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1.	Malmström, Erik, et al. (författare) Large-scale inference of protein tissue origin in gram-positive sepsis plasma using quantitative targeted proteomics. 2016 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Tidskriftsartikel (refereegranskat)abstract The plasma proteome is highly dynamic and variable, composed of proteins derived from surrounding tissues and cells. To investigate the complex processes that control the composition of the plasma proteome, we developed a mass spectrometry-based proteomics strategy to infer the origin of proteins detected in murine plasma. The strategy relies on the construction of a comprehensive protein tissue atlas from cells and highly vascularized organs using shotgun mass spectrometry. The protein tissue atlas was transformed to a spectral library for highly reproducible quantification of tissue-specific proteins directly in plasma using SWATH-like data-independent mass spectrometry analysis. We show that the method can determine drastic changes of tissue-specific protein profiles in blood plasma from mouse animal models with sepsis. The strategy can be extended to several other species advancing our understanding of the complex processes that contribute to the plasma proteome dynamics.
2.	Mohanty, Tirthankar, et al. (författare) A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis 2023 Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-17 Tidskriftsartikel (refereegranskat)abstract Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.
3.	Scott, Aaron M., et al. (författare) Population scale proteomics enables adaptive digital twin modelling in sepsis 2024 Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Sepsis is one of the leading causes of mortality in the world. Currently, the heterogeneity of sepsis makes it challenging to determine the molecular mechanisms that define the syndrome. Here, we leverage population scale proteomics to analyze a well-defined cohort of 1364 blood samples taken at time-of-admission to the emergency department from patients suspected of sepsis. We identified panels of proteins using explainable artificial intelligence that predict clinical outcomes and applied these panels to reduce high-dimensional proteomics data to a low-dimensional interpretable latent space (ILS). Using the ILS, we constructed an adaptive digital twin model that accurately predicted organ dysfunction, mortality, and early-mortality-risk patients using only data available at time-of-admission. In addition to being highly effective for investigating sepsis, this approach supports the flexible incorporation of new data and can generalize to other diseases to aid in translational research and the development of precision medicine.Competing Interest StatementThe authors have declared no competing interest.Funding StatementL.M. is funded by the Swedish Research Council (grant number VR-2020-02419), the Wallenberg foundation (grant number 2016.0023) and Alfred Österlunds Foundation. J.M. is a Wallenberg academy fellow (KAW 2017.0271) and is also funded by the Swedish Research Council (Vetenskapsrådet, VR) (2019-01646 and 2018-05795), the Wallenberg foundation (KAW2016.0023, KAW2019.0353 and KAW2020.0299), and Alfred Österlunds Foundation. E.M. is funded by Wenner-Gren Foundation (FT2020-0003), the Crafoord Foundation, and the Swedish Society of Medicine (SLS-985287). F.K. is funded by Region Skåne ALF project and the Crafoord Foundation. A.L. is funded by the Swedish Research Council VR 2023-02707 and Region Skåne ALF project 2022-0146.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval for the study was obtained from the Swedish National Ethics Committee (file numbers 2022-01454-01, 2014/741 and 2016/271).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesData produced in the present study are available upon reasonable request to the authors
4.	Carlsson, Jörgen, et al. (författare) Conjugate chemistry and cellular processing of EGF-dextran 1999 Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 38:3, s. 313-321 Tidskriftsartikel (refereegranskat)abstract Conjugates with specific binding to the epidermal growth factor receptor, EGFR, of interest for radionuclide based imaging and therapy were prepared using mouse epidermal growth factor, mEGF, and dextran. In one type of conjugate, mEGF was coupled to dextran by reductive amination in which the free amino group on the mEGF N-terminal reacted with the aldehyde group on the reductive end of dextran. The end-end coupled conjugate could be further activated by the cyanopyridinium agent CDAP, thereby introducing tyrosines to the dextran part. In the other type of conjugate, the cyanylating procedure using CDAP was applied, first to activate dextran and then allowing for the amino terminus of mEGF to randomly attach to the dextran. In the latter case, radionuclide-labelled tyrosines or glycines could be added in the same conjugation step. All types of mEGF-dextran conjugates had EGFR-specific binding since the binding could be displaced by an excess of non-radioactive mEGF. The conjugates were to a large extent internalized in the test cells and the associated radioactivity was retained intracellularly for different times depending on both the type of cells and conjugate applied. Different intracellular 'traffic routes' for the radionuclides are discussed as well as applications for both imaging and therapy.
