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- van der Lee, S. J., et al.
(författare)
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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
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Tidskriftsartikel (refereegranskat)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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- 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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- Corstanje, A., et al.
(författare)
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The shape of the radio wavefront of extensive air showers as measured with LOFAR
- 2015
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 61, s. 22-31
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Tidskriftsartikel (refereegranskat)abstract
- Extensive air showers, induced by high energy cosmic rays impinging on the Earth’s atmosphere, produce radio emission that is measured with the LOFAR radio telescope. As the emission comes from a finite distance of a few kilometers, the incident wavefront is non-planar. A spherical, conical or hyperbolic shape of the wavefront has been proposed, but measurements of individual air showers have been inconclusive so far. For a selected high-quality sample of 161 measured extensive air showers, we have reconstructed the wavefront by measuring pulse arrival times to sub-nanosecond precision in 200 to 350 individual antennas. For each measured air shower, we have fitted a conical, spherical, and hyperboloid shape to the arrival times. The fit quality and a likelihood analysis show that a hyperboloid is the best parameterization. Using a non-planar wavefront shape gives an improved angular resolution, when reconstructing the shower arrival direction. Furthermore, a dependence of the wavefront shape on the shower geometry can be seen. This suggests that it will be possible to use a wavefront shape analysis to get an additional handle on the atmospheric depth of the shower maximum, which is sensitive to the mass of the primary particle.
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- Nelles, A., et al.
(författare)
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Measuring a Cherenkov ring in the radio emission from air showers at 110-190 MHz with LOFAR
- 2015
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 65, s. 11-21
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Tidskriftsartikel (refereegranskat)abstract
- Measuring radio emission from air showers offers a novel way to determine properties of the primary cosmic rays such as their mass and energy. Theory predicts that relativistic time compression effects lead to a ring of amplified emission which starts to dominate the emission pattern for frequencies above ∼100∼100 MHz. In this article we present the first detailed measurements of this structure. Ring structures in the radio emission of air showers are measured with the LOFAR radio telescope in the frequency range of 110–190 MHz. These data are well described by CoREAS simulations. They clearly confirm the importance of including the index of refraction of air as a function of height. Furthermore, the presence of the Cherenkov ring offers the possibility for a geometrical measurement of the depth of shower maximum, which in turn depends on the mass of the primary particle.
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- de Miranda, Noel F. C. C., et al.
(författare)
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Transforming Growth Factor beta Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2
- 2015
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 148:7, s. 1427-1437.e8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor beta receptor II (TGFBR2). TGF beta signaling therefore is believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGF beta. We investigated how TGF beta signaling might continue in MSI-H CRC cells. METHODS: We sequenced the 10-adenines microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGF beta signaling was detected by SMAD2 phosphorylation and through use of a TGF beta-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells, which do not respond to TGF beta, and their activities were measured. RESULTS: SMAD2 was phosphorylated in most MSI-H CRC tissues (strong detection in 44% and weak detection in 34% of MSI-H tumors). Phosphorylation of SMAD2 in MSI-H cells required TGFBR2-even the form encoding a frameshift mutation. Transcription and translation of TGFBR2 with a 1-nucleotide deletion at its microsatellite sequence still produced a full-length TGFBR2 protein. However, protein expression required preservation of the TGFBR2 microsatellite sequence; cells in which this sequence was replaced with a synonymous nonmicrosatellite sequence did not produce functional TGFBR2 protein. CONCLUSION: TGF beta signaling remains active in some MSI-H CRC cells despite the presence of frameshift mutations in the TGFBR2 gene because the mutated gene still expresses a functional protein. Strategies to reactivate TGF beta signaling in colorectal tumors might not be warranted, and the functional effects of mutations at other regions of microsatellite instability should be evaluated.
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- Paridaans, NP, et al.
(författare)
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Low-Dose versus Standard-Dose Intravenous Immunoglobulin to Prevent Fetal Intracranial Hemorrhage in Fetal and Neonatal Alloimmune Thrombocytopenia: A Randomized Trial
- 2015
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Ingår i: Fetal diagnosis and therapy. - : S. Karger AG. - 1421-9964 .- 1015-3837. ; 38:2, s. 147-153
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Objective:</i></b> Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e. 0.5 g/kg. <b><i>Methods:</i></b> This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH. <b><i>Results:</i></b> A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 × 10<sup>9</sup>/l (range 8-269) in the 0.5 g/kg group versus 110 × 10<sup>9</sup>/l (range 11-279) in the 1 g/kg group (p = 0.644). <b><i>Conclusion:</i></b> The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.
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| 9. |
- Kamphuis, MM, et al.
(författare)
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Fetal and Neonatal Alloimmune Thrombocytopenia: Management and Outcome of a Large International Retrospective Cohort
- 2017
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Ingår i: Fetal diagnosis and therapy. - : S. Karger AG. - 1421-9964 .- 1015-3837. ; 41:4, s. 251-257
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Objective:</i></b> To evaluate the management and outcome of a large international cohort of cases of pregnancies complicated by fetal and neonatal alloimmune thrombocytopenia (FNAIT). <b><i>Methods:</i></b> This was an observational prospective and retrospective cohort study of all cases of FNAIT entered into the international multicentre No IntraCranial Haemorrhage (NOICH) registry during the period of 2001-2010. We evaluated human platelet antigen (HPA) specificity, the antenatal and postnatal interventions performed, and clinical outcome. <b><i>Results:</i></b> A total of 615 pregnancies complicated by FNAIT from 10 countries were included. Anti-HPA-1a was the most commonly implicated antibody. Antenatal treatment was administered in 273 pregnancies (44%), varying from intrauterine platelet transfusion to maternal administration of immunoglobulins, steroids, or a combination of those. Intracranial haemorrhage was diagnosed in 23 fetuses or neonates (3.7%). Overall perinatal mortality was 1.14% (n = 7). <b><i>Conclusion:</i></b> This study presents the largest cohort of cases of FNAIT published. Our data show that antenatal treatment for FNAIT results in favourable perinatal outcome. Over time, in most centres, treatment for FNAIT changed from an invasive to a complete non-invasive procedure.
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