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| 2. |
- Kleinau, Sandra, et al.
(författare)
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Importance of CD23 for collagen-induced arthritis : delayed onset and reduced severity in CD23-deficient mice
- 1999
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 162:7, s. 4266-4270
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Tidskriftsartikel (refereegranskat)abstract
- Increased expression of the low affinity receptor for IgE, FcepsilonRII/CD23 has been observed in rheumatoid arthritis. In view of this, we have investigated the expression and influence of CD23 in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. CD23+ cells were analyzed in lymph nodes of DBA/1 mice immunized with bovine collagen type II (BCII) in CFA or with CFA only. The percentage of CD23+ lymph node cells was increased in both BCII/CFA- and CFA-immunized mice at 1, 3, and 7 wk after immunization compared with unimmunized mice, indicating a role for the adjuvant to trigger general inflammation and CD23 expression. To investigate the functional role of CD23 in CIA, CD23-deficient mice on the DBA/1 genetic background were studied. After immunization with BCII/CFA, these mice developed CIA with delayed onset and reduced severity compared with wild-type mice. These findings suggest that an increased number of CD23+ cells is part of an inflammatory response and that CD23 expression is of pathogenic importance in the arthritic process.
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| 3. |
- Li, Xiujuan, et al.
(författare)
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Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The acute phase of myocardial infarction (MI) is accompanied by edema contributing to tissue damage and disease outcome. Here, we aimed to identify the mechanism whereby vascular endothelial growth factor (VEGF)-A induces myocardial edema in the acute phase of MI to eventually promote development of therapeutics to specifically suppress VEGFA-regulated vascular permeability while preserving collateral vessel formation.Methods and Results: VEGFA regulates vascular permeability and edema by activation of VEGF receptor-2 (VEGFR2), leading to induction of several signaling pathways including the cytoplasmic tyrosine kinase c-Src. The activated c-Src in turn phosphorylates vascular endothelial (VE)-cadherin, leading to dissociation of endothelial adherens junctions. A particular tyrosine at position 949 in mouse VEGFR2 has been shown to be required for activation of c-Src. Wild-type mice and mice with phenylalanine replacing tyrosine (Y) 949 in VEGFR2 (Vegfr2Y949F/Y949F) were challenged with MI through permanent ligation of the left anterior descending coronary artery. The infarct size was similar in wild-type and mutant mice, but left ventricular wall edema and fibrinogen deposition, indicative of vascular leakage, were reduced in the Vegfr2Y949F/Y949F strain. When challenged with large infarcts, the Vegfr2Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of myeloperoxidase were low in the infarcted Vegfr2Y949F/Y949F hearts, correlating with improved survival. In vivo tyrosine phosphorylation of VE-cadherin at Y685, implicated in regulation of vascular permeability, was induced by circulating VEGFA in the wild-type but remained at baseline levels in the Vegfr2Y949F/Y949F hearts.Conclusion: Suppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.
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| 4. |
- Martinsson, Eva, et al.
(författare)
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School nurses' experience of working in school health service during the COVID-19 pandemic in Sweden
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI Multidisciplinary Digital Publishing Institute. - 1661-7827 .- 1660-4601. ; 18:13, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic has had a vast influence on Swedish society. Related recommendations and political decisions have greatly affected schools. This study aimed to describe school nurses' experience working in Sweden during the pandemic in 2020. The study used a qualitative method with an inductive approach. Interviews with 17 school nurses in five focus groups and one individual interview were conducted. Qualitative content analysis was used. The impact of the pandemic on school nurses can be described through three categories: "Changes in working methods in relation to the students/guardians", "Impact on cooperation with school staff", and "The school nurse's prerequisites for major changes." Overall, school nurses experienced a transition to a digital way of working. Policies and decisions on global and local levels affected the work situations of school nurses as well as the school nurses' social, cultural, and professional experience. The highest priority for school nurses is students, and school nurses adapted their working methods to give support to students during the changing circumstances. School nurses are both pragmatic and highly creative. Cooperation with other school professions is critical, as is support and guidance during crisis situations.
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| 5. |
- Martinsson, Eva, et al.
(författare)
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School Nurses’ Perceptions About Student's Wellbeing During the Covid-19 Pandemic in Sweden
- 2022
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Ingår i: Journal of School Nursing. - : SAGE Publications. - 1059-8405 .- 1546-8364.