5.	Eklund, Erik, et al. (författare) Dermatan is a better substrate for 4-O-sulfation than chondroitin : implications in the generation of 4-O-sulfated, L-iduronate-rich galactosaminoglycans 2000 Ingår i: Archives of Biochemistry and Biophysics. - : Elsevier BV. - 0003-9861. ; 383:2, s. 171-177 Tidskriftsartikel (refereegranskat)abstract The biosynthesis of dermatan sulfate is a complex process that involves, inter alia, formation of L-iduronic acid residues by C5-epimerization of D-glucuronic acid residues already incorporated into the growing polymer. It has been shown previously that this reaction is promoted by the presence of the sulfate donor 3'-phosphoadenosine-5'-phosphosulfate. In the present investigation, the role of sulfation in the biosynthesis of L-iduronic acid-rich galactosaminoglycans was examined more closely by a study of the substrate specificities and kinetic properties of the sulfotransferases involved in dermatan sulfate biosynthesis. Comparison of the acceptor reactivities of oligosaccharides from chondroitin and dermatan, in an in vitro system containing microsomes from cultured human skin fibroblasts and 3'-phosphoadenosine-5'-phosphosulfate, showed that Km values for the dermatan fragments were substantially lower than those for their chondroitin counterparts. Calculation of Vmax values likewise showed that dermatan was the better substrate. Whereas dermatan incorporated [35S]sulfate exclusively at the C4 position of N-acetylgalactosamine residues, approximately equal amounts of radioactivity were found at the C4 and C6 positions in the labelled chondroitin. Under standard assay conditions, the 4-O-sulfation of dermatan proceeded about six times faster than the 4-O-sulfation of chondroitin. On the basis of these results, we propose that L-iduronic acids, formed in the course of the biosynthesis of dermatan sulfates, enhance sulfation of their adjacent N-acetylgalactosamine residues, and will thereby be locked in the L-ido configuration.
6.	Hartman, Erik, et al. (författare) Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis 2023 Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-13 Tidskriftsartikel (refereegranskat)abstract The incorporation of machine learning methods into proteomics workflows improves the identification of disease-relevant biomarkers and biological pathways. However, machine learning models, such as deep neural networks, typically suffer from lack of interpretability. Here, we present a deep learning approach to combine biological pathway analysis and biomarker identification to increase the interpretability of proteomics experiments. Our approach integrates a priori knowledge of the relationships between proteins and biological pathways and biological processes into sparse neural networks to create biologically informed neural networks. We employ these networks to differentiate between clinical subphenotypes of septic acute kidney injury and COVID-19, as well as acute respiratory distress syndrome of different aetiologies. To gain biological insight into the complex syndromes, we utilize feature attribution-methods to introspect the networks for the identification of proteins and pathways important for distinguishing between subtypes. The algorithms are implemented in a freely available open source Python-package ( https://github.com/InfectionMedicineProteomics/BINN ).
7.	Kilsgård, Ola, et al. (författare) Differential compartmentalization of Streptococcus pyogenes virulence factors and host protein binding properties as a mechanism for host adaptation 2016 Ingår i: International Journal of Medical Microbiology. - : Elsevier BV. - 1438-4221. ; 306:7, s. 504-516 Tidskriftsartikel (refereegranskat)abstract . Streptococcus pyogenes is an important human pathogen responsible for substantial morbidity and mortality worldwide. Although . S. pyogenes is a strictly human pathogen with no other known animal reservoir, several murine infection models exist to explore different aspects of the bacterial pathogenesis. Inoculating mice with wild-type . S. pyogenes strains can result in the generation of new bacterial phenotypes that are hypervirulent compared to the original inoculum. In this study, we used a serial mass spectrometry based proteomics strategy to investigate if these hypervirulent strains have an altered distribution of virulence proteins across the intracellular, surface associated and secreted bacterial compartments and if any change in compartmentalization can alter the protein-protein interaction network between bacteria and host proteins. Quantitative analysis of the . S. pyogenes surface and secreted proteomes revealed that animal passaged strains are associated with significantly higher amount of virulence factors on the bacterial surface and in the media. This altered virulence factor compartmentalization results in increased binding of several mouse plasma proteins to the bacterial surface, a trend that was consistent for mouse plasma from several different mouse strains. In general, both the wild-type strain and animal passaged strain were capable of binding high amounts of human plasma proteins. However, compared to the non-passaged strains, the animal passaged strains displayed an increased ability to bind mouse plasma proteins, in particular for M protein binders, indicating that the increased affinity for mouse blood plasma proteins is a consequence of host adaptation of this pathogen to a new host. In conclusion, plotting the total amount of virulence factors against the total amount of plasma proteins associated to the bacterial surface could clearly separate out animal passaged strains from wild type strains indicating a virulence model that could predict the virulence of a . S. pyogenes strain in mice and which could be used to identify key aspects of this bacteria's pathogenesis.
