| 1. |
- Emerging Risk Factors, Collaboration, et al.
(författare)
-
The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases
- 2007
-
Ingår i: Eur J Epidemiol. - 0393-2990. ; 22:12, s. 839-69
-
Tidskriftsartikel (refereegranskat)abstract
- Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Chumak, A. V., et al.
(författare)
-
Advances in Magnetics Roadmap on Spin-Wave Computing
- 2022
-
Ingår i: IEEE Transactions on Magnetics. - 0018-9464. ; 58:6
-
Tidskriftsartikel (refereegranskat)abstract
- Magnonics addresses the physical properties of spin waves and utilizes them for data processing. Scalability down to atomic dimensions, operation in the GHz-to-THz frequency range, utilization of nonlinear and nonreciprocal phenomena, and compatibility with CMOS are just a few of many advantages offered by magnons. Although magnonics is still primarily positioned in the academic domain, the scientific and technological challenges of the field are being extensively investigated, and many proof-of-concept prototypes have already been realized in laboratories. This roadmap is a product of the collective work of many authors that covers versatile spin-wave computing approaches, conceptual building blocks, and underlying physical phenomena. In particular, the roadmap discusses the computation operations with Boolean digital data, unconventional approaches like neuromorphic computing, and the progress towards magnon-based quantum computing. The article is organized as a collection of sub-sections grouped into seven large thematic sections. Each sub-section is prepared by one or a group of authors and concludes with a brief description of current challenges and the outlook of further development for each research direction. Author
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Vogel, G. F., et al.
(författare)
-
Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants
- 2023
-
Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 25:6
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. Conclusion: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.
|
|
| 8. |
- Zheng, TH, et al.
(författare)
-
Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease
- 2021
-
Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 70:8, s. 1538-1549
-
Tidskriftsartikel (refereegranskat)abstract
- Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.DesignWe conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.ResultsWe demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.ConclusionHEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
|
|
| 9. |
- Maas, R. R., et al.
(författare)
-
Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases
- 2017
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 82:6, s. 1004-1015
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: 3-Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days–33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic “putaminal eye” was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. Interpretation: MEGDHEL syndrome is a progressive deafness–dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004–1015. © 2017 American Neurological Association
|
|
| 10. |
- Carreras, A., et al.
(författare)
-
In vivo genome and base editing of a human PCSK9 knock-in hypercholesterolemic mouse model
- 2019
-
Ingår i: Bmc Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- Background Plasma concentration of low-density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates cholesterol homeostasis, has recently emerged as an approach to reduce cholesterol levels. The development of humanized animal models is an important step to validate and study human drug targets, and use of genome and base editing has been proposed as a mean to target disease alleles.ResultsTo address the lack of validated models to test the safety and efficacy of techniques to target human PCSK9, we generated a liver-specific human PCSK9 knock-in mouse model (hPCSK9-KI). We showed that plasma concentrations of total cholesterol were higher in hPCSK9-KI than in wildtype mice and increased with age. Treatment with evolocumab, a monoclonal antibody that targets human PCSK9, reduced cholesterol levels in hPCSK9-KI but not in wildtype mice, showing that the hypercholesterolemic phenotype was driven by overexpression of human PCSK9. CRISPR-Cas9-mediated genome editing of human PCSK9 reduced plasma levels of human and not mouse PCSK9, and in parallel reduced plasma concentrations of total cholesterol; genome editing of mouse Pcsk9 did not reduce cholesterol levels. Base editing using a guide RNA that targeted human and mouse PCSK9 reduced plasma levels of human and mouse PCSK9 and total cholesterol. In our mouse model, base editing was more precise than genome editing, and no off-target editing nor chromosomal translocations were identified.ConclusionsHere, we describe a humanized mouse model with liver-specific expression of human PCSK9 and a human-like hypercholesterolemia phenotype, and demonstrate that this mouse can be used to evaluate antibody and gene editing-based (genome and base editing) therapies to modulate the expression of human PCSK9 and reduce cholesterol levels. We predict that this mouse model will be used in the future to understand the efficacy and safety of novel therapeutic approaches for hypercholesterolemia.