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Tidskriftsartikel (refereegranskat)abstract
- The coronavirus 2019 (Covid-19) pandemic has affected both the private and public lives of people worldwide. Countries have chosen different strategies to reduce the spread of infection, including school closures and distance learning. This study aimed to describe school nurses’ perceptions about the wellbeing of students during the Covid-19 pandemic in Sweden. Interviews in five focus groups and one individual were conducted with 17 school nurses in Sweden. The interviews were analyzed using a qualitative content analysis. According to the school nurses’ perceptions, students were concerned about spreading infection, becoming infected themselves, their academic performances, and longing for socialization. The change in the school situation involved a slower pace and less anxiety for some students, more or less physical activity, and an increase in screen time.
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| 11. |
- Richards, Mark, et al.
(författare)
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Claudin5 protects the peripheral endothelial barrier in an organ and vessel-type-specific manner
- 2022
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunctional and leaky blood vessels resulting from disruption of the endothelial cell (EC) barrier accompanies numerous diseases. The EC barrier is established through endothelial cell tight and adherens junctions. However, the expression pattern and precise contribution of different junctional proteins to the EC barrier is poorly understood. Here, we focus on organs with continuous endothelium to identify structural and functional in vivo characteristics of the EC barrier. Assembly of multiple single-cell RNAseq datasets into a single integrated database revealed the variability and commonalities of EC barrier patterning. Across tissues, Claudin5 exhibited diminishing expression along the arteriovenous axis, correlating with EC barrier integrity. Functional analysis identified tissue-specific differences in leakage properties and response to the leakage agonist histamine. Loss of Claudin5 enhanced histamine-induced leakage in an organotypic and vessel type-specific manner in an inducible, EC-specific, knock-out mouse. Mechanistically, Claudin5 loss left junction ultrastructure unaffected but altered its composition, with concomitant loss of zonula occludens-1 and upregulation of VE-Cadherin expression. These findings uncover the organ-specific organisation of the EC barrier and distinct importance of Claudin5 in different vascular beds, providing insights to modify EC barrier stability in a targeted, organ-specific manner.
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| 12. |
- Richards, Mark, et al.
(författare)
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Intra-vessel heterogeneity establishes enhanced sites of macromolecular leakage downstream of laminin alpha 5
- 2021
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 35:12
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial cells display heterogeneous properties based on location and function. How this heterogeneity influences endothelial barrier stability both between and within vessel subtypes is unexplored. In this study, we find that endothelial cells exhibit heterogeneous barrier properties on inter-organ and intra-vessel levels. Using intravital microscopy and sequential stimulation of the ear dermis with vascular endothelial growth factor-A (VEGFA) and/or histamine, we observe distinct, reappearing sites, common for both agonists, where leakage preferentially takes place. Through repetitive stimulation of the diaphragm and trachea, we find inter-organ conservation of such predetermined leakage sites. Qualitatively, predetermined sites display distinct leakage properties and enhanced barrier breakdown compared to less susceptible regions. Mechanistically, laminin alpha 5 is reduced at predetermined sites, which is linked to reduced junctional vascular endothelial (VE)-cadherin and enhanced VEGFA-induced VE-cadherin phosphorylation. These data highlight functional intra-vessel heterogeneity that defines predetermined sites with distinct leakage properties and that may disproportionately impact pathological vascular leakage.
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| 13. |
- Sáinz-Jaspeado, Miguel, et al.
(författare)
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VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis
- 2024
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Ingår i: Life Science Alliance. - : Life Science Alliance. - 2575-1077. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- The endothelial junction component vascular endothelial (VE)–cadherin governs junctional dynamics in the blood and lymphatic vasculature. Here, we explored how lymphatic junction stability is modulated by elevated VEGFA signaling to facilitate metastasis to sentinel lymph nodes. Zippering of VE-cadherin junctions was established in dermal initial lymphatic vessels after VEGFA injection and in tumor-proximal lymphatics in mice. Shape analysis of pan-cellular VE-cadherin fragments revealed that junctional zippering was accompanied by accumulation of small round-shaped VE-cadherin fragments in the lymphatic endothelium. In mice expressing a mutant VEGFR2 lacking the Y949 phosphosite (Vegfr2Y949F/Y949F) required for activation of Src family kinases, zippering of lymphatic junctions persisted, whereas accumulation of small VE-cadherin fragments was suppressed. Moreover, tumor cell entry into initial lymphatic vessels and subsequent metastatic spread to lymph nodes was reduced in mutant mice compared with WT, after challenge with B16F10 melanoma or EO771 breast cancer. We conclude that VEGFA mediates zippering of VE-cadherin junctions in initial lymphatics. Zippering is accompanied by increased VE-cadherin fragmentation through VEGFA-induced Src kinase activation, correlating with tumor dissemination to sentinel lymph nodes.
