| 1. |
- Ericsson, Olle, et al.
(författare)
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Clinical validation of a novel automated cell-free DNA screening assay for trisomies 21, 13, and 18 in maternal plasma.
- 2019
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Ingår i: Prenatal diagnosis. - : Wiley. - 1097-0223 .- 0197-3851. ; 39:11, s. 1011-1015
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate clinical performance of a new automated cell-free (cf)DNA assay in maternal plasma screening for trisomies 21, 18, and 13, and to determine fetal sex.Maternal plasma samples from 1200 singleton pregnancies were analyzed with a new non-sequencing cfDNA method, which is based on imaging and counting specific chromosome targets. Reference outcomes were determined by either cytogenetic testing, of amniotic fluid or chorionic villi, or clinical examination of neonates.The samples examined included 158 fetal aneuploidies. Sensitivity was 100% (112/112) for trisomy 21, 89% (32/36) for trisomy 18, and 100% (10/10) for trisomy 13. The respective specificities were 100%, 99.5%, and 99.9%. There were five first pass failures (0.4%), all in unaffected pregnancies. Sex classification was performed on 979 of the samples and 99.6% (975/979) provided a concordant result.The new automated cfDNA assay has high sensitivity and specificity for trisomies 21, 18, and 13 and accurate classification of fetal sex, while maintaining a low failure rate. The study demonstrated that cfDNA testing can be simplified and automated to reduce cost and thereby enabling wider population-based screening.
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| 2. |
- 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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| 3. |
- Ljungquist, Oskar, et al.
(författare)
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Convalescent plasma treatment in severely immunosuppressed patients hospitalized with COVID-19 : an observational study of 28 cases
- 2022
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Ingår i: Infectious Diseases. - : Taylor & Francis Group. - 2374-4235 .- 2374-4243 .- 1651-1980. ; 54:4, s. 283-291
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immunosuppressed patients are particularly vulnerable to severe infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), risking prolonged viremia and symptom duration. In this study we describe clinical and virological treatment outcomes in a heterogeneous group of patients with severe immunosuppression due to various causes suffering from COVID-19 infection, who were all treated with convalescent plasma (CCP) along with standard treatment.Methods: We performed an observational, retrospective case series between May 2020 to March 2021 at three sites in Skåne, Sweden, with a population of nearly 1.4 million people. All patients hospitalized for COVID-19 who received CCP with the indication severe immunosuppression as defined by the treating physician were included in the study (n = 28).Results: In total, 28 severely immunocompromised patients, half of which previously had been treated with rituximab, who had received in-hospital convalescent plasma treatment of COVID-19 were identified. One week after CCP treatment, 13 of 28 (46%) patients had improved clinically defined as a decrease of at least one point at the WHO-scale. Three patients had increased score points of whom two had died. For 12 patients, the WHO-scale was unchanged.Conclusion: As one of only few studies on CCP treatment of COVID-19 in hospitalized patients with severe immunosuppression, this study adds descriptive data. The study design prohibits conclusions on safety and efficacy, and the results should be interpreted with caution. Prospective, randomized trials are needed to investigate this further.
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| 4. |
- Micke, Patrick, et al.
(författare)
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The prognostic impact of the tumour stroma fraction : A machine learning-based analysis in 16 human solid tumour types
- 2021
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Background: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed.Methods: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns.Findings: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR (95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59 (1.49-8.62)) associations of the tumour stroma fraction with survival.Interpretation: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance.
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| 5. |
- Agnarsson, Björn, 1977, et al.
(författare)
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Evanescent Light-Scattering Microscopy for Label-Free Interfacial Imaging: From Single Sub-100 nm Vesicles to Live Cells
- 2015
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-086X .- 1936-0851. ; 9:12, s. 11849-11862
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Tidskriftsartikel (refereegranskat)abstract
- Advancement in the understanding of biomolecular interactions has benefited greatly from the development of surface-sensitive bioanalytical sensors. To further increase their broad impact, significant efforts are presently being made to enable label-free and specific biomolecule detection with high sensitivity, allowing for quantitative interpretation and general applicability at low cost. In this work, we have addressed this challenge by developing a waveguide chip consisting of a flat silica core embedded in a symmetric organic cladding with a refractive index matching that of water. This is shown to reduce stray light (background) scattering and thereby allow for label-free detection of faint objects, such as individual sub-20 rim gold nanoparticles as well as sub-100 nm lipid vesicles. Measurements and theoretical analysis revealed that light-scattering signals originating from single surface-bound lipid vesicles enable characterization of their sizes without employing fluorescent lipids as labels. The concept is also demonstrated for label-free measurements of protein binding to and enzymatic (phospholipase A2) digestion of individual lipid vesicles, enabling an analysis of the influence on the measured kinetics of the dye-labeling of lipids required in previous assays. Further, diffraction-limited imaging of cells (platelets) binding to a silica surface showed that distinct subcellular features could be visualized and temporally resolved during attachment, activation, and spreading. Taken together, these results underscore the versatility and general applicability of the method, which due to its simplicity and compatibility with conventional microscopy setups may reach a widespread in life science and beyond.
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| 6. |
- Agnarsson, Björn, 1977, et al.
