performed to study the expression and localisation of MHC II (HLA-DR), HLA-DM, MHC I (HLA-ABC), CD1d, Invariant chain, Lamp-1, CD68, CD63, B7.1, B7.2, ICAM-1, Cathepsin D/S/L and the IEC specific marker A33 in the IECs. We found that the IECs from the biopsies constitutively express MHC II, HLA-DM, MHC I, Invariant chain, Lamp-1, CD 68, CD63 and A33, and these markers were also found in the IFN-g treated HT-29 cells. All these molecules were found apically in the IECs of the biopsies, localised mainly in vesicular structures. Interestingly, in the baso-latereral area of the IEC, only MHC II, MHC I, Lamp 1, CD68, CD63 and A33 were found and also here with vesicular staining pattern which matches the molecules previously found on exosomes derived professional APCs and human IEC lines. CD1d, B7, ICAM-1, CD9 and cathepsin D and L were absent in the IEC compartment, but cathepsin S showed a relatively weak staining in the apical part of the IEC. The staining pattern and the morphological localisation of these markers suggest a prominent antigen processing/loading and trafficking compartment, and a possible baso-lateral release of exosomes in the normal human IEC.
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| 19. |
- Roos, Dirk, et al.
(författare)
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Hematologically important mutations : The autosomal forms of chronic granulomatous disease (third update)
- 2021
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Ingår i: Blood Cells, Molecules, and Diseases. - : Elsevier BV. - 1079-9796. ; 92
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Tidskriftsartikel (refereegranskat)abstract
- Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22phox, NCF1, encoding p47phox, NCF2, encoding p67phox and NCF4, encoding p40phox. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b558 chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91phox (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.
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