| 1. |
- Byrne, Julianne, et al.
(författare)
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The PanCareSurFup consortium : research and guidelines to improve lives for survivors of childhood cancer
- 2018
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Ingår i: European Journal of Cancer. - : ELSEVIER SCI LTD. - 0959-8049 .- 1879-0852. ; 103:Nov, s. 238-248
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Tidskriftsartikel (refereegranskat)abstract
- Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF. Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public. Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors. Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health.
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| 2. |
- Reulen, Raoul C, et al.
(författare)
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Risk Factors for Primary Bone Cancer After Childhood Cancer : A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study
- 2023
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 41:21, s. 3735-3746
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy.METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship.RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation ( P trend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m 2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m 2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.
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| 3. |
- Allodji, Rodrigue S., et al.
(författare)
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Risk of subsequent primary leukaemias among 69,460 five-year survivors of childhood cancer diagnosed from 1940 to 2008 in Europe: A cohort study within PanCareSurFup
- 2019
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 117, s. 71-83
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survivors of childhood cancers are at risk of developing subsequent primary leukaemias (SPLs), but the long-term risks beyond 20 years of treatment are still unclear. We investigated the risk of SPLs in five-year childhood cancer survivors using a large-scale pan-European (PanCareSurFup) cohort and evaluated variations in the risk by cancer and demographic factors. Methods: This largest-ever assembled cohort comprises 69,460 five-year childhood cancer survivors from 12 European countries. Standardised incidence ratios (SIRs) and absolute excess risks (AERs) were calculated. Results: One hundred fifteen survivors developed an SPL including 86 myeloid leukaemias (subsequent primary myeloid leukaemias [SPMLs]), 17 lymphoid leukaemias and 12 other types of leukaemias; of these SPLs, 31 (27%) occurred beyond 20 years from the first childhood cancer diagnosis. Compared with the general population, childhood cancer survivors had a fourfold increased risk (SIR = 3.7, 95% confidence interval [CI]: 3.1 to 4.5) of developing leukaemia, and eight leukaemias per 100,000 person-years (AER = 7.5, 95% CI: 6.0 to 9.2) occurred in excess of that expected. The risks remained significantly elevated beyond 20 years from the first primary malignancy (SIR = 2.4, 95% CI: 1.6 to 3.4). Overall, the risk ratio for SPML (SIR = 5.8, 95% CI: 4.6 to 7.1) was higher than that for other SPLs. Conclusions: We demonstrate that beyond 20 years after childhood cancer diagnosis, survivors experience an increased risk for SPLs compared with that expected from the general population. Our findings highlight the need for awareness by survivors and their healthcare providers for potential risk related to SPL. © 2019 Elsevier Ltd
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| 4. |
- Bright, Chloe J, et al.
(författare)
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Risk of Soft-Tissue Sarcoma Among 69 460 Five-Year Survivors of Childhood Cancer in Europe
- 2018
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 110:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer survivors are at risk of subsequent primary soft-tissue sarcomas (STS), but the risks of specific STS histological subtypes are unknown. We quantified the risk of STS histological subtypes after specific types of childhood cancer.Methods: We pooled data from 13 European cohorts, yielding a cohort of 69 460 five-year survivors of childhood cancer. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated.Results: Overall, 301 STS developed compared with 19 expected (SIR = 15.7, 95% confidence interval [CI] = 14.0 to 17.6). The highest standardized incidence ratios were for malignant peripheral nerve sheath tumors (MPNST; SIR = 40.6, 95% CI = 29.6 to 54.3), leiomyosarcomas (SIR = 29.9, 95% CI = 23.7 to 37.2), and fibromatous neoplasms (SIR = 12.3, 95% CI = 9.3 to 16.0). SIRs for MPNST were highest following central nervous system tumors (SIR = 80.5, 95% CI = 48.4 to 125.7), Hodgkin lymphoma (SIR = 81.3, 95% CI = 35.1 to 160.1), and Wilms tumor (SIR = 76.0, 95% CI = 27.9 to 165.4). Standardized incidence ratios for leiomyosarcoma were highest following retinoblastoma (SIR = 342.9, 95% CI = 245.0 to 466.9) and Wilms tumor (SIR = 74.2, 95% CI = 37.1 to 132.8). AERs for all STS subtypes were generally low at all years from diagnosis (AER < 1 per 10 000 person-years), except for leiomyosarcoma following retinoblastoma, for which the AER reached 52.7 (95% CI = 20.0 to 85.5) per 10 000 person-years among patients who had survived at least 45 years from diagnosis of retinoblastoma.Conclusions: For the first time, we provide risk estimates of specific STS subtypes following childhood cancers and give evidence that risks of MPNSTs, leiomyosarcomas, and fibromatous neoplasms are particularly increased. While the multiplicative excess risks relative to the general population are substantial, the absolute excess risk of developing any STS subtype is low, except for leiomyosarcoma after retinoblastoma. These results are likely to be informative for both survivors and health care providers.
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| 5. |
- Brännvall, Rickard, 1975-, et al.
(författare)
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HEIDA : Software Examples for Rapid Introduction of Homomorphic Encryption for Privacy Preservation of Health Data
- 2023
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Ingår i: Studies in health technology and informatics. - : IOS Press. ; 302, s. 267-271
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Tidskriftsartikel (refereegranskat)abstract
- Adequate privacy protection is crucial for implementing modern AI algorithms in medicine. With Fully Homomorphic Encryption (FHE), a party without access to the secret key can perform calculations and advanced analytics on encrypted data without taking part of either the input data or the results. FHE can therefore work as an enabler for situations where computations are carried out by parties that are denied plain text access to sensitive data. It is a scenario often found with digital services that process personal health-related data or medical data originating from a healthcare provider, for example, when the service is delivered by a third-party service provider located in the cloud. There are practical challenges to be aware of when working with FHE. The current work aims to improve accessibility and reduce barriers to entry by providing code examples and recommendations to aid developers working with health data in developing FHE-based applications. HEIDA is available on the GitHub repository: https://github.com/rickardbrannvall/HEIDA.
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| 6. |
- Brännvall, Rickard, 1975-, et al.
(författare)
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Homomorphic encryption enables private data sharing for digital health : Winning entry to the Vinnova innovation competition Vinter 2021-22
- 2022
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Ingår i: 34th Workshop of the Swedish Artificial Intelligence Society, SAIS 2022. - : Institute of Electrical and Electronics Engineers Inc.. - 9781665471268
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Konferensbidrag (refereegranskat)abstract
- People living with type 1 diabetes often use several apps and devices that help them collect and analyse data for a better monitoring and management of their disease. When such health related data is analysed in the cloud, one must always carefully consider privacy protection and adhere to laws regulating the use of personal data. In this paper we present our experience at the pilot Vinter competition 2021-22 organised by Vinnova. The competition focused on digital services that handle sensitive diabetes related data. The architecture that we proposed for the competition is discussed in the context of a hypothetical cloud-based service that calculates diabetes self-care metrics under strong privacy preservation. It is based on Fully Homomorphic Encryption (FHE)-a technology that makes computation on encrypted data possible. Our solution promotes safe key management and data life-cycle control. Our benchmarking experiment demonstrates execution times that scale well for the implementation of personalised health services. We argue that this technology has great potentials for AI-based health applications and opens up new markets for third-party providers of such services, and will ultimately promote patient health and a trustworthy digital society.
