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- Stray-Pedersen, Asbjorg, et al.
(författare)
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Primary immunodeficiency diseases : Genomic approaches delineate heterogeneous Mendelian disorders
- 2017
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Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 139:1, s. 232-245
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Tidskriftsartikel (refereegranskat)abstract
- Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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- Jacob, P., et al.
(författare)
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Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13
- 2023
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Ingår i: NPJ GENOMIC MEDICINE. - 2056-7944. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants' impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.
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- Kazandjian, D, et al.
(författare)
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Molecular underpinnings of clinical disparity patterns in African American vs. Caucasian American multiple myeloma patients
- 2019
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Ingår i: Blood cancer journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:2, s. 15-
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Tidskriftsartikel (refereegranskat)abstract
- Caucasian Americans (CA) compared with African Americans (AA) have a twofold increased incidence of multiple myeloma (MM) and have an earlier age of diagnosis. However, there is sparse information regarding underlying biological differences across racial/ethnic groups. We characterized genetic alterations using a targeted next-generation sequencing assay called myTYPE, developed at MSKCC, allowing capture of somatic mutations, IgH translocations, gains/losses, and hyperdiploidy. Samples were obtained from the NIH Plasma Cell Dyscrasia Racial Disparity Cohort. In total, 68 patient samples were successfully sequenced and manually curated based on well-established databases. Of the 68 patient samples (47 CA, 21 AA), 84% had at least one type of genomic alteration. Importantly, the IgH translocation, t(11;14), was observed more frequently in the AA group (0 vs. 29%, p = 0.001). Known oncogenic somatic non-synonymous mutations were found in 18 genes and indels in 2 genes. KRAS mutations were the most common mutation found in 16% of patients followed by NRAS and BRAF mutations. TP53 somatic mutations appeared to be more common in CA but lacked significance. This proof-of-principle study indicates the presence of varying underlying tumor biology between racial groups and supports the need of future prospective trials to capture these molecular characteristics.
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- Medina, I., et al.
(författare)
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Activity of caffeic acid in different fish lipid matrices: A review
- 2012
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Ingår i: Food Chemistry. - : Elsevier BV. - 0308-8146 .- 1873-7072. ; 131:3, s. 730-740
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Forskningsöversikt (refereegranskat)abstract
- Caffeic acid, a hydroxycinnamic acid common in different vegetable sources, has been employed as a natural antioxidant for inhibiting oxidation of fish lipids present in different food matrices. The aim of this review is to discuss the mechanisms involved in the antioxidative and prooxidative effects of caffeic acid found in different model systems containing fish lipids. These model systems include bulk fish oils, liposomes from cod roe phospholipids, fish oil emulsions, washed cod mince, regular horse mackerel mince and a fish oil fortified fitness bar. The data reported show that the antioxidant activity depends on the physical state of the lipids and the composition of the intrinsic matrix in which they are situated. Caffeic acid significantly prevented rancidity in both unwashed and washed fish mince, the latter which was fortified with haemoglobin. In the unwashed mince, the activity was however clearly dependent on the lipid to antioxidant ratio. In these systems, an important redox cycle between caffeic acid and the endogenous reducing agents ascorbic acid and tocopherol were further thought to play an important role for the protective effects. The effect of caffeic acid was also highly dependent on the storage temperature, showing higher effectiveness above than below 0 degrees C. Caffeic acid was not able to inhibit oxidation of bulk fish oils, fish oil in water emulsions and the fish-oil enriched fitness bar. In the liposome system, caffeic acid inhibited haemoglobin (Hb)-promoted oxidation but strongly mediated Fe(2+) mediated oxidation. In conclusion, caffeic acid can significantly prevent Hb-mediated oxidation in fish muscle foods but its activity in food emulsions and liposomes is highly dependent on the pH, the emulsifier used and the prooxidants present.
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- Standal, Inger Beate, et al.
