| 1. |
- Rajewsky, N., et al.
(författare)
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LifeTime and improving European healthcare through cell-based interceptive medicine
- 2020
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 587:7834, s. 377-386
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Tidskriftsartikel (refereegranskat)abstract
- LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.
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| 2. |
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| 3. |
- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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| 4. |
- Pelletier, F., et al.
(författare)
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Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:2
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Tidskriftsartikel (refereegranskat)abstract
- Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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| 5. |
- Went, M, et al.
(författare)
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Author Correction: Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 213-
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Tidskriftsartikel (refereegranskat)abstract
- The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
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| 6. |
- Aleksandrov, D., et al.
(författare)
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Halo excitations in fragmentation of He-6 at 240 MeV/u on carbon and lead targets
- 2000
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Ingår i: Nuclear Physics A. - 0375-9474. ; 669:1-2, s. 51-64
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Tidskriftsartikel (refereegranskat)abstract
- Dissociation of a 240 MeV/u beam of He-6, incident on carbon and lead targets, has been studied in kinematically complete experiments to investigate low-lying excitation modes in the halo nucleus He-6. It is shown that alignment effects characterize the inelastic scattering and allow an unambiguous assignment of the spin of a narrow resonance observed in the excitation energy spectrum. The differential cross sections for the He-6 inelastic scattering on carbon and lead targets were deduced from the measured moments of the two neutrons and the a-particle. An analysis of these distributions shows that quadrupole and, possibly, monopole excitations characterize the hadronic interaction, while the dipole mode is dominating in Coulomb dissociation. Neither theoretically predicted new resonance states in He-6 nor nuclear excitation of a dipole mode were found. Direct evidence has been obtained for strong suppression of Coulornb post-acceleration in direct Coulomb breakup in a lead target.
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| 7. |
- Aleksandrov, D., et al.
(författare)
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Invariant mass spectrum and alpha-n correlation function studied in the fragmentation of He-6 on a carbon target
- 1998
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Ingår i: Nuclear Physics A. - 0375-9474. ; 633:2, s. 234-246
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Tidskriftsartikel (refereegranskat)abstract
- Momentum distributions and invariant mass spectra from the breakup of He-6 ions with an energy of 240 MeV/u interacting with a carbon target have been studied. The data were used to extract information about the reaction mechanism which is influenced by the structure of He-6. It is found that the dominant reaction mechanism is a two-step process: knock out of one neutron followed by the decay of the He-5 resonance. The shape of the (alpha+n) two-body invariant mass spectrum is interpreted as mainly reflecting the 5He ground state which is a J(pi) = 3/2(-) resonance. However, no evidence for correlations between cu particles and neutrons is observed in the momentum widths of the distributions. It is demonstrated that a combined analysis of the two-body invariant mass spectrum and an appropriate correlation function may be used to determine the properties of the intermediate resonance. (C) 1998 Elsevier Science B.V.
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| 8. |
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| 9. |
- Chulkov, L. V., et al.
(författare)
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Large spin alignment of the unbound He-5 fragment after fragmentation of 240 MeV/nucleon He-6
- 1997
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 79:2, s. 201-204
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral fragmentation of a 240 MeV/nucleon beam of the halo nucleus He-6 incident on carbon target has been studied in a kinematically complete experiment. It is found that one-neutron stripping to the unbound nucleus He-5 is the dominant fragmentation mechanism and that it leads to a spin alignment of He-5 in a plane perpendicular to the He-5 momentum vector. This is expected to be a common feature for all neutron halo nuclei.
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| 10. |
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| 11. |
- Went, Molly, et al.
(författare)
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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
- 2018
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
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| 12. |
- Johnson, D C, et al.
(författare)
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Genetic factors influencing the risk of multiple myeloma bone disease.
- 2016
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 30, s. 883-888
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Tidskriftsartikel (refereegranskat)abstract
- A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totalling 3774) which had been radiologically surveyed for MBD. Each patient had been genotyped for ~600 000 SNPs with genotypes for six million common variants imputed using 1000Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio [OR]=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, OR=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.Leukemia accepted article preview online, 16 December 2015. doi:10.1038/leu.2015.342.
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| 13. |
- Markenroth, Karin, 1973, et al.