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| 7. |
- Collin, Mattias, et al.
(författare)
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Constitutive expression of the antibacterial CXC chemokine GCP-2/CXCL6 by epithelial cells of the male reproductive tract.
- 2008
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Ingår i: Journal of Reproductive Immunology. - : Elsevier BV. - 1872-7603 .- 0165-0378. ; 79, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- The reproductive tract is continuously challenged by potential pathogens present in the environment. Therefore, robust host defense mechanisms are essential both for the health of the individual and for fertilization. Antibiotic innate immunity peptides possess broad antimicrobial activity. Recently, we found that the CXC chemokine, granulocyte chemotactic protein (GCP)-2/CXCL6, possesses antibacterial activity. In the present study, we investigated, therefore, the presence of GCP-2/CXCL6 in the human male reproductive system. GCP-2/CXCL6 was detected at 19nM (mean; range: 5-47nM; n=14) in seminal plasma of fertile donors, i.e. at levels more than 100 times higher than those previously reported for the related chemokine IL-8/CXCL8. No GCP-2/CXCL6 could be detected in blood plasma of healthy donors, indicating local production in the male reproductive tract. In vasectomized donors, significantly lower levels of GCP-2/CXCL6 were found (mean: 3nM; range 2-7nM; n=7), demonstrating that the testis and epididymis contribute significantly to the GCP-2/CXCL6 content of seminal plasma. Strong expression of GCP-2/CXCL6 was found in the epithelium of the testis, epididymis and seminal vesicles, while the prostate epithelium showed weak expression, as determined by immunohistochemistry. A biological function is suggested, viz. at concentrations of the order of those found in seminal plasma, GCP-2/CXCL6 has antibacterial activity against the urogenital pathogen Neisseria gonorrhoeae. GCP-2/CXCL6 in seminal plasma may play roles in both host defense of the male urogenital tract and during fertilization.
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| 8. |
- Dinkla, Katrin, et al.
(författare)
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Identification of a streptococcal octapeptide motif involved in acute rheumatic fever
- 2007
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 282:26, s. 18686-18693
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Tidskriftsartikel (refereegranskat)abstract
- Acute rheumatic fever is a serious autoimmune sequela of pharyngitis caused by certain group A streptococci. One mechanism applied by streptococcal strains capable of causing acute rheumatic fever is formation of an autoantigenic complex with human collagen IV. In some geographic regions with a high incidence of acute rheumatic fever pharyngeal carriage of group C and group G streptococci prevails. Examination of such strains revealed the presence of M-like surface proteins that bind human collagen. Using a peptide array and recombinant proteins with targeted amino acid substitutions, we could demonstrate that formation of collagen complexes during streptococcal infections depends on an octapeptide motif, which is present in collagen binding M and M-like proteins of different beta-hemolytic streptococcal species. Mice immunized with streptococcal proteins that contain the collagen binding octapeptide motif developed high serum titers of anti-collagen antibodies. In sera of rheumatic fever patients such a collagen autoimmune response was accompanied by specific reactivity against the collagen-binding proteins, linking the observed effect to clinical cases. Taken together, the data demonstrate that the identified octapeptide motif through its action on collagen plays a crucial role in the pathogenesis of rheumatic fever. Eradication of streptococci that express proteins with the collagen binding motif appears advisable for controlling rheumatic fever.
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| 9. |
- Egesten, Arne, et al.
(författare)
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SpeB of Streptococcus pyogenes differentially modulates antibacterial and receptor activating properties of human chemokines.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: CXC chemokines are induced by inflammatory stimuli in epithelial cells and some, like MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11, are antibacterial for Streptococcus pyogenes. METHODOLOGY/PRINCIPAL FINDINGS: SpeB from S. pyogenes degrades a wide range of chemokines (i.e. IP10/CXCL10, I-TAC/CXCL11, PF4/CXCL4, GROalpha/CXCL1, GRObeta/CXCL2, GROgamma/CXCL3, ENA78/CXCL5, GCP-2/CXCL6, NAP-2/CXCL7, SDF-1/CXCL12, BCA-1/CXCL13, BRAK/CXCL14, SRPSOX/CXCL16, MIP-3alpha/CCL20, Lymphotactin/XCL1, and Fractalkine/CX3CL1), has no activity on IL-8/CXCL8 and RANTES/CCL5, partly degrades SRPSOX/CXCL16 and MIP-3alpha/CCL20, and releases a 6 kDa CXCL9 fragment. CXCL10 and CXCL11 loose receptor activating and antibacterial activities, while the CXCL9 fragment does not activate the receptor CXCR3 but retains its antibacterial activity. CONCLUSIONS/SIGNIFICANCE: SpeB destroys most of the signaling and antibacterial properties of chemokines expressed by an inflamed epithelium. The exception is CXCL9 that preserves its antibacterial activity after hydrolysis, emphasizing its role as a major antimicrobial on inflamed epithelium.
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| 10. |
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| 11. |
- Fidler, Miranda M., et al.
(författare)
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Risk of Subsequent Bone Cancers Among 69 460 Five-Year Survivors of Childhood and Adolescent Cancer in Europe
- 2018
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 110:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We investigate the risks of subsequent primary bone cancers after childhood and adolescent cancer in 12 European countries. For the first time, we satisfactorily address the risks beyond 40 years from diagnosis and beyond 40 years of age among all survivors.Methods: This largest-ever assembled cohort comprises 69 460 five-year survivors of cancer diagnosed before age 20 years. Standardized incidence ratios, absolute excess risks, and multivariable-adjusted relative risks and relative excess risks were calculated. All statistical tests were two-sided.Results: Overall, survivors were 21.65 times (95% confidence interval = 18.97 to 24.60 times) more likely to be diagnosed with a subsequent primary bone cancer than expected from the general population. The greatest excess numbers of bone cancers were observed after retinoblastoma, bone sarcoma, and soft tissue sarcoma. The excess number of bone cancers declined linearly with both years since diagnosis and attained age (all P < .05). Beyond 40 years from diagnosis and age 40 years, there were at most 0.45 excess bone cancers among all survivors per 10 000 person-years at risk; beyond 30 years from diagnosis and age 30 years, there were at most 5.02 excess bone cancers after each of retinoblastoma, bone sarcoma, and soft tissue sarcoma, per 10 000 person-years at risk.Conclusions: For all survivors combined and the cancer groups with the greatest excess number of bone cancers, the excess numbers observed declined with both age and years from diagnosis. These results provide novel, reliable, and unbiased information about risks and risk factors among long-term survivors of childhood and adolescent cancer.
