| 1. |
- Lindstrand, Anna, et al.
(författare)
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From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
- 2019
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Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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| 2. |
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| 3. |
- Rudman, Ann, et al.
(författare)
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Sjuksköterskor i frontlinjen av COVID-19 pandemin : vilka blev konsekvenserna? Teknisk rapport om enkät och datainsamling
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna rapport summerar datainsamlingen som genomfördes av SCB (Statistiska centralbyrån) i projektet ”Sjuksköterskor i frontlinjen av COVID-19 pandemin: Vilka blev konsekvenserna?”. Projektet är finansierat av AFA försäkring (Diarienr 200311). I kapitel 1 beskrivs bakgrund till LUST (Longitudinell Undersökning om Sjuksköterskors Tillvaro) studien. I kapitel 2 beskrivs studien utifrån design, rekrytering och datainsamling. I kapitel 3 redovisas översikt över innehållet i enkäten som skickades ut studiedeltagarna. Projektet bedrivs på Högskolan Dalarna och inom ramen för Petter Gustavssons forskargrupp vid Karolinska Institutet.Sjuksköterskor har varit i frontlinjen av COVID-19-pandemin och de stressorer som de utsatts för i sitt arbete inom hälso- och sjukvården kan orsaka hälsoproblem. I föreliggande projekt har en nationell kartläggning av sjuksköterskors arbetssituation och hälsa under COVID-19 pandemin gjorts. Undersökningen är gjord utifrån de tre sjuksköterskekohorter som följts inom ramen för LUST-studien sedan 2002 (Gustavsson et al., 2013; Rudman, Hörberg, et al., 2020; Rudman et al., 2010). I LUST-studien har närmare 4500 sjuksköterskestudenter följts med uppföljande enkäter från deras utbildningstid 11 till 15 år efter examen. En uppföljande enkätundersökning genomfördes i september 2021 till januari 2022 vilket motsvarar 15 till 19 år efter examen. En speciellt anpassad enkät med relevans och aktualitet för arbetet under pandemin hade utvecklats gemensamt med forskare som har expertis gällande sjuksköterskor i olika verksamheter som belastats under COVID-19 pandemin. Enkäterna besvarades när pandemin pågått i ungefär ett år och nio månader.I samarbete med SCB har datainsamlingen genomförts som en postenkät med påminnelser och med möjlighet att besvara frågorna online. Svarsfrekvensen för enkätstudien blev 57% för hela undersökningen (för samtliga kohorter), vilket bedöms vara en hög svarsfrekvens med tanke på hur belastad sjuksköterskekåren har varit under COVID-19 pandemin.
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| 4. |
- Semb, Gunvor, et al.
(författare)
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A Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 1. Planning and management.
- 2017
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - : Taylor & Francis. - 2000-656X .- 2000-6764. ; 51:1, s. 2-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Longstanding uncertainty surrounds the selection of surgical protocols for the closure of unilateral cleft lip and palate, and randomised trials have only rarely been performed. This paper is an introduction to three randomised trials of primary surgery for children born with complete unilateral cleft lip and palate (UCLP). It presents the protocol developed for the trials in CONSORT format, and describes the management structure that was developed to achieve the long-term engagement and commitment required to complete the project.METHOD: Ten established national or regional cleft centres participated. Lip and soft palate closure at 3-4 months, and hard palate closure at 12 months served as a common method in each trial. Trial 1 compared this with hard palate closure at 36 months. Trial 2 compared it with lip closure at 3-4 months and hard and soft palate closure at 12 months. Trial 3 compared it with lip and hard palate closure at 3-4 months and soft palate closure at 12 months. The primary outcomes were speech and dentofacial development, with a series of perioperative and longer-term secondary outcomes.RESULTS: Recruitment of 448 infants took place over a 9-year period, with 99.8% subsequent retention at 5 years.CONCLUSION: The series of reports that follow this introductory paper include comparisons at age 5 of surgical outcomes, speech outcomes, measures of dentofacial development and appearance, and parental satisfaction. The outcomes recorded and the numbers analysed for each outcome and time point are described in the series.TRIAL REGISTRATION: ISRCTN29932826.
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| 5. |
- Borgegard, Tomas, et al.
(författare)
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Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.
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| 6. |
- Borgegård, Tomas, et al.
(författare)
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Alzheimer's Disease : Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.
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| 8. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 9. |
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| 10. |
- Gustavsson, Larisa, et al.
(författare)
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Screening of Apple Cultivars for Resistance to European Canker, Neonectria ditissima
- 2013
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Ingår i: Acta Horticulturae. - 0567-7572 .- 2406-6168. ; 976, s. 529-536
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Konferensbidrag (refereegranskat)abstract
- European canker, caused by the fungus Neonectria ditissima, is a severe problem in apple production both in Sweden and in many other northern European countries. Even when applying fungicides and good horticultural practices, canker damage occurs almost yearly in nurseries and orchards. Some years, devastating outbreaks destroy numerous trees. To date, complete resistance to N. ditissima is not known in apple. For further research and plant breeding, heritable variation in quantitative resistance should be investigated by phenotyping large sets of cultivars. In the present project, 55 apple cultivars were screened for resistance to N. ditissima. One-year-old shoots from mature trees were inoculated in the greenhouse with a standardized volume and concentration of conidia suspension using different inoculation methods. Two-year-old trees of five cultivars were inoculated in the field. Length of the occurring cankers was measured at regular intervals throughout a period of up to three months. The investigated cultivars showed considerable differences in colonization rate. In cultivars known to be highly resistant, i.e., 'Santana', lesions progressed much slower compared to susceptible cultivars like 'Cox's Orange Pippin' and 'James Grieve'. Since the inoculation-based phenotyping is demanding in labour and time (duration), especially when the test is performed on grafted trees, qPCR-based assessment of fungal biomass at early stages of infection was explored as an alternative or complementary approach for phenotyping.
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