(författare)
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He-8-He-6: a comparative study of nuclear fragmentation reactions
- 2001
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Ingår i: Nuclear Physics A. - 0375-9474. ; 679:3-4, s. 462-480
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Tidskriftsartikel (refereegranskat)abstract
- Dissociation of 227 MeV/u He-8 in a carbon target has been studied in kinematically complete experiments. The data include the relative energy spectrum, angular distributions in the neutron knock-out channel (He-6 + n) as well as diffractive dissociation and inelastic scattering into the (He-6 + 2n) channel. The data are compared with corresponding results from the well-known halo nucleus He-6. In both cases it is found that neutron knock-out is the: dominating reaction channel. The relative energy spectrum (He-6 + n) shows a structure, which is interpreted as being due to the I-pi = 3/2(-) resonance in the He-7 ground state with about equal contribution from its I-pi = 1/2(-) spin-orbit partner. The He-7 resonance shows a spin alignment similar to that observed in He-5, but with a smaller anisotropy indicating that the structure of the He-8 ground state is more complicated than that of He-6. The data in the (He-6 + 2n) channel were used to identify resonances in the excitation energy spectrum of He-8. If the spectrum is interpreted as two overlapping resonances, the spin-parity assignment for these is found to be 2(+) and 1(-), respectively.
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| 14. |
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| 15. |
- Nilsson, Thomas, 1965, et al.
(författare)
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He-6 and neutron momentum distributions from He-8 in nuclear break-up reactions at 240 MeV/u
- 1996
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Ingår i: Nuclear Physics A. - 0375-9474. ; 598:3, s. 418-434
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Tidskriftsartikel (refereegranskat)abstract
- Neutron and He-6 momentum distributions from He-8 break-up reactions in a C target have been measured at 240 MeV/u. The two-neutron removal cross section was found to be sigma(-2n) = 0.27 +/- 0.03 b. The nature of the momentum distributions is interpreted in some simple reaction scenarios.
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| 16. |
- Nilsson, Thomas, 1965, et al.
(författare)
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Neutron Momentum Distributions from Core Break-up Reactions of Halo Nuclei
- 1995
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Ingår i: Europhysics Letters. - 0295-5075 .- 1286-4854. ; 30:1, s. 19-24
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Tidskriftsartikel (refereegranskat)abstract
- Neutron angular distributions from violent break-up reactions of Li-11 and Be-11 have been measured at 28 MeV/u and 280 MeV/u and at 41 MeV/u and 460 MeV/u, respectively. The derived neutron momentum distributions show a narrow component in transverse momentum that is within uncertainties independent of beam energy and target charge. This component is suggested to be simply related to the momentum distribution of the loosely bound halo neutron(s) in the projectiles.
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| 17. |
- Zinser, M., et al.
(författare)
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Invariant-mass spectroscopy of Li-10 and Li-11
- 1997
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Ingår i: Nuclear Physics A. - 0375-9474. ; 619:1-2, s. 151-176
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Tidskriftsartikel (refereegranskat)abstract
- Break-up of secondary Li-11 ion beams (280 MeV/nucleon) on C and Pb targets into Li-9 and neutrons is studied experimentally. Cross sections and neutron multiplicity distributions are obtained, characterizing different reaction mechanisms. Invariant-mass spectroscopy for Li-11 and Li-10 is performed. The E1 strength distribution, deduced from electromagnetic excitation of Li-11 up to an excitation energy of 4 MeV comprises similar to 8% of the Thomas-Reiche-Kuhn energy-weighted sumrule strength. Two low-lying resonance-like structures are observed for Li-10 at decay energies of 0.21(5) and 0.62(10) MeV, the former one carrying 26(10)% of the strength and likely to be associated with an s-wave neutron decay. A strong di-neutron correlation in Li-11 can be discarded. Calculations in a quasi-particle RPA approach are compared with the experimental results for Li-10 and Li-11. (C) 1997 Elsevier Science B.V.
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| 18. |
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| 19. |
- Chulkov, L. V., et al.