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
- Liu, Jimmy Z, et al.
(författare)
-
Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.
- 2013
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:6, s. 670-5
-
Tidskriftsartikel (refereegranskat)abstract
- Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
|
|
| 14. |
|
|
| 15. |
- McMaster, ML, et al.
(författare)
-
Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia
- 2018
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 4182-
-
Tidskriftsartikel (refereegranskat)abstract
- Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.
|
|
| 16. |
|
|
| 17. |
- Muus, Christoph, et al.
(författare)
-
Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
- 2021
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:3, s. 546-559
-
Tidskriftsartikel (refereegranskat)abstract
- Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2(+)TMPRSS2(+) cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
- Hess, Timo, et al.
(författare)
-
Dissecting the genetic heterogeneity of gastric cancer
- 2023
-
Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
|
|
| 21. |
- Huntley, RP, et al.
(författare)
-
Guidelines for the functional annotation of microRNAs using the Gene Ontology
- 2016
-
Ingår i: RNA (New York, N.Y.). - : Cold Spring Harbor Laboratory. - 1469-9001 .- 1355-8382. ; 22:5, s. 667-676
-
Tidskriftsartikel (refereegranskat)abstract
- MicroRNA regulation of developmental and cellular processes is a relatively new field of study, and the available research data have not been organized to enable its inclusion in pathway and network analysis tools. The association of gene products with terms from the Gene Ontology is an effective method to analyze functional data, but until recently there has been no substantial effort dedicated to applying Gene Ontology terms to microRNAs. Consequently, when performing functional analysis of microRNA data sets, researchers have had to rely instead on the functional annotations associated with the genes encoding microRNA targets. In consultation with experts in the field of microRNA research, we have created comprehensive recommendations for the Gene Ontology curation of microRNAs. This curation manual will enable provision of a high-quality, reliable set of functional annotations for the advancement of microRNA research. Here we describe the key aspects of the work, including development of the Gene Ontology to represent this data, standards for describing the data, and guidelines to support curators making these annotations. The full microRNA curation guidelines are available on the GO Consortium wiki (http://wiki.geneontology.org/index.php/MicroRNA_GO_annotation_manual).
|
|
| 22. |
|
|
| 23. |
- Luecken, Malte D., et al.
(författare)
-
The discovAIR project : a roadmap towards the Human Lung Cell Atlas
- 2022
-
Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 60:2
-
Forskningsöversikt (refereegranskat)abstract
- The Human Cell Atlas (HCA) consortium aims to establish an atlas of all organs in the healthy human body at single-cell resolution to increase our understanding of basic biological processes that govern development, physiology and anatomy, and to accelerate diagnosis and treatment of disease. The Lung Biological Network of the HCA aims to generate the Human Lung Cell Atlas as a reference for the cellular repertoire, molecular cell states and phenotypes, and cell-cell interactions that characterise normal lung homeostasis in healthy lung tissue. Such a reference atlas of the healthy human lung will facilitate mapping the changes in the cellular landscape in disease. The discovAIR project is one of six pilot actions for the HCA funded by the European Commission in the context of the H2020 framework programme. discovAIR aims to establish the first draft of an integrated Human Lung Cell Atlas, combining single-cell transcriptional and epigenetic profiling with spatially resolving techniques on matched tissue samples, as well as including a number of chronic and infectious diseases of the lung. The integrated Human Lung Cell Atlas will be available as a resource for the wider respiratory community, including basic and translational scientists, clinical medicine, and the private sector, as well as for patients with lung disease and the interested lay public. We anticipate that the Human Lung Cell Atlas will be the founding stone for a more detailed understanding of the pathogenesis of lung diseases, guiding the design of novel diagnostics and preventive or curative interventions.
|
|
| 24. |
- Olin, JW, et al.
(författare)
-
A plasma proteogenomic signature for fibromuscular dysplasia
- 2020
-
Ingår i: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 116:1, s. 63-77
-
Tidskriftsartikel (refereegranskat)abstract
- AimsFibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.Methods and resultsFemales with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.ConclusionFMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.
|
|
| 25. |
- Sikkema, Lisa, et al.