(författare)
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Waveguide structure
- 2018
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Patent (övrigt vetenskapligt/konstnärligt)abstract
- A waveguide structure for evanescent wave microscopy and/or spectroscopy, comprising an optically transparent core layer, a lower dielectric cladding layer and an upper dielectric cladding layer arranged on opposite sides of the core layer. The core layer has a refractive index higher than the refractive indices of the cladding layers. The upper cladding layer is made of an organic material. A sample well is arranged on an upper surface of the core layer formed by a cavity in the upper cladding layer, the sample well being adapted to contain a sample medium with one or more sample objects. The core layer is made of a first dielectric inorganic material, and the upper cladding layer has a refractive index which closely matches the refractive index of the sample medium. A method for manufacturing such waveguide structure, and a measurement system comprising the waveguide structure are also disclosed.
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| 7. |
- Ahlgren, Kerstin M., et al.
(författare)
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Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model
- 2011
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 41:1, s. 235-245
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.
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| 8. |
- Ahlsson, Fredrik, et al.
(författare)
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Females born large for gestational age have a doubled risk of giving birth to large for gestational age infants
- 2007
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 96:3, s. 358-362
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To analyse if females born large for gestational age (LGA) have an increased risk to give birth to LGA infants and to study anthropometric characteristics in macrosomic infants of females born LGA.Methods: The investigation was performed as an intergenerational retrospective study of women born between 1973 and 1983, who delivered their first infant between 1989 and 1999. Birth characteristics of 47 783 females, included in the Swedish Birth Register both as newborns and mothers were analysed. LGA was defined as >2 SD in either birth weight or length for gestational age. The infants were divided into three subgroups: born tall only, born heavy only and born both tall and heavy for gestational age. Multiple logistic and linear regression analyses were performed.Results: Females, born LGA with regard to length or weight, had a two-fold (adjusted OR 1.96, 95% Cl 1.54-2.48) increased risk to give birth to an LGA infant. Females, born LGA concerning weight only, had a 2.6 (adjusted OR 2.63, 95%, 1.85-3.75) fold increased risk of having an LGA offspring heavy only and no elevated risk of giving birth to an offspring that was tall only, compared to females born not LGA. In addition, maternal obesity was associated with a 2.5 (adjusted OR 2.56, 95%, 2.20-2.98) fold increased risk of having an LGA newborn, compared to mothers with normal weight.Conclusion: Females, born LGA, have an increased risk to give birth to LGA infants, compared to mothers born not LGA. Maternal overweight increases this risk even further.
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| 9. |
- Ahlsson, Fredrik, et al.
(författare)
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Gestational diabetes and offspring body disproportion
- 2010
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 99:1, s. 89-93
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Tidskriftsartikel (refereegranskat)abstract
- Aim: It has been demonstrated that females born large for gestational age (LGA) in weight but not length are at increased risk of being obese at childbearing age. We addressed the question whether women with gestational diabetes mellitus (GDM) are at increased risk of giving birth to such infants. Methods: Birth characteristics of 884 267 infants of non-diabetic mothers and 7817 of mothers with GDM were analysed. LGA was defined as birth weight or birth length > 2 standard deviation scores for gestational age. Multiple logistic regression analysis was performed. Results: The odds ratio (OR) for a woman with GDM to give birth to an LGA infant that was heavy alone was four times increased (OR: 3.71, 95% CI: 3.41-4.04). Furthermore, in the population of mothers giving birth to LGA infants, the proportion heavy alone was 68% in the group of women with GDM compared with 64.4% in the group of non-diabetic women. The risks were independent of gender of the foetus. Conclusion: Women with GDM have an almost four times higher risk of delivering an LGA infant that is heavy alone. The noted disproportion between weight and length in infants of such mothers may have an impact on the risk of later obesity.
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| 10. |
- Ahlsson, Fredrik, 1967-, et al.
(författare)
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School Performance After Preterm Birth
- 2015
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Ingår i: Epidemiology. - 1044-3983 .- 1531-5487. ; 26:1, s. 106-111
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Tidskriftsartikel (refereegranskat)abstract
- Background: An increased risk of poor school performance for children born preterm has been shown in many studies, but whether this increase is attributable to preterm birth per se or to other factors associated with preterm birth has not been resolved. Methods: We used data from the Swedish Medical Birth Register, the Longitudinal Integration Database for Sickness Insurance and Labor Market Study, the Swedish Multigeneration Register, and the National School Register to link records comprising the Swedish birth cohorts from 1974 through 1991. Linear regression was used to assess the association between gestational duration and school performance, both with and without controlling for parental and socioeconomic factors. In a restricted analysis, we compared siblings only with each other. Results: Preterm birth was strongly and negatively correlated with school performance. The distribution of school grades for children born at 31-33 weeks was on average 3.85 (95% confidence interval = -4.36 to -3.35) centiles lower than for children born at 40 weeks. For births at 22-24 weeks, the corresponding figure was -23.15 (-30.32 to -15.97). When taking confounders into account, the association remained. When restricting the analysis to siblings, however, the association between school performance and preterm birth after week 30 vanished completely, whereas it remained, less pronounced, for preterm birth before 30 weeks of gestation. Conclusions: Our study suggests that the association between school performance and preterm birth after 30 gestational weeks is attributable to factors other than preterm birth per se.
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