(författare)
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Three-body correlations in electromagnetic dissociation of Borromean nuclei: The He-6 case
- 2005
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Ingår i: Nuclear Physics A. - : Elsevier BV. - 0375-9474. ; 759:1-2, s. 23-42
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Tidskriftsartikel (refereegranskat)abstract
- Dissociation of He-6 on a lead target has been studied at 240 MeV/u. The four-momenta of the two neutrons in coincidence with alpha-particles have been measured and used to reconstruct the three-body energy and angular correlations in the final state. For the first time, three-body correlations were included in the analysis of the He-6 dissociation data, and compared with calculations assuming a dipole mode for the electromagnetic dissociation. In addition, the experimental data have been analyzed using a series expansion of the final transition amplitude into hyperspherical functions, showing the importance of both nn and alpha n final-state interactions. It is shown that the dissociation process is governed by a transition of one neutron from the p-shell in the 6He ground state to the s-shell in the continuum further indicating that the role of the transition through an intermediate He-5(3/2(-)) state is more important than expected. (c) 2005 Elsevier B.V. All rights reserved.
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| 20. |
- Da Silva Filho, M. I., et al.
(författare)
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Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts : Comparison with myeloma
- 2017
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:8, s. 1735-1742
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10 -5 with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 × 10 -11; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 × 10 -8). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated.
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| 21. |
- de Muynck, Ldan, et al.
(författare)
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Consensus Statement on the Use of Near-Infrared Fluorescence Imaging during Pancreatic Cancer Surgery Based on a Delphi Study: Surgeons' Perspectives on Current Use and Future Recommendations
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Despite the potential of fluorescence imaging during pancreatic cancer surgery, more research is needed to facilitate the approval of tumor-targeted probes, standardize imaging techniques, and most importantly, gain trust from surgeons. Despite advancements in the development of novel probes, preclinical research settings do not always accurately represent the surgical setting. This first-of-its-kind Delphi consensus survey highlights current experiences and attitudes towards fluorescence imaging during pancreatic cancer surgery, specifically from surgeon's perspectives. The results from this consensus survey highlight potential new directions for future research, which could facilitate the standardized use of fluorescence imaging during pancreatic surgery. Indocyanine green (ICG) is one of the only clinically approved near-infrared (NIR) fluorophores used during fluorescence-guided surgery (FGS), but it lacks tumor specificity for pancreatic ductal adenocarcinoma (PDAC). Several tumor-targeted fluorescent probes have been evaluated in PDAC patients, yet no uniformity or consensus exists among the surgical community on the current and future needs of FGS during PDAC surgery. In this first-published consensus report on FGS for PDAC, expert opinions were gathered on current use and future recommendations from surgeons' perspectives. A Delphi survey was conducted among international FGS experts via Google Forms. Experts were asked to anonymously vote on 76 statements, with >= 70% agreement considered consensus and >= 80% participation/statement considered vote robustness. Consensus was reached for 61/76 statements. All statements were considered robust. All experts agreed that FGS is safe with few drawbacks during PDAC surgery, but that it should not yet be implemented routinely for tumor identification due to a lack of PDAC-specific NIR tracers and insufficient evidence proving FGS's benefit over standard methods. However, aside from tumor imaging, surgeons suggest they would benefit from visualizing vasculature and surrounding anatomy with ICG during PDAC surgery. Future research could also benefit from identifying neuroendocrine tumors. More research focusing on standardization and combining tumor identification and vital-structure imaging would greatly improve FGS's use during PDAC surgery.
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| 22. |
- Humbert, F., et al.
(författare)
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Longitudinal and Transverse-Momentum Distributions of Li-9 Fragments from Break-up of Li-11
- 1995
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Ingår i: Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics. - 0370-2693. ; 347:3-4, s. 198-204
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Tidskriftsartikel (refereegranskat)abstract
- Transverse and longitudinal momentum distributions of Li-9 fragments from Li-11 break-up reactions in C, Al and Pb targets have been measured at 280 MeV/u. The two-neutron removal cross-section was measured to be sigma(-2n), = 0.26 +/- 0.02 b for the carbon target, sigma(-2n) = 0.47 +/- 0.08 b for the aluminum target and sigma(-2n), = 1.9 +/- 0.4 b for the lead target. No significant difference is observed between the narrow widths (FWHM approximate to 47 MeV/c) of the transverse and longitudinal momentum distributions of the Li-9 fragments. The physical implications of this are discussed.
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| 23. |
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| 24. |
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| 25. |
- Went, M, et al.
(författare)
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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3707-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.
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