8.	Malmström, Erik, et al. (författare) Targeted mass spectrometry analysis of neutrophil-derived proteins released during sepsis progression. 2014 Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 112:6, s. 1230-1243 Tidskriftsartikel (refereegranskat)abstract Early diagnosis of severe infectious diseases is essential for timely implementation of lifesaving therapies. In a search for novel biomarkers in sepsis diagnosis we focused on polymorphonuclear neutrophils (PMNs). Notably, PMNs have their protein cargo readily stored in granules and following systemic stimulation an immediate increase of neutrophil-borne proteins can be observed into the circulation of sepsis patients. We applied a combination of mass spectrometry (MS) based approaches, LC-MS/MS and selected reaction monitoring (SRM), to characterise and quantify the neutrophil proteome in healthy or disease conditions. With this approach we identified a neutrophil-derived protein abundance pattern in blood plasma consisting of 20 proteins that can be used as a protein signature for severe infectious diseases. Our results also show that SRM is highly sensitive, specific, and reproducible and, thus, a promising technology to study a complex, dynamic and multifactorial disease such as sepsis.
9.	Malmström, Erik, et al. (författare) The importance of fibroblasts in remodelling of the human uterine cervix during pregnancy and parturition. 2007 Ingår i: Molecular Human Reproduction. - : Oxford University Press (OUP). - 1460-2407. ; 13, s. 333-341 Tidskriftsartikel (refereegranskat)abstract It is well established that fibroblasts play a crucial role in pathophysiological extracellular matrix remodelling. The aim of this project is to elucidate their role in normal physiological remodelling. Specifically, the remodelling of the human cervix during pregnancy, resulting in an enabled passage of the child, is used as the model system. Fibroblast cultures were established from cervices of non-pregnant women, women after 36 weeks of pregnancy and women directly after partus. The cells were immunostained and quantified by western blots for differentiation markers. The cultures were screened for cytokine and metalloproteinase production and characterized by global proteome analysis. The cell cultures established from partal donors differ significantly from those from non-pregnant donors, which is in accordance with in vivo findings. A decrease in alpha-smooth actin and prolyl-4hydroxylase and an increase in interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMP)-1 and MMP-3 were observed in cultures from partal donors. 2D-gel electrophoresis followed by mass spectrometry showed that the expression of 59 proteins was changed significantly in cultures of partal donors. The regulated proteins are involved in protein kinase C signalling, Ca2+ binding, cytoskeletal organization, angiogenesis and degradation. Our data suggest that remodelling of the human cervix is orchestrated by fibroblasts, which are activated or recruited by the inflammatory processes occurring during the ripening cascade.
10.	Scott, Aaron M, et al. (författare) Generalized precursor prediction boosts identification rates and accuracy in mass spectrometry based proteomics 2023 Ingår i: Communications Biology. - 2399-3642. ; 6, s. 1-13 Tidskriftsartikel (refereegranskat)abstract Data independent acquisition mass spectrometry (DIA-MS) has recently emerged as an important method for the identification of blood-based biomarkers. However, the large search space required to identify novel biomarkers from the plasma proteome can introduce a high rate of false positives that compromise the accuracy of false discovery rates (FDR) using existing validation methods. We developed a generalized precursor scoring (GPS) method trained on 2.75 million precursors that can confidently control FDR while increasing the number of identified proteins in DIA-MS independent of the search space. We demonstrate how GPS can generalize to new data, increase protein identification rates, and increase the overall quantitative accuracy. Finally, we apply GPS to the identification of blood-based biomarkers and identify a panel of proteins that are highly accurate in discriminating between subphenotypes of septic acute kidney injury from undepleted plasma to showcase the utility of GPS in discovery DIA-MS proteomics.
