| 1. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 2. |
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| 3. |
- Gilbert, P. M., et al.
(författare)
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Substrate Elasticity Regulates Skeletal Muscle Stem Cell Self-Renewal in Culture
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 329:5995, s. 1078-1081
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Tidskriftsartikel (refereegranskat)abstract
- Stem cells that naturally reside in adult tissues, such as muscle stem cells (MuSCs), exhibit robust regenerative capacity in vivo that is rapidly lost in culture. Using a bioengineered substrate to recapitulate key biophysical and biochemical niche features in conjunction with a highly automated single-cell tracking algorithm, we show that substrate elasticity is a potent regulator of MuSC fate in culture. Unlike MuSCs on rigid plastic dishes (similar to 10(6) kilopascals), MuSCs cultured on soft hydrogel substrates that mimic the elasticity of muscle (12 kilopascals) self-renew in vitro and contribute extensively to muscle regeneration when subsequently transplanted into mice and assayed histologically and quantitatively by noninvasive bioluminescence imaging. Our studies provide novel evidence that by recapitulating physiological tissue rigidity, propagation of adult muscle stem cells is possible, enabling future cell-based therapies for muscle-wasting diseases.
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| 4. |
- Bogers, M., et al.
(författare)
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The open innovation research landscape : established perspectives and emerging themes across different levels of analysis
- 2017
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Ingår i: Industry and Innovation. - : Routledge. - 1366-2716 .- 1469-8390. ; 24:1, s. 8-40
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Tidskriftsartikel (refereegranskat)abstract
- This paper provides an overview of the main perspectives and themes emerging in research on open innovation (OI). The paper is the result of a collaborative process among several OI scholars–having a common basis in the recurrent Professional Development Workshop on ‘Researching Open Innovation’ at the Annual Meeting of the Academy of Management. In this paper, we present opportunities for future research on OI, organised at different levels of analysis. We discuss some of the contingencies at these different levels, and argue that future research needs to study OI–originally an organisational-level phenomenon–across multiple levels of analysis. While our integrative framework allows comparing, contrasting and integrating various perspectives at different levels of analysis, further theorising will be needed to advance OI research. On this basis, we propose some new research categories as well as questions for future research–particularly those that span across research domains that have so far developed in isolation.
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| 5. |
- Hammarsjö, A., et al.
(författare)
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High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses
- 2021
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Ingår i: Journal of Human Genetics. - : Springer Nature. - 1434-5161 .- 1435-232X. ; 66:10, s. 995-1008
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.
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| 7. |
- Lindholm, L, et al.
(författare)
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Genetic re-targeting of adenovirus using a hyperstable scFv domain and an affibody (R) molecule against Her2/neu
- 2004
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Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016 .- 1525-0024. ; 9, s. S250-S250
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Tidskriftsartikel (refereegranskat)abstract
- One important goal in gene therapy is to develop adenovirus (Ad) vectors that are genetically de-targeted as well as re-targeted. Genetic re-targeting of Ad using complex cell-binding ligands has previously not been possible. We have previously demonstrated that ligands for genetic re-targeting of adenoviruses must be able to fold correctly in the cytoplasm of virus producing cells, a milieu that is not conducive to the formation of disulphide bonds. Here, we describe functional Ad5 viruses with fibers and pIX capsid proteins genetically modified to contain two types of complex ligands. One is affibody® molecules, corresponding to small (6 kDa) binding proteins developed by combinatorial protein engineering using a single three-helix bundle staphylococcal protein A domain. The other type is hyperstable antibody scFv domains. The affibody molecule used here (ZH2N) is directed against Her2/neu. Recombinant viruses were constructed with ZH2N in three different positions: (i) at the C-terminus of shaft repeat 7 of de-knobbed fibers; (ii) at the C-terminus of pIX; and (iii) in the HI-loop of the fiber knob. Each of the viruses exhibited a characteristic phenotype regarding fiber content, growth and ability to infect Her2/neu expressing cells. In order to test the potentials of scFv liganded Ad vectors, a hyperstable antibody scFv against b-galactosidase was genetically incorporated into knobless fibers, in tandem with a mutated protein A domain reactive with IgG1 Fc that targeted the virus to Fc-expressing 293 cells. These fibers could be rescued into viable virions that retained the original antigen binding specificity of the scFv, demonstrating the basic potential of hyperstable scFvs for genetic re-targeting of Ad. Quite unexpectedly, the fiber content of Ad with knobless, scFv containing fibers was close to normal in contrast to other Ad with knobless fibers that generally has a much reduced fiber content. The hyperstable scFv was further fused to the C-terminus of the capsid protein pIX. The recombinant molecules could be rescued into viable viruses with wt fibers. The scFv retained its binding-specificity on the recombinant virions. The results demonstrate that, contrary to current beliefs, it is possible to construct Ad that genetically incorporates functional scFvs and other complex ligands into the virus fiber and pIX. The feasibility is demonstrated by the creation of different viruses that are re-targeted to Her2/neu. These viruses are currently in pre-clinical development.
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| 8. |
- Holgersson, G., et al.