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| 12. |
- Henriksen, Mona, et al.
(författare)
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Dynamics and retreat of the Late Weichselian Kongsfjorden ice stream, NW Svalbard
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 92, s. 235-245
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Tidskriftsartikel (refereegranskat)abstract
- Terrestrial cosmogenic nuclide dating in combination with detailed landform mapping in the Kongsf-jordhallet area, NW Svalbard, have provided new insight on configuration, dynamics, and deglaciation of the Late Weichselian Kongsfjorden ice stream. The minimum Late Weichselian ice surface elevation in Kongsfjorden was >449 m a.s.l. indicating considerably thicker ice and a steeper surface gradient than earlier suggested. For the adjacent inter-ice stream area an even steeper surface slope is reconstructed. The glacial landforms, as well as the surface exposure ages of erratic boulders at different elevations, suggest a gradual lowering of the ice surface. Deglaciation of the higher elevations was probably underway by 20.0 ka. At ca 16.6 ka a large moraine complex ('the Kongsfjorden moraine') was deposited close to the fjord mouth. The shape of the moraines, the steep ice surface gradient, as well as the correlation to fine laminated clay lacking ice rafted debris deposited in the trough beyond the moraine suggest that ice dynamics switched from ice-stream behaviour to a slower flowing outlet (tidewater) glacier. A Younger Dryas or Early Holocene advance of local valley glaciers is shown by moraine lobes cross-cutting the Late Weichselian lateral moraines. (C) 2013 Elsevier Ltd. All rights reserved.
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| 13. |
- Holst, Anders, et al.
(författare)
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Identifying causal relationships of cancer treatment and long-term health effects among 5-year survivors of childhood cancer in Southern Sweden
- 2022
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Ingår i: Communications medicine. - : Springer Science and Business Media LLC. - 2730-664X. ; 2, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survivors of childhood cancer can develop adverse health events later in life. Infrequent occurrences and scarcity of structured information result in analytical and statistical challenges. Alternative statistical approaches are required to investigate the basis of late effects in smaller data sets.Methods: Here we describe sex-specific health care use, mortality and causal associations between primary diagnosis, treatment and outcomes in a small cohort ( n = 2315) of 5-year survivors of childhood cancer ( n = 2129) in southern Sweden and a control group ( n = 11,882; age-, sex- and region-matched from the general population). We developed a constraint-based method for causal inference based on Bayesian estimation of distributions, and used it to investigate health care use and causal associations between diagnoses, treatments and outcomes. Mortality was analyzed by the Kaplan-Meier method. Results: Our results confirm a significantly higher health care usage and premature mortality among childhood cancer survivors as compared to controls. The developed method for causal inference identifies 98 significant associations ( p < 0.0001) where most are well known ( n = 73; 74.5%). Hitherto undescribed associations are identified ( n = 5; 5.1%). These were between use of alkylating agents and eye conditions, topoisomerase inhibitors and viral infections; pituitary surgery and intestinal infections; and cervical cancer and endometritis. We discuss study-related biases ( n = 20; 20.4%) and limitations. Conclusions: The findings contribute to a broader understanding of the consequences of cancer treatment. The study shows relevance for small data sets and causal inference, and presents the method as a complement to traditional statistical approaches.
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| 14. |
- Irestorm, Elin, et al.
(författare)
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Cognitive Fatigue and Processing Speed in Children Treated for Brain Tumours
- 2021
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Ingår i: Journal of the International Neuropsychological Society. - 1355-6177. ; 27:9, s. 865-874
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Tidskriftsartikel (refereegranskat)abstract
- Objective:The relationship between fatigue and cognition has not been fully elucidated in children and adolescent survivors of brain tumours. The aim of the present study was to investigate the potential relationship between fatigue and cognitive impairments in these survivors, as this group is at risk for both types of deficits.Methods:Survivors of paediatric brain tumours (n = 45) underwent a neuropsychological testing on average 4 years after diagnosis. Mean age at follow-up was 13.41 years. Cognition was assessed with neuropsychological tests, and fatigue with the Pediatric Quality of Life (PedsQL™) Multidimensional Fatigue Scale. Regression analysis, adjusted for cranial radiotherapy and age at diagnosis, was used to investigate the associations between cognitive variables and fatigue subscales. Cognitive variables associated with fatigue were subsequently exploratively assessed.Results:Significant associations were found for cognitive fatigue and measures of cognitive processing speed; Coding: p = .003, r = .583, 95% CI [9.61; 22.83] and Symbol Search: p = .001, r = .585, 95% CI [10.54; 24.87]. Slower processing speed was associated with poorer results for cognitive fatigue. Survivors with the largest decrease in processing speed from baseline to follow-up also experienced the most cognitive fatigue. Survivors expressed more cognitive fatigue compared to other types of fatigue.Conclusions:The association between cognitive fatigue and cognitive processing speed in children and adolescents treated for brain tumours is in concordance with the results previously reported in adults. Some survivors experience fatigue without impairment in processing speed, indicating the need for comprehensive assessments. Moreover, the study supports that fatigue is a multidimensional concept which should be measured accordingly.
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| 15. |
- Jovic, Sandra, et al.
(författare)
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The neutrophil-recruiting chemokine GCP-2/CXCL6 is expressed in cystic fibrosis airways and retains its functional properties after binding to extracellular DNA.
- 2016
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 9:1, s. 112-123
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Tidskriftsartikel (refereegranskat)abstract
- Infections in cystic fibrosis (CF), often involving Pseudomonas aeruginosa, result from a dysregulated airway immunity where one hallmark is the accumulation of necrotic and apoptotic immune cells, in particular neutrophils. In addition, neutrophils actively release DNA, forming neutrophil extracellular traps (NETs) that contain antimicrobial proteins. Altogether, free DNA in complex with actin accumulates in the airway lumen, resulting in highly viscous sputum that provides an anionic matrix, binding cationic antimicrobial proteins. In this study, granulocyte chemotactic protein 2 (GCP-2)/CXCL6, a neutrophil-activating chemokine with bactericidal properties, was detected in the airway epithelium of CF patients and was also present in azurophilic and specific granules of neutrophils. Elastase of neutrophils, but not of P. aeruginosa, completely degraded CXCL6 (chemokine (C-X-C motif) ligand 6). In addition, CXCL6 colocalized with extracellular DNA in both CF sputa and in in vitro-formed NETs. In vitro, CXCL6 bound DNA with a KD of 2,500 nM. Interestingly, both the bactericidal and the receptor-activating properties of CXCL6 (against neutrophils) remained largely unaffected in the presence of DNA. However, the chemotactic properties of CXCL6 were reduced by the presence of DNA. Taken together, CXCL6 is expressed in CF, retaining its functional properties even after binding to the anionic scaffold that extracellular DNA provides in CF.Mucosal Immunology advance online publication, 20 May 2015; doi:10.1038/mi.2015.43.