(författare)
-
An integrated cell atlas of the lung in health and disease
- 2023
-
Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
-
Tidskriftsartikel (refereegranskat)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
|
|
| 26. |
- Slavc, I, et al.
(författare)
-
Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a "MEMMAT-like" Metronomic Antiangiogenic Approach
- 2022
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:20
-
Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy (“MEMMAT-like”) before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the “MEMMAT-like” therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.
|
|
| 27. |
|
|
| 28. |
- Aboushelbaya, R., et al.
(författare)
-
Orbital Angular Momentum Coupling in Elastic Photon-Photon Scattering
- 2019
-
Ingår i: Physical Review Letters. - 0031-9007. ; 123:11
-
Tidskriftsartikel (refereegranskat)abstract
- In this Letter, we investigate the effect of orbital angular momentum (OAM) on elastic photon-photon scattering in a vacuum for the first time. We define exact solutions to the vacuum electromagnetic wave equation which carry OAM. Using those, the expected coupling between three initial waves is derived in the framework of an effective field theory based on the Euler-Heisenberg Lagrangian and shows that OAM adds a signature to the generated photons thereby greatly improving the signal-to-noise ratio. This forms the basis for a proposed high-power laser experiment utilizing quantum optics techniques to filter the generated photons based on their OAM state.
|
|
| 29. |
|
|
| 30. |
- Conlon, Thomas M, et al.
(författare)
-
Inhibition of LTβR signalling activates WNT-induced regeneration in lung
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588:7836, s. 151-156
-
Tidskriftsartikel (refereegranskat)abstract
- Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3-6. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.
|
|
| 31. |
- De Genst, Erwin, et al.
(författare)
-
Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure
- 2022
-
Ingår i: Nature Communications. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 2041-1723.
-
Tidskriftsartikel (refereegranskat)abstract
- The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca2+ ATPase and its reversible inhibitor phospholamban, induces heart failure by inhibiting calcium cycling. While phospholamban is a bona-fide therapeutic target, approaches to selectively inhibit this protein remain elusive. Here, we report the in vivo application of intracellular acting antibodies (intrabodies), derived from the variable domain of camelid heavy-chain antibodies, to modulate the function of phospholamban. Using a synthetic VHH phage-display library, we identify intrabodies with high affinity and specificity for different conformational states of phospholamban. Rapid phenotypic screening, via modified mRNA transfection of primary cells and tissue, efficiently identifies the intrabody with most desirable features. Adeno-associated virus mediated delivery of this intrabody results in improvement of cardiac performance in a murine heart failure model. Our strategy for generating intrabodies to investigate cardiac disease combined with modified mRNA and adeno-associated virus screening could reveal unique future therapeutic opportunities.
|
|
| 32. |
- Ding, Mei, et al.
(författare)
-
Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells
- 2021
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; , s. 16767-
-
Tidskriftsartikel (refereegranskat)abstract
- Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.
|
|
| 33. |
- Ellinghaus, David, et al.
(författare)
-
Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
-
Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
|
|
| 34. |
- Heyng, Alexander M., et al.