(författare)
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Quality of Filleted Atlantic Mackerel (Scomber Scombrus) During Chilled and Frozen Storage: Changes in Lipids, Vitamin D, Proteins, and Small Metabolites, including Biogenic Amines
- 2018
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Ingår i: Journal of Aquatic Food Product Technology. - : Informa UK Limited. - 1049-8850 .- 1547-0636. ; 27:3, s. 338-357
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Tidskriftsartikel (refereegranskat)abstract
- Quality changes of vacuum-packed Atlantic mackerel (Scomber scombrus) fillets during 12 months’ frozen storage at −27°C and 9 days’ chilled storage at +4°C were evaluated. Freezing at −27°C preserved the long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), both in light and dark muscle, vitamin D, and the low molecular weight metabolites (LMW) (studied by high resolution nuclear magnetic resonance spectroscopy, HR NMR). Protein oxidation took place, especially between 1 and 7 months, decreasing water holding capacity and protein extractability. During chilled storage, no lipid or protein oxidation was observed, but lipolysis increased, and several LMW metabolites relevant for sensory and nutritional quality degraded into non-favorable compounds. The content of biogenic amines was high at day 9 (e.g., 18 mg histamine/100 g), jeopardizing safety. Preservation of mackerel fillets by freezing at −27°C is thus a better option compared to prolonged chilled storage at +4°C; the quality was well preserved for 12 months’ frozen storage.
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| 12. |
- Sveinsdóttir, Hildur I., et al.
(författare)
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Effect of antioxidants on the sensory quality and physicochemical stability of Atlantic mackerel (Scomber scombrus) fillets during frozen storage
- 2020
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Ingår i: Food Chemistry. - : Elsevier BV. - 0308-8146 .- 1873-7072. ; 321
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to evaluate the shelf-life of mechanically filleted well-fed Atlantic mackerel during frozen storage at −25 °C and effect of treatment with antioxidants (sodium erythorbate and a polyphosphate mixture) and different antioxidant application methods (dipping, spraying and glazing). Both physicochemical measurements and sensory analysis were applied. Antioxidant treatments prolonged shelf-life of mackerel. Sensory analysis indicated that untreated fillets had a shelf-life of less than 2.5 months, while all antioxidant treated fillets exceeded that. The most effective treatment, dipping fillets into a sodium erythorbate solution, yielding a shelf-life of 15 months. Physicochemical methods used to evaluate degradation of lipids in the fillets were free fatty acids (FFA), lipid hydroperoxides (PV) and thiobarbituric acid reactive substances (TBARS). They did not correlate with sensory results and might therefore be a questionable choice for evaluation of oxidation and development of rancid flavour and odour in complex matrixes such as Atlantic mackerel.
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| 13. |
- Yellapantula, V, et al.
(författare)
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Comprehensive detection of recurring genomic abnormalities: a targeted sequencing approach for multiple myeloma
- 2019
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Ingår i: Blood cancer journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:12, s. 101-
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Tidskriftsartikel (refereegranskat)abstract
- Recent genomic research efforts in multiple myeloma have revealed clinically relevant molecular subgroups beyond conventional cytogenetic classifications. Implementing these advances in clinical trial design and in routine patient care requires a new generation of molecular diagnostic tools. Here, we present a custom capture next-generation sequencing (NGS) panel designed to identify rearrangements involving the IGH locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay. We sequenced 154 patients with plasma cell disorders and performed a head-to-head comparison with the results from conventional clinical assays, i.e., fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarray. Our custom capture NGS panel had high sensitivity (>99%) and specificity (>99%) for detection of IGH translocations and relevant chromosomal gains and losses in multiple myeloma. In addition, the assay was able to capture novel genomic markers associated with poor outcome such as bi-allelic events involving TP53. In summary, we show that a multiple myeloma designed custom capture NGS panel can detect IGH translocations and CNAs with very high concordance in relation to FISH and SNP microarrays and importantly captures the most relevant and recurrent somatic mutations in multiple myeloma rendering this approach highly suitable for clinical application in the modern era.
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