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| 16. |
- Kilsgård, Ola, et al.
(författare)
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Peptidylarginine deiminases present in the airways during tobacco smoking and inflammation can citrullinate the host defense peptide LL-37, resulting in altered activities.
- 2012
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Ingår i: American journal of respiratory cell and molecular biology. - 1535-4989 .- 1044-1549. ; 46:2, s. 240-8
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial colonization of the lower respiratory tract is frequently seen in chronic obstructive pulmonary disease (COPD), and may cause exacerbations leading to disease progression. Antimicrobial peptides comprise an important part of innate lung immunity, and not least the cathelicidin human cationic antimicrobial protein-18/LL-37. Peptidylarginine deiminases (PADIs) post-translationally modify proteins by converting cationic peptidylarginine residues to neutral peptidylcitrulline. An increased presence of PADI2 and citrullinated proteins was demonstrated in the lungs of smokers. In this study, preformed PADI4, stored in granulocytes and extracellularly in the lumina of bronchi, was found in lung tissue of individuals suffering from COPD. In vitro, recombinant human PADI2 and PADI4 both caused a time- and dose-dependent citrullination of LL-37. The citrullination resulted in impaired antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, and nontypable Haemophilus influenzae, but less so against Pseudomonas aeruginosa. Using artificial lipid bilayers, we observed discrete differences when comparing the disrupting activity of native and citrullinated LL-37, suggesting that differences in cell wall composition are important during interactions with whole bacteria. Furthermore, citrullinated LL-37 showed higher chemotactic activity against mononuclear leukocytes than did native LL-37, but was less efficient at neutralizing lipolysaccharide, and also in converting apoptotic neutrophils into a state of secondary necrosis. In addition, citrullinated LL-37 was more prone to degradation by proteases, whereas the V8 endopetidase of S. aureus cleaved the modified peptide at additional sites, compared with native LL-37. Together, these findings demonstrate novel mechanisms whereby the inflammation-dependent deiminases PADI2 and PADI4 can alter the activites of antibacterial polypeptides, affecting the course of inflammatory disorders such as COPD.
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| 17. |
- Linge, Carl Petrus, et al.
(författare)
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Enrichment of Complement, Immunoglobulins, and Autoantibody Targets in the Proteome of Platelets from Patients with Systemic Lupus Erythematosus
- 2022
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 122:9, s. 1486-1501
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Tidskriftsartikel (refereegranskat)abstract
- Background Systemic lupus erythematosus (SLE) is a complex disease characterized by autoimmunity toward apoptotic cells, excessive amounts of circulating immune complexes, and complement activation. A decreased platelet size has been observed in SLE and their nonhemostatic functions may play an active role in the disease. The main objective of this study was to find clues that could explain their decreased size and functional role, analyzing the entire platelet proteome. Methods Platelets were isolated from 23 patients with SLE. The five individuals with the highest and lowest average platelet forward scatter were selected for further analysis. Platelet protein content was analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS) and compared with platelets from five healthy controls. Data are available via ProteomeXchange with identifier PXD031202. Results Out of 2,572 proteins identified, 396 had significantly different levels (ANOVA q-value ≤ 0.01). Forty proteins, including immunoglobulin-, complement- and phosphatidylserinebinding proteins had higher abundance in platelets from SLE patients, largely independent of size (fold difference of ≥1.5 and a t-test p-value of ≤0.05 as cut-off). Functional characterization revealed increased degranulation and skewed hemostatic balance in platelets from SLE patients. In the SLE proteome, immunoglobulin proteins were negatively correlated to serum complement C3 and C4 and the highest relative levels were detected in platelets of normal size. Conclusion Platelets from SLE patients shared a specific protein profile, including immunoglobulins, complement proteins, and autoantigens, largely independent of the platelet size and in agreement with an integrated role for platelets in SLE.
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| 18. |
- Linge, Helena M., et al.
(författare)
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Mixed methods assessment of impact on health awareness in adult childhood cancer survivors after viewing their personalized digital treatment summary and follow-up recommendations
- 2021
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The survival rate after childhood cancer has improved to 80%. The majority of childhood cancer survivors (CCS) will experience late complications which require follow up care, including access to their individual cancer treatment summary. The need to understand CCS needs and preferences in terms of ways to receive information e.g. digitally, becomes important. This study aims to through a mixed methods approach a) examine how CCS’ health awareness was impacted by viewing their personalized digital treatment summary and follow-up recommendations, b) explore E health literacy, and c) determine self-reported survivorship experiences and health care usage. Methods: Survivors with a recent visit to the Late effects clinic were eligible for the study (n = 70). A representative sample of primary diagnoses were invited (n = 28). 16 CCS were enrolled. Recent medical visits, e health literacy and impressions of the digital treatment summary were assessed by a survey in conjunction with viewing their digital treatment summary on a computer screen. Their experience of reading and understanding their digital treatment summary in the context of their health related survivorship experiences were assessed in focus groups. The transcribed data was analyzed with conventional qualitative content analysis. Results: The self-reported medical problems largely reflected that, only 6,3% reported no cancer-related reasons for seeking medical attention. Of the medical specialists, the primary care physician was the most frequently visited specialist (68.8%). High E health literacy was not associated with treatment features but with educational level (p = 0.003, CI: 3.9–14.6) and sex (p = 0.022, CI: − 13.6- -1.3). All survivors graded the digital treatment summary above average in terms of being valuable, agreeable and comprehensive. The focus group interviews identified three themes: 1) The significance of information, 2) The impact of awareness; and 3) Empowerment. Conclusions: Reading the treatment summaries furthered the survivors understanding of their health situation and consequently aided empowerment. A digital treatment summary, provided by knowledgeable health care professionals, may increase the self-managed care and adherence to follow-up recommendations. Further insights into e health literacy in larger samples of CCS may determine to what extent health-related information can be communicated via digital resources to this at risk population.
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| 19. |
- Linge, Helena M, et al.