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| 14. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
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| 15. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
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| 16. |
- Testini, Chiara, et al.
(författare)
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Myc-dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor-2
- 2019
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20:11
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Tidskriftsartikel (refereegranskat)abstract
- Exaggerated signaling by vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR2, in pathologies results in poor vessel function. Still, pharmacological suppression of VEGFA/VEGFR2 may aggravate disease. Delineating VEGFR2 signaling in vivo provides strategies for suppression of specific VEGFR2-induced pathways. Three VEGFR2 tyrosine residues (Y949, Y1212, and Y1173) induce downstream signaling. Here, we show that knock-in of phenylalanine to create VEGFR2 Y1212F in C57Bl/6 and FVB mouse strains leads to loss of growth factor receptor-bound protein 2- and phosphoinositide 3′-kinase (PI3K)p85 signaling. C57Bl/6 Vegfr2Y1212F/Y1212F show reduced embryonic endothelial cell (EC) proliferation and partial lethality. FVB Vegfr2Y1212F/Y1212F show reduced postnatal EC proliferation. Reduced EC proliferation in Vegfr2Y1212F/Y1212F explants is rescued by c-Myc overexpression. We conclude that VEGFR2 Y1212 signaling induces activation of extracellular-signal-regulated kinase (ERK)1/2 and Akt pathways required for c-Myc-dependent gene regulation, endothelial proliferation, and vessel stability.
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| 17. |
- Thomée, Sara, et al.
(författare)
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Phubbing at work : Mobile phone behavior in social contexts at the workplace and associations with the psychosocial work environment
- 2022
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Ingår i: 15th EAOHP Conference 2022. - 9780992878665 ; , s. 589-589
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Phubbing (from phone and snubbing) is the phenomenon of interacting with one'ssmartphone rather than with physically present persons. The smartphone entices multitasking,we can quickly find ourselves mentally elsewhere and in communication with others than wherewe physically are. This means changed behaviors also in traditionally social contexts at work.Breaks at work give an opportunity to recover, but also to chat and socialize with co-workers –a social exchange that seems to be positive for developing collegial cohesion and trust, andfacilitates access to collegial social support. In pilot interviews with safety representatives in the electrical trade, concerns were raised that preoccupation with mobile phones in the breakrooms contributed to reduced social communication in working groups, impaired communication aboutwork tasks and the work environment, less commitment to work, and reduced access to socialsupport. These factors, by extension, may have significance for occupational safety and health,socialization, and productivity. In this research project granted by the Swedish Research Council for Health, Working Life and Welfare, we explore mobile phone behaviors, especially phubbing, in social contexts of working life.Objectives: To explore the occurrence of phubbing in social contexts at workplaces, e.g., in thebreakrooms, how phubbing at work is perceived on different levels in the organization andwhich norms are at play. Further objectives include whether phubbing is associated with socialwork environment factors such as organizational commitment and social support, and whetheror not phubbing at work is an issue that needs to be addressed.Methods: The project has an exploratory approach and combines qualitative and quantitativemethods. Ongoing studies include a) surveys in workplaces in the electrical trade, health careand dentistry, b) interviews with employees, managers, and HR, in the said trades, and c) asurvey to members of the Swedish Electrical worker union (N=13000). Studies a-c map mobilephone behaviors during the working day, perceptions about these behaviors, their causes andconsequences, and the presence of norms and policies regarding mobile phone use at work.Based on these studies, a longitudinal survey in a random sample from the Swedish workingpopulation (n=6000) is planned to examine associations between “phubbing” at work and socialenvironment factors, at baseline and after 6 months.Results: This is an ongoing study. Preliminary results will be presented at the conference, ifaccepted.
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| 18. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.
- 2023
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Ingår i: JCO Precision Oncology (JCO PO). - : American Society of Clinical Oncology. - 2473-4284. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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| 19. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer
- 2023
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Ingår i: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; :7
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.Methods: We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.Results: During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Conclusion: Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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