(författare)
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Molecular profiling using tissue microarrays as a tool to identify predictive biomarkers in laryngeal cancer treated with radiotherapy
- 2010
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Ingår i: Cancer Genomics & Proteomics. - 1109-6535 .- 1790-6245. ; 7:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To explore the usefulness of the expression of five potential cancer biomarkers in predicting outcome in patients with laryngeal cancer. Materials and Methods: In the present study, the Swedish National Cancer Registry databases were used to identify patients with laryngeal cancer diagnosed during the years 1978-2004 in the Uppsala-Örebro region and treated with radiotherapy. The expression of Ki-67, MutS homolog 2, (MSH2), p53, B-cell CLL/lymphoma 2 (Bcl-2) and cyclin D1 in the cancer cells was assessed immunohistochemically using tissue microarrays (TMAs) and its predictve value on survival and relapse was analyzed using Cox regression models. Results: A total of 39 patients were included in the present study. Nuclear MSH2 staining was statistically significantly correlated to Ki-67 expression (p=0.022). However, univariate and multivariate Cox analyses showed no statistically significant association between the expression of the investigated biomarkers and overall survival or relapse. Conclusion: The present exploratory study does not show any significant predictive value of the biomarkers examined with respect to survival or relapse. However, with larger patient cohorts, we believe that protein profiling using TMAs and immunohistochemistry is a feasible strategy for prognostic and predictive biomarker screening in laryngeal cancer.
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| 9. |
- Lundström, Ulla, et al.
(författare)
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Advances in understanding the podzolization process resulting from a multidisciplinary study of three coniferous forest soils in the Nordic Countries
- 2000
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Ingår i: Geoderma. - 0016-7061 .- 1872-6259. ; 94:04-feb, s. 335-353
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Tidskriftsartikel (refereegranskat)abstract
- Geochemical, mineralogical, micromorphological, microbiological, hydrochemical and hpdrological joint investigations were performed at two coniferous podzolic sites in the north of Sweden and at one in the south of Finland. Mycorrhizal fungi were found to create numerous pens (3-10-mu m diameter) in many weatherable mineral grains in the eluvial (E) horizon. During the growing season, identified low molecular weight (LMW) organic acids such as citric, shikimic, oxalic and fumaric acids comprised 0.5-5% of the DOC and 0.5-15% of the total acidity in soil solutions. Between 20% and 40% of the dissolved Al was bound to the identified LMW organic acids. Mineral dissolution via complexing LMW acids, probably exuded in part by the mycorrhiza hyphae, is likely to be a major weathering process in podzols. We found no evidence for a decreasing C/metal ratio of the migrating organo-metal complexes that could explain the precipitation of secondary Fe and AL in the illuvial (B) horizon. Instead, microbial degradation of organic ligands resulting in the release of ionic,Al and Fe to the soil solution may he an important process facilitating the formation of solid Al-SI-OH and Fe-OH phases in the podzol B horizon. However, within the B horizon transport as proto-imogilite (PI) sols might be possible. In the B horizon, the extractable,Al and Fe was predominantly inorganic. The large specific surface area (SSA) removable by oxalate extraction, the high point of zero charge salt effect (PZSE), the low cation exchange capacity (CEC) and the high sulphate exchange capacity (SEC), painted to the presence of short-range ordered variable charge phases. Imogolite type material (ITM) was indeed identified in all B horizons by IR spectroscopy and crystalline imogolite was found in the deep B horizon of one profile. Mossbauer spectroscopy indicated that Fe in the form of ferrihydrite was formed by intergrowth with an Al-Si-OH phase. The high amounts of Fe and Al transported from the O to the E horizon indicate that there could be an upward transport of these elements before they are leached to the B horizon. We hypothesize that the LMW Al complexes an transported by hyphae to the mor (O) layer, partly released and subsequently complexed by high molecular weight (HMW) acids.
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| 10. |
- Dodig-Crnkovic, Tea, et al.
(författare)
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Facets of individual-specific health signatures determined from longitudinal plasma proteome profiling
- 2020
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Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 57
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Tidskriftsartikel (refereegranskat)abstract
- Background: Precision medicine approaches aim to tackle diseases on an individual level through molecular profiling. Despite the growing knowledge about diseases and the reported diversity of molecular phenotypes, the descriptions of human health on an individual level have been far less elaborate. Methods: To provide insights into the longitudinal protein signatures of well-being, we profiled blood plasma collected over one year from 101 clinically healthy individuals using multiplexed antibody assays. After applying an antibody validation scheme, we utilized > 700 protein profiles for in-depth analyses of the individuals' short-term health trajectories. Findings: We found signatures of circulating proteomes to be highly individual-specific. Considering technical and longitudinal variability, we observed that 49% of the protein profiles were stable over one year. We also identified eight networks of proteins in which 11-242 proteins covaried over time. For each participant, there were unique protein profiles of which some could be explained by associations to genetic variants. Interpretation: This observational and non-interventional study identifyed noticeable diversity among clinically healthy subjects, and facets of individual-specific signatures emerged by monitoring the variability of the circulating proteomes over time. To enable more personal hence precise assessments of health states, longitudinal profiling of circulating proteomes can provide a valuable component for precision medicine approaches.
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