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- Jiao, Xiang, et al.
(author)
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PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
- 2017
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
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Journal article (peer-reviewed)abstract
- Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
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| 2. |
- Lindstrand, Anna, et al.
(author)
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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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In: Genome Medicine. - : BMC. - 1756-994X. ; 11:1
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Journal article (peer-reviewed)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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| 6. |
- Heins, Anna Lena, et al.
(author)
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Quantitative flow cytometry to understand population heterogeneity in response to changes in substrate availability in escherichia coli and saccharomyces cerevisiae chemostats
- 2019
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In: Frontiers in Bioengineering and Biotechnology. - : Frontiers Media SA. - 2296-4185. ; 7:AUG
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Journal article (peer-reviewed)abstract
- Microbial cells in bioprocesses are usually described with averaged parameters. But in fact, single cells within populations vary greatly in characteristics such as stress resistance, especially in response to carbon source gradients. Our aim was to introduce tools to quantify population heterogeneity in bioprocesses using a combination of reporter strains, flow cytometry, and easily comprehensible parameters. We calculated mean, mode, peak width, and coefficient of variance to describe distribution characteristics and temporal shifts in fluorescence intensity. The skewness and the slope of cumulative distribution function plots illustrated differences in distribution shape. These parameters are person-independent and precise. We demonstrated this by quantifying growth-related population heterogeneity of Saccharomyces cerevisiae and Escherichia coli reporter strains in steady-state of aerobic glucose-limited chemostat cultures at different dilution rates and in response to glucose pulses. Generally, slow-growing cells showed stronger responses to glucose excess than fast-growing cells. Cell robustness, measured as membrane integrity after exposure to freeze-thaw treatment, of fast-growing cells was strongly affected in subpopulations of low membrane robustness. Glucose pulses protected subpopulations of fast-growing but not slower-growing yeast cells against membrane damage. Our parameters could successfully describe population heterogeneity, thereby revealing physiological characteristics that might have been overlooked during traditional averaged analysis.
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| 7. |
- Lundin, Anders, et al.
(author)
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Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models
- 2018
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In: Stem Cell Reports. - : Cell Press. - 2213-6711. ; 10:3, s. 1030-1045
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Journal article (peer-reviewed)abstract
- In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology.
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| 8. |
- Skoglund, Charlotte, et al.
(author)
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Association of Attention-Deficit/Hyperactivity Disorder With Teenage Birth Among Women and Girls in Sweden
- 2019
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In: JAMA Network Open. - : AMER MEDICAL ASSOC. - 2574-3805. ; 2:10
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Journal article (peer-reviewed)abstract
- IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) is associated with a plethora of adverse health outcomes throughout life. While Swedish specialized youth clinics have carefully and successfully targeted risk of unplanned pregnancies in adolescents, important risk groups, such as women and girls with ADHD, might not be identified or appropriately assisted by these interventions. OBJECTIVES To determine whether women and girls with ADHD are associated with increased risk of teenage birth compared with their unaffected peers and to examine the association of ADHD with risk factors for adverse obstetric and perinatal outcomes, such as smoking, underweight or overweight, and substance use disorder. DESIGN, SETTING, AND PARTICIPANTS This nationwide cohort study included data from 6 national longitudinal population-based registries in Sweden. All nulliparous women and girls who gave birth in Sweden between January 1, 2007, and December 31, 2014, were included. Data analyses were conducted from October 7, 2018, to February 8, 2019. EXPOSURES Women and girls treated with stimulant or nonstimulant medication for ADHD (Anatomic Therapeutic Chemical classification code N06BA) in the Swedish Prescribed Drug