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- Au, A. E., et al.
(författare)
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Altered B-lymphopoiesis in mice with deregulated thrombopoietin signaling
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Thrombopoietin (TPO) is the master cytokine regulator of megakaryopoiesis. In addition to regulation of megakaryocyte and platelet number, TPO is important for maintaining proper hematopoietic stem cell (HSC) function. It was previously shown that a number of lymphoid genes were upregulated in HSCs from Tpo(-/-)mice. We investigated if absent or enhanced TPO signaling would influence normal B-lymphopoiesis. Absent TPO signaling in Mpl(-/-)mice led to enrichment of a common lymphoid progenitor (CLP) signature in multipotential lineage-negative Sca-1(+)c-Kit(+) (LSK) cells and an increase in CLP formation. Moreover, Mpl(-/-)mice exhibited increased numbers of PreB2 and immature B-cells in bone marrow and spleen, with an increased proportion of B-lymphoid cells in the G1 phase of the cell cycle. Conversely, elevated TPO signaling in Tpo(Tg) mice was associated with reduced B-lymphopoiesis. Although at steady state, peripheral blood lymphocyte counts were normal in both models, Mpl(-/-)E mu-myc mice showed an enhanced preneoplastic phase with increased numbers of splenic PreB2 and immature B-cells, a reduced quiescent fraction, and augmented blood lymphocyte counts. Thus, although Mpl is not expressed on lymphoid cells, TPO signaling may indirectly influence B-lymphopoiesis and the preneoplastic state in Myc-driven B-cell lymphomagenesis by lineage priming in multipotential progenitor cells.
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- Au, A. E., et al.
(författare)
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Proinflammatory microenvironment promotes lymphoma progression in mice with high megakaryocyte and TPO levels
- 2023
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:8, s. 1560-1571
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Tidskriftsartikel (refereegranskat)abstract
- Platelets have been shown to enhance the survival of lymphoma cell lines, but it is unclear if they play a role in lymphoma. Here we investigate a potential role for platelets and/or megakaryocytes in Eµ-myc lymphoma progression. Eµ-myc tumour cells were transplanted into recipient wild-type control mice, Mpl-/-, or TpoTg mice, which exhibit normal, low and high platelet and megakaryocyte counts, respectively. Transplanted TpoTg mice exhibited enhanced lymphoma progression with increased WBC counts, spleen and lymph node weights and enhanced liver infiltration when compared to wild-type. Conversely, tumour bearing Mpl-/- mice presented with reduced WBC counts, lymph node weights and less liver infiltration when compared to wild-type. Utilizing a Mpl-deficient thrombocytopenic immunocompromised mouse model, our results were confirmed with the human NHL GRANTA cell line. While we found that platelets and platelet released molecules supported Eµ-myc tumour cell survival in vitro, pharmacological inhibition of platelet function or anticoagulation in Eµ-myc transplanted wild-type mice did not improve disease outcome. Furthermore, transient platelet depletion or sustained Bcl-xL dependent thrombocytopenia did not alter lymphoma progression. Cytokine analysis of the bone marrow fluid microenvironment revealed increased levels of the proinflammatory molecule interleukin (IL)-1 in TpoTg mice, whereas levels were lowered in Mpl-/- mice. Moreover, RNA sequencing of blood-resident Eµ-myclymphoma cells from TpoTgand wild-type mice after tumour transplant revealed upregulation of hallmark gene sets associated with inflammatory response in TpoTg mice. We propose that a pro-inflammatory microenvironment in TpoTgmice promoted lymphoma progression.
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- Laabei, M., et al.
(författare)
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Predicting the virulence of MRSA from its genome sequence
- 2014
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 24:5, s. 839-849
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Tidskriftsartikel (refereegranskat)abstract
- Microbial virulence is a complex and often multifactorial phenotype, intricately linked to a pathogen's evolutionary trajectory. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major virulence factors of many bacterial pathogens, including Staphylococcus aureus. Here, we assayed the toxicity and adhesiveness of 90 MRSA (methicillin resistant S. aureus) isolates and found that while there was remarkably little variation in adhesion, toxicity varied by over an order of magnitude between isolates, suggesting different evolutionary selection pressures acting on these two traits. We performed a genome-wide association study (GWAS) and identified a large number of loci, as well as a putative network of epistatically interacting loci, that significantly associated with toxicity. Despite this apparent complexity in toxicity regulation, a predictive model based on a set of significant single nucleotide polymorphisms (SNPs) and insertion and deletions events (indels) showed a high degree of accuracy in predicting an isolate's toxicity solely from the genetic signature at these sites. Our results thus highlight the potential of using sequence data to determine clinically relevant parameters and have further implications for understanding the microbial virulence of this opportunistic pathogen.