(författare)
-
Environmental changes in northern New Zealand since the Middle Holocene inferred from stable isotope records (delta N-15, delta C-13) of Lake Pupuke
- 2012
-
Ingår i: Journal of Paleolimnology. - : Springer Science and Business Media LLC. - 0921-2728 .- 1573-0417. ; 48:2, s. 351-366
-
Tidskriftsartikel (refereegranskat)abstract
- Maar lakes in the Auckland Volcanic Field are important high-resolution archives of Holocene environmental change in the Southern Hemisphere mid-latitudes. Stable carbon and nitrogen isotope analyses were applied on bulk organic matter and the green alga Botryococcus from a sediment core from Lake Pupuke (Auckland, North Island, New Zealand) spanning the period since 7,165 cal. year BP. The origin of organic matter was established using total-organic-carbon-to-nitrogen ratios (TOC/TN) as well as organic carbon (delta C-13(OM)) and nitrogen (delta N-15) isotope composition of potential modern sources. This approach demonstrated that the contribution of allochthonous organic matter to the lake sediment was negligible for most of the record. The sedimentary TOC/TN ratios that are higher than Redfield ratio (i.e. > 7) are attributed to N-limiting conditions throughout the record. Variations of nitrogen and carbon isotopes during the last 7,165 years are interpreted as changes in the dominant processes in the lake. While epilimnetic primary productivity controlled isotope composition before 6,600 cal. year BP, microbial processes, especially denitrification and methane oxidation, caused overall shifts of the delta N-15 and delta C-13 values since the Mid-Holocene. Comparisons with climate reconstructions from the Northern Island suggest that changes in the wind-induced lake overturn and a shift to more pronounced seasonality were the most likely causes for lake-internal changes since 6,600 cal. year BP.
|
|
| 35. |
- Jobs, M, et al.
(författare)
-
DASH-2: flexible, low-cost, and high-throughput SNP genotyping by dynamic allele-specific hybridization on membrane arrays
- 2003
-
Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 13:5, s. 916-924
-
Tidskriftsartikel (refereegranskat)abstract
- Genotyping technologies need to be continually improved in terms of their flexibility, cost-efficiency, and throughput, to push forward genome variation analysis. To this end, we have leveraged the inherent simplicity of dynamic allele-specific hybridization (DASH) and coupled it to recent innovations of centrifugal arrays and iFRET. We have thereby created a new genotyping platform we term DASH-2, which we demonstrate and evaluate in this report. The system is highly flexible in many ways (any plate format, PCR multiplexing, serial and parallel array processing, spectral-multiplexing of hybridization probes), thus supporting a wide range of application scales and objectives. Precision is demonstrated to be in the range 99.8–100%, and assay costs are 0.05 USD or less per genotype assignment. DASH-2 thus provides a powerful new alternative for genotyping practice, which can be used without the need for expensive robotics support.
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
- Kreij, Karl, 1975-, et al.
(författare)
-
On-line detection of microbial contaminations in animal cell reactor cultures using an electronic nose device
- 2005
-
Ingår i: Cytotechnology (Dordrecht). - : Springer Science and Business Media LLC. - 0920-9069 .- 1573-0778. ; 48:1-3, s. 41-58
-
Tidskriftsartikel (refereegranskat)abstract
- An electronic nose (EN) device was used to detect microbial and viral contaminations in a variety of animal cell culture systems. The emission of volatile components from the cultures accumulated in the bioreactor headspace, was sampled and subsequently analysed by the EN device. The EN, which was equipped with an array of 17 chemical gas sensors of varying selectivity towards the sampled volatile molecules, generated response patterns of up to 85 computed signals. Each 15 or 20 min a new gas sample was taken generating a new response pattern. A software evaluation tool visualised the data mainly by using principal component analysis. The EN was first used to detect microbial contaminations in a Chinese hamster ovary (CHO) cell line producing a recombinant human macrophage colony stimulating factor (rhM-CSF). The CHO cell culture was contaminated by Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida utilis which all were detected. The response patterns from the CHO cell culture were compared with monoculture references of the microorganisms. Second, contaminations were studied in an Sf-9 insect cell culture producing another recombinant protein (VP2 protein). Contaminants were detected from E. coli, a filamentous fungus and a baculovirus. Third, contamination of a human cell line, HEK-293, infected with E. coli exhibited comparable results. Fourth, bacterial contaminations could also be detected in cultures of a MLV vector producer cell line. Based on the overall experiences in this study it is concluded that the EN method has in a number of cases the potential to be developed into a useful on-line contamination alarm in order to support safety and economical operation for industrial cultivation. © Springer 2005.
|
|
| 39. |
|
|
| 40. |
- Lieshout-Krikke, Ryanne W., et al.