Register between July 1, 2005, and December 31, 2014. MAIN OUTCOMES AND MEASURES Maternal age at birth. Secondary outcome measures were body mass index, smoking habits, and psychiatric comorbidities. RESULTS Among 384 103 nulliparous women and girls aged 12 to 50 years who gave birth between 2007 and 2014 included in the study, 6410 (1.7%) (mean [SD] age, 25.0 [5.5] years) were identified as having ADHD. The remaining 377 693 women and girls without ADHD (mean [SD] age, 28.5 [5.1] years) served as the control group. Teenage deliveries were more common among women and girls with ADHD than among women and girls without ADHD (15.3% vs 2.8%; odds ratio [OR], 6.23 [95% CI, 5.80-6.68]). Compared with women and girls without ADHD, those with ADHD were more likely to present with risk factors for adverse obstetric and perinatal outcomes, including smoking during the third trimester (OR, 6.88 [95% CI, 6.45-7.34]), body mass index less than 18.50 (OR, 1.29 [95% CI, 1.12-1.49]), body mass index more than 40.00 (OR, 2.01 [95% CI, 1.60-2.52]), and alcohol and substance use disorder (OR, 20.25 [95% CI, 18.74-21.88]). CONCLUSIONS AND RELEVANCE This study found that women and girls with ADHD were associated with an increased risk of giving birth as teenagers compared with their unaffected peers. The results suggest that standard of care for women and girls with ADHD should include active efforts to prevent teenage pregnancies.
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- Stecksén, Anna, 1982-
(author)
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Stroke thrombolysis on equal terms? : implementation and ADL outcome
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Stroke thrombolysis is a method for restoring cerebral blood flow after ischemic stroke, with high priority in the Swedish national guidelines. implementation of stroke thrombolysis in Swedish routine stroke care has shown marked differences between demographic groups, hospital types, and regions. The general aim of this thesis were to examine the implementation of ischemic stroke thrombolysis in Swedish routine stroke care with an equity perspective; to gain more insight into the factors that influence implementation, how the treatment has reached patient groups, and differences in long-term outcomes between women and men. Analysis of data from research interviews with clinicians working within stroke care displayed that the facilitators of and barriers to the implementation of stroke thrombolysis could broadly be categorized into those related to individuals, to social interactions and context, and to organizational and resource issues. Key facilitating factors expressed in interviews were work pride and motivation, good leadership, involvement of all staff members in the implementation process, and quality assurance. Major barriers concerned lack of competence and experience, outdated attitudes regarding stroke management, counterproductive power structures, lack of continuity, and insufficient human resources. National quality register data displayed that stroke thrombolysis treatment expanded to reach more patients with mild deficits. Groups with higher education were more likely to receive treatment, compared to groups with lower educational level. These education group differences have, however, decreased over time in relative terms, but not in absolute terms. Further, there were considerable between-hospitals differences in treatment rates for patients with milder deficits, associated with hospital’s overall stroke thrombolysis rates. Moreover, larger non-university hospitals displayed treatment rate differences between educational groups that were not attributable to patient characteristics. Among thrombolysis-treated women and men, that was independent in ADL before their stroke and survived the first year post-stroke, women experienced higher probability to be dependent in ADL at both 3 and 12 months post-stroke, compared to men. This difference remained significant despite comprehensive adjustments for individual characteristics, symptom severity, and acute effects from stroke thrombolysis.This thesis displays that clinicians face barriers and facilitators at several levels, suggesting implementation interventions could be targeted towards both the individual-, the social interactions and context-, and also the organisation and available resources level. Assurance of clinicians’ individual competence, peer support, and clinical leadership seem to be important areas to intervene. Stroke thrombolysis rates have expanded over time, and an increase in stroke thrombolysis delivery to patients with mild stroke symptoms has contributed to this increase. However, it seems considerable differences between hospitals inhibit equity of care delivery. Further, socioeconomically disadvantaged groups receive less often stroke thrombolysis. Type of hospital seems to play a role, yet the reasons for this difference are not fully understood. This thesis also display that stroke thrombolysis-treated women that survive 1 year after stroke, appears to face higher risk for dependency in ADL, compared to men.
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