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- Navarro, C. M., et al.
(författare)
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Treatment of humerus fractures in the elderly: A systematic review covering effectiveness, safety, economic aspects and evolution of practice
- 2018
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The objective of this Health Technology Assessment was to evaluate effectiveness, complications and cost-effectiveness of surgical or non-surgical treatment for proximal, diaphyseal or distal fractures of the humerus in elderly patients. Secondary objectives were to evaluate the intervention costs per treatment of proximal humerus fractures (PHF) and to investigate treatment traditions of PHF in Sweden. The assessment contains a systematic review of clinical and health economic studies comparing treatment options for humerus fractures in elderly patients. The results regarding the effectiveness of treatments are summarized in meta-analyses. The assessment also includes a cost analysis for treatment options and an analysis of registry data of PHF. For hemiarthroplasty (HA) and non-operative treatment, there was no clinically important difference for moderately displaced PHF at one-year follow-up regarding patient rated outcomes, (standardized mean difference [SMD]) -0.17 (95% CI: -0.56; 0.23). The intervention cost for HA was at least USD 5500 higher than non-surgical treatment. The trend in Sweden is that surgical treatment of PHF is increasing. When functional outcome of percutaneous fixation/plate fixation/prosthesis surgery and non-surgical treatment was compared for PHF there were no clinically relevant differences, SMD -0.05 (95% CI: -0.26; 0.15). There was not enough data for interpretation of quality of life or complications. Evidence was scarce regarding comparisons of different surgical options for humerus fracture treatment. The cost of plate fixation of a PHF was at least USD 3900 higher than non-surgical treatment, costs for complications excluded. In Sweden the incidence of plate fixation of PHF increased between 2005 and 2011. There is moderate/low certainty of evidence that surgical treatment of moderately displaced PHF in elderly patients has not been proven to be superior to less costly non-surgical treatment options. Further research of humerus fractures is likely to have an important impact.
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- Navarro, C. M., et al.
(författare)
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Treatment of radius or ulna fractures in the elderly: A systematic review covering effectiveness, safety, economic aspects and current practice
- 2019
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Background The objective of the present study was to evaluate effectiveness, complications and cost-effectiveness of any surgical or non-surgical treatment for radius or ulna fractures in elderly patients. Secondary objectives were to analyze present treatment traditions of distal radius fractures (DRF) in Sweden and to calculate resource usage for its treatment. The assessment contains a systematic review of clinical and health economic studies comparing treatment options for radius or ulna fractures. The results regarding the effectiveness of the treatments are summarized in meta-analyses. In addition, the assessment contains a cost analysis for different treatment options commonly used for DRF care, and an analysis of registry data on the incidence and treatment of DRF. In total 31 randomized controlled trials were included in meta-analyses. When comparing functional outcome for plate fixation versus non-surgical treatment for DRF, there were no clinically important differences at one-year follow-up (mean difference [MD], -3.29, 95% CI, -7.03; 0.44). Similar results were found when comparing plating and percutaneous methods with respect to functional outcome (standardized mean difference [SMD], -0.07, 95% CI, -0.21; 0.07) and grip strength (MD, -3.47, 95% CI, -11.21; 4.28). There were no differences for minor complications, (risk difference [RD], -0.01, 95% CI, -0.07; 0.05) whereas major complications were less common for the percutaneous group, (RD, 0.02, 95% CI, 0.02; 0.03). Given the low number of studies, the evidence above was rated as moderate certainty. The cost for plate fixation versus plaster cast was estimated to 1698 compared to 137 US dollars. For DRF, plate fixation increased in Sweden between 2005 and 2013, and was the most common surgical method in 2013. Surgical treatment of moderately displaced distal radius fractures in elderly patients offers no clear benefit compared to non-surgical treatment. Plating procedures have become more common during the second millennium and involve higher costs and higher risk of major complications than percutaneous options. BASZADEGAN H, 1990, ACTA ORTHOPAEDICA SCANDINAVICA, V61, P528
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- Abu-Elyazeed, R R, et al.
(författare)
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Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age : results from a randomised, controlled, double-blind trial
- 2013
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 31:51, s. 6136-6143
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed.METHODS: Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix™; HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus.RESULTS: No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants.CONCLUSION: The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus.
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