| 1. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 2. |
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| 3. |
- Bernatsky, Sasha, et al.
(författare)
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Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma
- 2017
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE.
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| 4. |
- Chernysheva, Ekaterina, et al.
(författare)
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Band alignment at Ag/ZnO(0001) interfaces : A combined soft and hard x-ray photoemission study
- 2018
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Ingår i: Physical Review B. - : AMER PHYSICAL SOC. - 2469-9950 .- 2469-9969. ; 97:23
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Tidskriftsartikel (refereegranskat)abstract
- Band alignment at the interface between evaporated silver films and Zn- or O-terminated polar orientations of ZnO is explored by combining soft and hard x-ray photoemissions on native and hydrogenated surfaces. Ultraviolet photoemission spectroscopy (UPS) is used to track variations of work function, band bending, ionization energy, and Schottky barrier during silver deposition. The absolute values of band bending and the bulk position of the Fermi level are determined on continuous silver films by hard x-ray photoemission spectroscopy (HAXPES) through a dedicated modeling of core levels. Hydrogenation leads to the formation of similar to 0.3 monolayer of donorlike hydroxyl groups on both ZnO-O and ZnO-Zn surfaces and to the release of metallic zinc on ZnO-Zn. However, no transition to an accumulation layer is observed. On bare surfaces, silver adsorption is cationic on ZnO(000 (1) over bar)-O [anionic on ZnO(0001)-Zn] at the earliest stages of growth as expected from polarity healing before adsorbing as a neutral species. UPS and HAXPES data appear quite consistent. The two surfaces undergo rather similar band bendings for all types of preparation. The downward band bending of V-bb,(ZnO-O) = -0.4 eV and V-bb,(ZnO-Zn) = -0.6 eV found for the bare surfaces is reinforced upon hydrogenation (V-bb,(ZnO-O+H) = -1.1 eV, V-bb,(ZnO-Zn+H) = -1.2 eV). At the interface with Ag, a unique value of band bending of -0.75 eV is observed. While exposure to atomic hydrogen modulates strongly the energetic positions of the surface levels, a similar Schottky barrier of 0.5-0.7 eV is found for thick silver films on the two surfaces.
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| 5. |
- Machiela, Mitchell J., et al.
(författare)
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Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:8, s. 1663-1676
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Tidskriftsartikel (refereegranskat)abstract
- Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
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| 6. |
- Adjuik, Martin A., et al.
(författare)
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The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data
- 2015
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
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| 8. |
- Jardin, Fabrice, et al.
(författare)
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Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.
- 2016
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 91:9, s. 923-30
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Tidskriftsartikel (refereegranskat)abstract
- Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.
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| 9. |
- Jung, Christian, et al.
(författare)
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A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
- 2019
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Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
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| 10. |
- Marzoli, Andrea, et al.
(författare)
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The Central Atlantic Magmatic Province (CAMP) in Morocco
- 2019
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Ingår i: Journal of Petrology. - : Oxford University Press (OUP). - 0022-3530 .- 1460-2415. ; 60:5, s. 945-996
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Tidskriftsartikel (refereegranskat)abstract
- The Central Atlantic Magmatic Province (CAMP) is a large igneous province (LIP) composed of basic dykes, sills, layered intrusions and lava flows emplaced before Pangea break-up and currently distributed on the four continents surrounding the Atlantic Ocean. One of the oldest, best preserved and most complete sub-provinces of the CAMP is located in Morocco. Geochemical, geochronologic, petrographic and magnetostratigraphic data obtained in previous studies allowed identification of four strato-chemical magmatic units, i.e. the Lower, Intermediate, Upper and Recurrent units. For this study, we completed a detailed sampling of the CAMP in Morocco, from the Anti Atlas in the south to the Meseta in the north. We provide a complete mineralogical, petrologic (major and trace elements on whole-rocks and minerals), geochronologic (40Ar/39Ar and U–Pb ages) and geochemical set of data (including Sr–Nd–Pb–Os isotope systematics) for basaltic and basaltic–andesitic lava flow piles and for their presumed feeder dykes and sills. Combined with field observations, these data suggest a very rapid (<0·3 Ma) emplacement of over 95% of the preserved magmatic rocks. In particular, new and previously published data for the Lower to Upper unit samples yielded indistinguishable 40Ar/39Ar (mean age = 201·2 ± 0·8 Ma) and U–Pb ages (201·57 ± 0·04 Ma), suggesting emplacement coincident with the main phase of the end-Triassic biotic turnover (c.201·5 to 201·3 Ma). Eruptions are suggested to have been pulsed with rates in excess of 10 km3/year during five main volcanic pulses, each pulse possibly lasting only a few centuries. Such high eruption rates reinforce the likelihood that CAMP magmatism triggered the end-Triassic climate change and mass extinction. Only the Recurrent unit may have been younger but by no more than 1 Ma. Whole-rock and mineral geochemistry constrain the petrogenesis of the CAMP basalts. The Moroccan magmas evolved in mid-crustal reservoirs (7–20 km deep) where most of the differentiation occurred. However, a previous stage of crystallization probably occurred at even greater depths. The four units cannot be linked by closed-system fractional crystallization processes, but require distinct parental magmas and/or distinct crustal assimilation processes. EC-AFC modeling shows that limited crustal assimilation (maximum c.5–8% assimilation of e.g. Eburnean or Pan-African granites) could explain some, but not all the observed geochemical variations. Intermediate unit magmas are apparently the most contaminated and may have been derived from parental magmas similar to the Upper basalts (as attested by indistinguishable trace element contents in the augites analysed for these units). Chemical differences between Central High Atlas and Middle Atlas samples in the Intermediate unit could be explained by distinct crustal contaminants (lower crustal rocks or Pan-African granites for the former and Eburnean granites for the latter). The CAMP units in Morocco are likely derived from 5–10% melting of enriched peridotite sources. The differences observed in REE ratios for the four units are attributed to variations in both source mineralogy and melting degree. In particular, the Lower basalts require a garnet peridotite source, while the Upper basalts were probably formed from a shallower melting region straddling the garnet–spinel transition. Recurrent basalts instead are relatively shallow-level melts generated mainly from spinel peridotites. Sr–Nd–Pb–Os isotopic ratios in the CAMP units from Morocco are similar to those of other CAMP sub-provinces and suggest a significant enrichment of the mantle-source regions by subducted crustal components. The enriched signature is attributed to involvement of about 5–10% recycled crustal materials introduced into an ambient depleted or PREMA-type mantle, while involvement of mantle-plume components like those sampled by present-day Central Atlantic Ocean Island Basalts (OIB, e.g. Cape Verde and Canary Islands) is not supported by the observed compositions. Only Recurrent basalts may possibly reflect a Central Atlantic plume-like signature similar to the Common or FOZO components.
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