(författare)
-
Selection strategies for newly registered blood donors in European countries
- 2017
-
Ingår i: Blood Transfusion. - 1723-2007. ; 15:6, s. 495-501
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Two selection strategies for newly-registered blood donors are available: a singlevisit selection called the standard selection procedure (SSP), and a two-stage selection named predonation and donation screening (PDS). This study reviews the selection strategies for newly-registered donors currently applied in European countries.Material and methods: We collected data on donor selection procedures, blood donation, laboratory screening and HIV, HCV and HBV positive donors/donations from 2010 to 2013 in 30 European countries by using questionnaires. We grouped the countries according to the applied selection strategy, and for each country, we calculated the 4-year prevalence of confirmed positive results indicating the presence of overall and recent HIV, HCV and HBV infections among first-time and repeat donations and among newly-registered donors.Results: Most of the 24 countries (80%) apply the SSP strategy for selection of newly-registered donors. Twenty-two countries (73.3%) employ a nucleic acid amplification testing in addition to the mandatory serological screening. The survey confirms a higher overall prevalence of HIV, HCV and HBV infections among first-time donations and newly-registered donors than among repeat donations. In contrast, the prevalence of recently acquired HIV and HCV infections was lower among first-time donations and newly-registered donors than among repeat donations, but higher for recent HBV infections (6.7/105 vs 2.6/105 in the SSP setting and 4.3/105 vs 0.5/105 in one country using PDS). The relatively low numbers of infected donors selected by PDS impeded accurate assessment of the prevalence of recent infections in first-time donations.Discussion: The data from European countries provide inconclusive evidence that applying PDS reduces the risk of donations being made in the diagnostic window of first-time donors. The impact of PDS on the risk of window-period donations and blood donor management needs further investigation.
|
|
| 41. |
- Liu, Ilon, et al.
(författare)
-
The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location
- 2022
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:12, s. 1881-1894
-
Tidskriftsartikel (refereegranskat)abstract
- Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
|
|
| 42. |
|
|
| 43. |
- Redlinger-Pohn, Jakob D., et al.
(författare)
-
Fines mobility and distribution in streaming fibre networks : experimental evidence and numerical modeling
- 2020
-
Ingår i: Cellulose. - : Springer Science and Business Media B.V.. - 0969-0239 .- 1572-882X. ; 27:16, s. 9663-9682
-
Tidskriftsartikel (refereegranskat)abstract
- The motion of flocculated fibres in a streaming suspension is governed by the balance of the network strength and hydrodynamic forces. With increasing flow rate through a channel, (1) the network initially occupying all space, (2) is then compressed to the centre, and (3) ultimately dispersed. This classical view neglects fibres-fines: we find that the distribution of these small particles differs in streaming suspensions. While it is known that fibre-fines can escape the fibre network, we find that the distribution of fibre-fines is non-homogenous in the network during compression: fibre-fines can be caged and retarded in the streaming fibre network. Hence, the amount of fibre-fines is reduced outside of a fibre network and enriched at the network’s interface. Aiming on selectively removing fibre-fines from a streaming network by suction, we identify a reduction of the fines removal rate. That documents a hindered mobility of fibre-fines when moving through the network of fibres. Additionally, we found evidence, that the mobility of fibre-fines is dependent on the fibre-fines quality, and is higher for fibrillar fines. Consequently, we suggest that the quality of fibre-fines removed from the suspension can be controlled with the flow regime in the channel. Finally, we present a phenomenological model to compute the length dependent fibre distribution in an arbitary geometry. For a fibre suspension channel flow we are able to predict a length-dependent fibre segregation near the channel’s centre. The erosion of a plug of long fibres was however underestimated by our model. Interestingly, our model with parameters fitted to streaming fibre suspension qualitatively agreed with the motion of micro-fibrillated cellulose. This gives hope that devices for handling flocculated fibre suspensions can be designed in the future with greater confidence.
|
|
| 44. |
- Sticker, D., et al.