(författare)
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The human CXC chemokine granulocyte chemotactic protein 2 (GCP-2)/CXCL6 possesses membrane-disrupting properties and is antibacterial
- 2008
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Ingår i: Antimicrobial Agents and Chemotherapy. - 1098-6596 .- 0066-4804. ; 52:7, s. 2599-2607
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Tidskriftsartikel (refereegranskat)abstract
- Granulocyte chemotactic protein 2 (GCP-2)/CXCL6 is a CXC chemokine expressed by macrophages and epithelial and mesenchymal cells during inflammation. Through binding and activation of its receptors (CXCR1 and CXCR2), it exerts neutrophil-activating and angiogenic activities. Here we show that GCP-2/CXCL6 itself is antibacterial. Antibacterial activity against gram-positive and gram-negative pathogenic bacteria of relevance to mucosal infections was seen at submicromolar concentrations (minimal bactericidal concentration at which 50% of strains tested were killed, 0.063 +/- 0.01 to 0.37 +/- 0.03 muM). In killed bacteria, GCP-2/CXCL6 associated with bacterial surfaces, which showed membrane disruption and leakage. A structural prediction indicated the presence of three antiparallel NH(2)-terminal beta-sheets and a short amphipathic COOH-terminal alpha-helix; the latter feature is typical of antimicrobial peptides. However, when the synthetic derivatives corresponding to the NH(2)-terminal (50 amino acids) and COOH-terminal (19 amino acids, corresponding to the putative alpha-helix) regions were compared, higher antibacterial activity was observed for the NH(2)-terminus-derived peptide, indicating that the holopeptide is necessary for full antibacterial activity. An artificial model of bacterial membranes confirmed these findings. The helical content of GCP-2/CXCL6 in the presence or absence of lipopolysaccharide or negatively charged membranes was studied by circular dichroism. As with many antibacterial peptides, membrane disruption by GCP-2/CXCL6 was dose-dependently reduced in the presence of NaCl, which, we here demonstrate, inhibited the binding of the peptide to the bacterial surface. Compared with CXC chemokines ENA-78/CXCL5 and NAP-2/CXCL7, GCP-2/CXCL6 showed a 90-fold-higher antibacterial activity. Taken together, GCP/CXCL6, in addition to its chemotactic and angiogenic properties, is likely to contribute to direct antibacterial activity during localized infection.
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| 20. |
- Linge, Helena, et al.
(författare)
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Midkine is expressed and differentially processed during COPD exacerbations and ventilator-associated pneumonia associated with Staphylococcus aureus infection.
- 2013
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Ingår i: Molecular medicine (Cambridge, Mass.). - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 19, s. 314-323
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus is sometimes isolated from the airways during acute exacerbations of chronic obstructive pulmonary disease (COPD) but more commonly recognized as a cause of ventilator-associated pneumonia (VAP). Antimicrobial proteins, among them midkine (MK), are an important part of innate immunity in the airways. In this study, the levels and possible processing of MK in relation to S. aureus infection of the airways were investigated, comparing COPD and VAP, thus comparing a state of disease with preceding chronic inflammation and remodeling (COPD) with acute inflammation (i.e. VAP). MK was detected in the small airways and alveoli of COPD lung tissue but less so in normal lung tissue. MK at below micromolar concentrations killed S. aureus in vitro. Proteolytic processing of MK by the staphylococcal metalloprotease AL but not cysteine protease SA, resulted in impaired bactericidal activity. Degradation was foremost seen in the COOH-terminal portion of the molecule that harbors high bactericidal activity. In addition, MK was detected in sputum from patients suffering from VAP caused by S. aureus but less so in sputum from COPD-exacerbations associated with the same bacterium. Recombinant MK was degraded more rapidly in sputum from the COPD patients than from the VAP patients and a greater proteolytic activity in COPD sputum was confirmed by zymography. Taken together, proteases of both bacteria and the host contribute to degradation of the antibacterial protein MK, resulting in an impaired defense of the airways, in particular in COPD where the state of chronic inflammation could be of importance.
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| 21. |
- Linge, Helena, et al.
(författare)
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Protein FOG - a streptococcal inhibitor of neutrophil function.
- 2004
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Ingår i: Microbiology. - : Microbiology Society. - 1465-2080 .- 1350-0872. ; 150:Pt 12, s. 4211-4221
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Tidskriftsartikel (refereegranskat)abstract
- Several strains of group G streptococci (GGS) form aggregates when grown in vitro. Aggregating strains interact with fibrinogen, and this study reports the isolation of a novel self-associating and fibrinogen-binding protein of GGS, denoted protein FOG. Sequencing of the fog gene revealed structural similarity with M proteins of both GGS and group A streptococci (GAS). Analogous to GAS, GGS were found to multiply in human blood. All strains of GGS express protein G, a protein known to interact with the constant region of immunoglobulin G and albumin. Surprisingly, a clinical isolate expressing protein G, but lacking protein FOG, was killed in human whole blood; however, the addition of intact soluble protein FOG restored the ability of the bacteria to survive and multiply in human blood. This is believed to be the first report of a soluble M-like protein salvaging an M-negative strain from being killed. The antibactericidal property of protein FOG is dependent on its fibrinogen-binding activity. Thus, in plasma, FOG precipitates fibrinogen, and when added to whole blood, protein FOG triggers the formation of visible aggregates comprising fibrinogen and neutrophils that are disabled in their killing of the bacteria. Moreover, the results emphasize the importance of an intact FOG molecule, as presented on the bacterial surface, for full protective effect.
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| 22. |
- Linge, Helena
(författare)
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Protein FOG at the interface between G streptococci and human host defence lines
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Group G streptococci (GGS) may be of four different species and may infect humans and also animals. S. dysgalactiae equisimilis most commonly cause human GGS infections. These bacteria are part of the normal flora, but can cause pharyngitis, erysipelas and impetigo. In the immunocompromised host severe conditions, such as sepsis and necrotising fasciitis, may develop. In this thesis the interactions between GGS and various parts of human defence lines are investigated. A novel M protein from GGS, denoted FOG, was isolated, recombinantly expressed, and purified. FOG-positive strains survive in human whole blood wheras a FOG-negative strain did not. Addition of soluble FOG, but not protein G, leads to restoration of survival of the FOG-negative strain. Intact protein FOG mediated aggregation of neutrophils in the presence of fibrinogen which disabled these cells in excerting antibacterial activities. In vitro and in vivo, protein FOG interacts with collagen I, an abundant extracellular matrix protein of human skin. As streptococcal skin infections often preceed invasive disease, the FOG mediated binding to collagen is important and may be the first step of infection. A FOG-positive strain exhibited adhesional advantages compared to a FOG-negative strain. FOG, like protein G, recruits IgG from human plasma in a non-immune fashion. C1q, initiator of the classical pathway of complement, binds exclusively to the IgG bound via FOG but not to the IgG bound via protein G. IgG opsonisation via FOG but not via protein G led to an O2- production by neutrophils. FOG is released from the bacterial surface into the growth medium of bacterial early stationary growth phase and also by neutrophil elastase. Like M1, an M protein of GAS, FOG binds to monocytes and triggers secretion of the chemokines MIG (CXCL9) and IL-8 (CXCL-8). GGS are less susceptible than GAS, to antimicrobial effects of MIG in physiological NaCl concentrations corresponding to that of sweat and plasma but not of saliva, and also to these NaCl concentrations alone.
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| 23. |
- Linge, Helena, et al.
(författare)
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Protein FOG is a moderate inducer of MIG/CXCL9, and group G streptococci are more tolerant than group A streptococci to this chemokine's antibacterial effect
- 2007
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Ingår i: Microbiology. - : Microbiology Society. - 1465-2080 .- 1350-0872. ; 153, s. 3800-3808
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus dysgalactiae subsp. equisimilis (group G streptococci; GGS) cause disease in humans but are often regarded as commensals in comparison with Streptococcus pyogenes (group A streptococci; GAS). The current study investigated the degree and kinetics of the innate immune response elicited by the two species. This was assessed as expression of the chemokine MIG/CXCL9 and bacterial susceptibility to its bactericidal effect. No significant difference in MIG/CXCL9 expression from THP-1 or Detroit 562 cells was observed when comparing whole GGS or GAS as stimuli. The study demonstrates that protein FOG was released from the bacterial surface directly and by neutrophil elastase. Expression of MIG/CXCL9 following stimulation with soluble M proteins of the two species (the recently described protein FOG of GGS and protein M1 of GAS) was reduced for protein FOG in both the monocytic and the epithelial cell line. When the antibacterial effects of MIG/CXCL9 were examined in conditions of increased ionic strength, MIG/CXCL9 killed GAS more efficiently than GGS. Also in the absence of MIG/CXCL9, GGS were more tolerant to increased salt concentrations than GAS. In summary, both GGS and GAS evoke MIG/CXCL9 expression but they differ in susceptibility to its antibacterial effects. This may in part explain the success of GGS as a commensal and its potential as a pathogen.
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| 24. |
- Linge, Helena, et al.
(författare)
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Secure Sharing of Health-Related Data : Research Description of the VINTER, DELFIN, and HEIDA Projects
- 2023
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Ingår i: Studies in Health Technology and Informatics. - : NLM (Medline). - 0926-9630 .- 1879-8365. ; 302, s. 143-144
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Tidskriftsartikel (refereegranskat)abstract
- The need for secure and integrity-preserved data sharing has become increasingly important in the emerging era of changed demands on healthcare and increased awareness of the potential of data. In this research plan, we describe our path to explore the optimal use of integrity preservation in health-related data contexts. Data sharing in these settings is poised to increase health, improve healthcare delivery, improve the offering of services and products from commercial entities, and strengthen healthcare governance, all with a maintained societal trust. The HIE challenges relate to legal boundaries and to the importance of maintaining accuracy and utility in the secure sharing of health-related data.
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| 25. |
- Linge, Helena, et al.
(författare)
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The Antibacterial Chemokine MIG/CXCL9 Is Constitutively Expressed in Epithelial Cells of the Male Urogenital Tract and Is Present in Seminal Plasma.
- 2008
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Ingår i: Journal of Interferon and Cytokine Research. - : Mary Ann Liebert Inc. - 1079-9907 .- 1557-7465. ; 28:3, s. 190-196
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT The integrity of the urogenital tract against potentially invasive pathogens is important for the health of the individual, fertilization, and continuance of species. Antibiotic peptides with broad antimicrobial activity, among them chemokines, are part of the innate immune system. We investigated the presence of the antibacterial interferon (IFN)-dependent CXC chemokines, MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11, in the human male reproductive system. MIG/CXCL9 was detected at 25.0 nM (range 8.1-40.6 nM; n = 14), whereas IP-10/CXCL10 and I-TAC/CXCL11 were detected at lower levels (mean 1.8 nM, range 0.3-5.8 nM and mean 0.6, 0.2-1.6 nM, respectively) in seminal plasma of fertile donors. The levels of MIG/CXCL9 are more than 300-fold higher than those previously reported in blood plasma. In vasectomized donors, significantly lower levels of MIG/CXCL9 (mean 14.7 nM, range 6.6-21.8) were found, suggesting that the testis and epididymis, in addition to the prostate, significantly contribute to the MIG/CXCL9 content of seminal plasma. Strong expression of MIG/CXCL9 was found in the epithelium of testis, epididymis, and prostate, as detected by immunohistochemistry. MIG/CXCL9 at concentrations in the order of those found in seminal plasma possessed antibacterial activity against the urogenital pathogen Neisseria gonorrhoeae. The relatively high levels of MIG/CXCL9 in seminal plasma point to roles for this chemokine in both host defense of the male urogenital tract and during fertilization.
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| 26. |
- Linge, Petrus, et al.
(författare)
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NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 79:2, s. 254-261
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47phox, reducing production of reactive oxygen species (ROS) is strongly associated with the development of systemic lupus erythematosus (SLE). This study aimed at characterising NCF1-339 effects on neutrophil extracellular trap (NET) formation, type I interferon activity and antibody profile in patients with SLE. Methods: Neutrophil NET-release pathways (n=31), serum interferon (n=141) and finally antibody profiles (n=305) were investigated in SLE subjects from Lund, genotyped for NCF1-339. Then, 1087 SLE subjects from the rheumatology departments of four Swedish SLE centres, genotyped for NCF1-339, were clinically characterised to validate these findings. Results: Compared with patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with SLE with low-ROS NCF1-339 genotypes displayed impaired NET formation (p<0.01) and increased dependence on mitochondrial ROS (p<0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p<0.05) and positivity for anti-β2 glycoprotein I (p<0.01) and anticardiolipin antibodies (p<0.05) but were not associated with other antibodies. We confirmed an over-representation of having any antiphospholipid antibody, OR 1.40 (95% CI 1.01 to 1.95), anti-β2 glycoprotein I, OR 1.82 (95% CI 1.02 to 3.24) and the antiphospholipid syndrome (APS), OR 1.74 (95% CI 1.19 to 2.55) in all four cohorts (n=1087). Conclusions: The NCF1-339 SNP mediated decreased NADPH oxidase function, is associated with high interferon activity and impaired formation of NETs in SLE, allowing dependence on mitochondrial ROS. Unexpectedly, we revealed a striking connection between the ROS deficient NCF1-339 genotypes and the presence of phospholipid antibodies and APS.
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| 27. |
- Lood, Christian, et al.