(författare)
-
Using oxygen-consuming thermoset plastics to generate hypoxic conditions in microfluidic devices for potential cell culture applications
- 2020
-
Ingår i: 21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017. - : Chemical and Biological Microsystems Society. ; , s. 812-813
-
Konferensbidrag (refereegranskat)abstract
- The precise control of the oxygen concentration in a cellular environment allows the study of cells under physiologically relevant conditions. This work reports on a novel method for the generation of reduced dissolved oxygen concentrations in microfluidic chambers for cell- and organ-on-chip applications. Using a thermoset polymeric material (OSTEMERTM), which effectively scavenges dissolved oxygen (DO), microfluidic devices have been fabricated where oxygen was rapidly depleted from the microfluidic chamber. It is shown that hypoxic and anaerobic conditions can be generated through the inherent scavenging property of the material itself, without any additional chemical additives.
|
|
| 45. |
|
|
| 46. |
- Tegel, Hanna, et al.
(författare)
-
High throughput generation of a resource of the human secretome in mammalian cells
- 2020
-
Ingår i: New Biotechnology. - : Elsevier BV. - 1871-6784 .- 1876-4347. ; 58, s. 45-54
-
Tidskriftsartikel (refereegranskat)abstract
- The proteins secreted by human tissues and blood cells, the secretome, are important both for the basic understanding of human biology and for identification of potential targets for future diagnosis and therapy. Here, a high-throughput mammalian cell factory is presented that was established to create a resource of recombinant full-length proteins covering the majority of those annotated as 'secreted' in humans. The full-length DNA sequences of each of the predicted secreted proteins were generated by gene synthesis, the constructs were transfected into Chinese hamster ovary (CHO) cells and the recombinant proteins were produced, purified and analyzed. Almost 1,300 proteins were successfully generated and proteins predicted to be secreted into the blood were produced with a success rate of 65%, while the success rates for the other categories of secreted proteins were somewhat lower giving an overall one-pass success rate of ca. 58%. The proteins were used to generate targeted proteomics assays and several of the proteins were shown to be active in a phenotypic assay involving pancreatic beta-cell dedifferentiation. Many of the proteins that failed during production in CHO cells could be rescued in human embryonic kidney (HEK 293) cells suggesting that a cell factory of human origin can be an attractive alternative for production in mammalian cells. In conclusion, a high-throughput protein production and purification system has been successfully established to create a unique resource of the human secretome.
|
|
| 47. |
|
|
| 48. |
- Walter, M, et al.
(författare)
-
NUDT22 promotes cancer growth through pyrimidine salvage
- 2023
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 42:16, s. 1282-1293
-
Tidskriftsartikel (refereegranskat)abstract
- The NUDIX hydrolase NUDT22 converts UDP-glucose into glucose-1-phosphate and the pyrimidine nucleotide uridine monophosphate but a biological significance for this biochemical reaction has not yet been established. Glucose-1-phosphate is an important metabolite for energy and biomass production through glycolysis and nucleotides required for DNA replication are produced through energetically expensive de novo or energy-efficient salvage pathways. Here, we describe p53-regulated pyrimidine salvage through NUDT22-dependent hydrolysis of UDP-glucose to maintain cancer cell growth and to prevent replication stress. NUDT22 expression is consistently elevated in cancer tissues and high NUDT22 expression correlates with worse survival outcomes in patients indicating an increased dependency of cancer cells to NUDT22. Furthermore, we show that NUDT22 transcription is induced after inhibition of glycolysis, MYC-mediated oncogenic stress, and DNA damage directly through p53. NUDT22-deficient cancer cells suffer from growth retardation, S-phase delay, and slower DNA replication fork speed. Uridine supplementation rescues replication fork progression and alleviates replication stress and DNA damage. Conversely, NUDT22 deficiency sensitizes cells to de novo pyrimidine synthesis inhibition in vitro and reduces cancer growth in vivo. In conclusion, NUDT22 maintains pyrimidine supply in cancer cells and depletion of NUDT22 leads to genome instability. Targeting NUDT22 therefore has high potential for therapeutic applications in cancer therapy.
|
|
| 49. |
|
|
| 50. |
|
|