(författare)
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Decreased platelet size is associated with platelet activation and anti-phospholipid syndrome in systemic lupus erythematosus
- 2017
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 56:3, s. 408-416
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: . SLE is an autoimmune disease with increased cardiovascular morbidity and platelet activation. In the general population, increased platelet size predicts platelet reactivity and cardiovascular disease. The aim of this study was to investigate whether platelet size related to platelet activation and cardiovascular disease in SLE.Methods: . Fresh blood samples from SLE patients ( n = 148), healthy volunteers ( n = 79) and disease controls ( n = 40) were analysed for platelet size and activation by flow cytometry, ELISA and cell count. Associations to manifest cardiovascular disease, venous thrombosis and APS were adjusted for traditional cardiovascular risk factors using logistic regression analysis.Results: . SLE patients had decreased platelet size as compared with healthy controls ( P = 0.003). In SLE, decreased platelet size was related to increased platelet activation, in particular microparticle formation ( P < 0.0001, r = -0.46) and release of serotonin from dense granules ( P < 0.001, r = 0.57). SLE patients with aCL had decreased platelet size ( P = 0.02) and aCL decreased platelet size in vitro ( P = 0.007). In contrast to the general population, increased platelet size was not associated with cardiovascular disease. Instead, decreased platelet size was associated with secondary APS, even after adjusting for traditional cardiovascular risk factors ( P = 0.01, odds ratio 3.58).Conclusion: . Platelet size is decreased in SLE patients and associated with microparticle formation and APS. Future studies are needed to determine the underlying mechanism(s) as well as the potential predictive value of small platelets for disease complications in SLE.
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| 28. |
- Miller, Edmund J, et al.
(författare)
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Age-Related Changes in Immunological and Physiological Responses Following Pulmonary Challenge
- 2017
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 18:6
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Forskningsöversikt (refereegranskat)abstract
- This review examines the current status of knowledge of sepsis and pneumonia in the elderly population and how the dynamics of the pulmonary challenge affects outcome and consequences. Led by an unprecedented shift in demographics, where a larger proportion of the population will reach an older age, clinical and experimental research shows that aging is associated with certain pulmonary changes, but it is during infectious insult of the lungs, as in the case of pneumonia, that the age-related differences in responsiveness and endurance become obvious and lead to a worse outcome than in the younger population. This review points to the neutrophil, and the endothelium as important players in understanding age-associated changes in responsiveness to infectious challenge of the lung. It also addresses how the immunological set-point influences injury-repair phases, remote organ damage and how intake of drugs may alter the state of responsiveness in the users. Further, it points out the importance of considering age as a factor in inclusion criteria in clinical trials, in vitro/ex vivo experimental designs and overall interpretation of results.
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| 29. |
- Nitsche, Patric, et al.
(författare)
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Streptococcal protein fog: A novel matrix adhesin interacting with colagen I in vivo.
- 2006
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 281:3, s. 1670-1679
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Tidskriftsartikel (refereegranskat)abstract
- Group G streptococcus (GGS) is a human pathogen of emerging clinical significance. It causes skin and soft tissue infections, occasionally resulting in life-threatening conditions such as sepsis and necrotizing fasciitis. We recently identified FOG, a novel surface protein of GGS with fibrinogen binding and immune evasion properties. Here we investigated the role of FOG in streptococcal primary adhesion to host tissue. A FOG-expressing clinical isolate adhered more efficiently to human skin biopsies ex vivo and to the murine dermis in vivo than a FOG-deficient strain. Scanning and transmission electron microscopy of skin specimens exhibited that this property was assigned to the ability of FOG to interact with collagen I, a major interstitial component of the dermis. Overlay experiments with human skin extracts and radiolabeled FOG followed by matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis identified both the alpha 1- and alpha 2-chains of collagen I as targets for FOG. Transmission electron microscopy of the molecular complexes revealed thread-like FOG molecules binding via their NH2 termini to distinct sites on collagen I monomers and fibrils. The results demonstrate that FOG is important for GGS adhesion in vivo, implying a pathogenic role for this surface protein.
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| 30. |
- Nitsche-Schmitz, D. Patric, et al.
(författare)
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Group G streptococcal IgG binding molecules FOG and protein G have different impacts on opsonization by C1q
- 2007
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 282:24, s. 17530-17536
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Tidskriftsartikel (refereegranskat)abstract
- Recent epidemiological data on diseases caused by beta-hemolytic streptococci belonging to Lancefield group C and G ( GCS, GGS) underline that they are an emerging threat to human health. Among various virulence factors expressed by GCS and GGS isolates from human infections, M and M-like proteins are considered important because of their anti-phagocytic activity. In addition, protein G has been implicated in the accumulation of IgG on the bacterial surface through non-immune binding. The function of this interaction, however, is still unknown. Using isogenic mutants lacking protein G or the M-like protein FOG ( group G streptococci), respectively, we could show that FOG contributes substantially to IgG binding. A detailed characterization of the interaction between IgG and FOG revealed its ability to bind the Fc region of human IgG and its binding to the subclasses IgG1, IgG2, and IgG4. FOG was also found to bind IgG of several animal species. Surface plasmon resonance measurements indicate a high affinity to human IgG with a dissociation constant of 2.4 pM. The binding site was localized in a central motif of FOG. It has long been speculated about anti-opsonic functions of streptococcal Fc-binding proteins. The presented data for the first time provide evidence and, furthermore, indicate functional differences between protein G and FOG. By obstructing the interaction between IgG and C1q, protein G prevented recognition by the classical pathway of the complement system. In contrast, IgG that was bound to FOG remained capable of binding C1q, an effect that may have important consequences in the pathogenesis of GGS infections.
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| 31. |
- Nived, Ola, et al.
(författare)
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Disease duration, age at diagnosis and organ damage are important factors for cardiovascular disease in SLE
- 2020
-
Ingår i: Lupus science & medicine. - : BMJ. - 2053-8790. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To report the incidence rate ratios (IRR) of acute myocardial infarctions (AMI) and cerebrovascular events (CVE) in incident SLE cases from a defined population. To study the risk factors for cardiovascular events in all patients with SLE at our unit.METHODS: Patients with SLE diagnosed from 1981 to 2006 were followed through to 2016. IRRs of AMI and CVE were calculated. The AMI and CVE incidence patterns for patients with SLE were studied in relation to hypertension, smoking, renal dysfunction, anticardiolipin (aCL) antibodies at diagnosis, disease duration and organ damage before an event.RESULTS: 262 patients with SLE were included in the study; of these 175 were from the defined population. Overall, 37 AMI and 44 CVE were recorded. An increased IRR of 3 for AMI was found (p<0.001). Smoking, hypertension and reduced renal function were risk factors for AMI. An increased IRR of 3.3 for ischaemic CVE was found for women (p<0.001). Hypertension and aCL were risk factors for CVE. Organ damage before events was increased.CONCLUSIONS: Cardiovascular events are increased in SLE and are associated with hypertension, smoking and increased damage rate.
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| 32. |
- Petersson-Ahrholt, Magnus, et al.
(författare)
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Development and Implementation of Survivorship Tools to Enable Medical Follow-Up After Childhood Cancer Treatment in Southern Sweden
- 2019
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Ingår i: JCO clinical cancer informatics. - 2473-4276. ; 3, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Survival rates after childhood cancer have increased from 20% to 80% since the 1970s. The increased number of survivors emphasizes the importance of late effects and their monitoring. Late effects may have a strong impact on quality of life in survivors. The purpose of this study was to make key data in a quality registry available for direct clinical use, enabling health care professionals to perform efficient and appropriate long-term medical follow-up after childhood cancer treatment.METHODS: The population-based quality registry upon which this study is centered contains data on all individuals diagnosed with childhood cancer (diagnosed at 18 years of age or younger) in southern Sweden since January 1, 1970, and treatment data on 5-year survivors. Web tools, which were developed and implemented in a health care setting, generate a personalized treatment summary for each patient and enable risk group stratification of survivors.RESULTS: Generation of a personalized treatment summary and risk group stratification of survivors led to identification of women at risk for developing breast cancer as a consequence of childhood cancer treatment. Three novel cases of previously undiagnosed breast cancer were identified.CONCLUSION: The registry, together with the developed tools, enabled health care professionals to perform medical follow-up in this at-risk patient population.
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| 33. |
- Reulen, RC, et al.
(författare)
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Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study
- 2021
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 70:8, s. 1520-1528
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Tidskriftsartikel (refereegranskat)abstract
- Survivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide.MethodsThe PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence.Results427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN—comparable to the risk among members of the general population with at least two first-degree relatives affected.ConclusionsColonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.
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| 34. |
- Tydén, Helena, et al.
(författare)
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Low plasma concentrations of apolipoprotein M are associated with disease activity and endothelial dysfunction in systemic lupus erythematosus
- 2019
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Apolipoprotein M (apoM) is a 25-kDa apolipoprotein present in 5% of high-density lipoprotein (HDL) particles. It is suggested to be anti-atherogenic and to play a key role in sustaining endothelial barrier integrity. SLE patients have increased cardiovascular disease risk, and we aimed to investigate if apoM levels reflect endothelial function in SLE. Since apoM plasma levels decrease during inflammatory conditions, our aim was also to determine the impact of SLE disease activity on apoM plasma levels. Methods: Plasma concentrations of apoM were measured by ELISA in two patient groups with systemic lupus erythematosus (SLE) and in 79 healthy control individuals. In patient group I (n = 84), evaluation time points were selected with the objective to include a wide range of clinical and laboratory variables reflecting disease activity which was measured as SLEDAI. In patient group II consisting of 140 consecutive patients, endothelial function was measured by a finger plethysmograph. A low Reactive Hyperemia Index (RHI) value indicates endothelial dysfunction. Results: SLE patients had decreased levels of apoM compared to healthy controls (p < 0.01), with apoM levels correlating inversely with SLEDAI (r = - 0.31, p < 0.01) as well as with levels of CRP (r = - 0.26, p = 0.02) and positively with levels of C3 (r = 0.29, p < 0.01). ApoM levels were particularly low in patients with active disease from the kidney and skin and in patients with leukopenia or positive anti-dsDNA antibody test (p < 0.05). ApoM levels correlated with RHI values in young SLE patients (r = 0.32, p = 0.01), consistent with the important role of apoM in regulating endothelial integrity. Conclusions: ApoM levels may be regulated by SLE-related inflammatory processes and could be a marker of disease activity and endothelial dysfunction, in particular in young SLE patients. Further studies are needed to investigate the predictive value of apoM in the development of a cardiovascular disease.
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| 35. |
- Wiebe, Thomas, et al.
(författare)
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A population based pediatric oncology registry in Southern Sweden : the BORISS registry
- 2018
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 33:11, s. 1125-1129
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Tidskriftsartikel (refereegranskat)abstract
- A population based registry, with the acronym BORISS, was established. It contains all individuals (0-18 years of age at diagnosis) diagnosed with cancer from 1970-01-01 until 2016-12-31 in Southern Sweden. The treatment data has been entered into the registry after confirmation of the diagnosis by the Swedish national cancer registry and updates on vital status from the Swedish population registry. The number of individuals with a pediatric cancer diagnosed during these 46 years are 2928. Of these, 2065 are currently alive and 1882 individuals are 5-year survivors. Data on treatment and malignancy of the 5-year survivors has been collected from medical records and entered into the database. Treatment data contains surgical procedure, target organ of radiation therapy including dose and fractionation, and cytostatic treatment with dose (mg) per body surface area (m2) for all cytostatic agents. Data on individuals receiving stem cell treatment is included. The database is unique in that it is population based, contains all individuals and detailed treatment data on all 5-year survivors after childhood cancer in Southern Sweden since 1970. The database has contributed to several academic theses in the field of late effects after childhood cancer. BORISS also supports the Late Effect Clinic at Skåne University Hospital in Lund, Sweden with treatment details enabling a stratified surveillance.
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| 36. |
- Wirestam, Lina, et al.
(författare)
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Low Intra-Individual Variation in Mean Platelet Volume Over Time in Systemic Lupus Erythematosus
- 2021
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Platelets have recently emerged as important immune modulators in systemic lupus erythematosus (SLE), in addition to their role in thrombosis and cardiovascular disease. However, studies investigating mean platelet volume (MPV) in SLE are often scarce, conflicting and cross-sectional. In this study, MPV was measured in clinical routine throughout a defined time-period to quantify both individual MPV fluctuations and investigate if such variations are associated with disease activity and clinical phenotypes of SLE. Of our 212 patients, 34 patients had only one MPV value reported with the remaining 178 patients having between 2 and 19 visits with recorded MPV values. The intra-individual MPV variation was low, with a median variation of 0.7 fL. This was further supported by the finding that 84% of patients stayed within their reference interval category (i.e., small, normal or large) over time. In our cohort, no correlation between disease activity and MPV neither cross-sectionally nor longitudinally was found. Mean platelet volume values were significantly smaller in SLE patients (mean 10.5 fL) compared to controls (mean 10.8 fL), p < 0.0001. Based on the reference interval, 2.4% (n = 5) of patients had large-sized platelets, 84.4% (n = 179) had normal-sized and 13.2% (n = 28) had small-sized. A larger proportion (85.7%) of patients with small-sized platelets met the anti-dsDNA criterion (ACR10b; p = 0.003) compared to patients with normal and large (57.6%) sized platelets. In conclusion, the intra-individual MPV variation was of low magnitude and fluctuations in disease activity did not have any significant impact on MPV longitudinally. This lack of variability in MPV over time indicates that measuring MPV at any time-point is sufficient. Further studies are warranted to evaluate MPV as a possible biomarker in SLE, as well as to determine the underlying mechanisms influencing platelet size in SLE.
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