11.	Stenemo, Markus, et al. (författare) Cancer associated proteins in blood plasma : Determining normal variation 2016 Ingår i: Proteomics. - : Wiley. - 1615-9853. ; 16:13, s. 1928-1937 Tidskriftsartikel (refereegranskat)abstract Protein biomarkers have the potential to improve diagnosis, stratification of patients into treatment cohorts, follow disease progression and treatment response. One distinct group of potential biomarkers comprises proteins which have been linked to cancer, known as cancer associated proteins (CAPs). We determined the normal variation of 86 CAPs in 72 individual plasma samples collected from ten individuals using SRM mass spectrometry. Samples were collected weekly during 5 weeks from ten volunteers and over one day at nine fixed time points from three volunteers. We determined the degree of the normal variation depending on interpersonal variation, variation due to time of day, and variation over weeks and observed that the variation dependent on the time of day appeared to be the most important. Subdivision of the proteins resulted in two predominant protein groups containing 21 proteins with relatively high variation in all three factors (day, week and individual), and 22 proteins with relatively low variation in all factors. We present a strategy for prioritizing biomarker candidates for future studies based on stratification over their normal variation and have made all data publicly available. Our findings can be used to improve selection of biomarker candidates in future studies and to determine which proteins are most suitable depending on study design.
12.	Adolfsson, Erik, et al. (författare) Evaluation of bone growth in free formed fabricated scaffolds. 2007 Ingår i: Bioceramics 20, Nantes, France. Konferensbidrag (refereegranskat)
13.	Anderud, Jonas, et al. (författare) Guided bone augmentation using ceramic space-maintaining devices : The impact of chemistry 2015 Ingår i: Clinical, Cosmetic and Investigational Dentistry. - : Nakladatelstvi Lidove noviny. - 1179-1357. ; 7, s. 45-53 Tidskriftsartikel (refereegranskat)abstract The purpose of the study was to evaluate histologically, whether vertical bone augmentation can be achieved using a hollow ceramic space maintaining device in a rabbit calvaria model. Furthermore, the chemistry of microporous hydroxyapatite and zirconia were tested to determine which of these two ceramics are most suitable for guided bone generation. 24 hollow domes in two different ceramic materials were placed subperiosteal on rabbit skull bone. The rabbits were sacrificed after 12 weeks and the histology results were analyzed regarding bone-to-material contact and volume of newly formed bone. The results suggest that the effect of the microporous structure of hydroxyapatite seems to facilitate for the bone cells to adhere to the material and that zirconia enhance a slightly larger volume of newly formed bone. In conclusion, the results of the current study demonstrated that ceramic space maintaining devices permits new bone formation and osteoconduction within the dome.
14.	Anderud, Jonas, et al. (författare) The impact of surface roughness and permeability in hydroxyapatite bone regeneration membranes 2015 Ingår i: Clinical Oral Implants Research. - : Blackwell Munksgaard. - 0905-7161 .- 1600-0501. ; 27:8, s. 1047-1054 Tidskriftsartikel (refereegranskat)abstract Background: One of the crucial aspects in guided bone regeneration is the space maintenance. This is normally created by a membrane, which should primarily be accepted by the surrounding tissues without causing any adverse reactions. The impact of surface topography, biological acceptance as well as permeability of these membranes has been carefully discussed in the literature. Purpose: The purpose of this study was to evaluate histologically the bone forming properties inside of hollow hydroxyapatite space-maintaining devices with different inner surfaces and different permeabilities in an animal calvaria model in vivo. Materials and methods: A total of 36 hollow domes with three different designs made of hydroxyapatite were surgically attached to the skulls of rabbits. Group 1 had a moderately rough inner surface. Group 2 had a smooth inner surface. Group 3 had the same properties as Group 1 but had macroscopic holes on the top. The domes were left to heal for 12 weeks and were then processed for undecalcified ground sectioning. Histological evaluations were performed using a light microscope and scanning electron microscopy. The bone-implant contact (BIC) percentage along the device was calculated. Results: The median percentage of BIC was higher for Group 1 compared with Group 2 (P = 0.004). Group 1 produced a larger median BIC compared with Group 3 (P < 0.0001). Conclusions: Within the limits of this preclinical study, these findings suggest that a moderately rough inner surface of a ceramic membrane along with a non-permeable device produces more bone than a smooth inner surface.
15.	Asklund, Thomas, et al. (författare) Considerable improvement in survival for patients aged 60-84 years with high grade malignant gliomas - Data from the Swedish Brain Tumour Population-based Registry 2013 Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 52:5, s. 1043-1046 Tidskriftsartikel (refereegranskat)
16.	Asklund, Thomas, et al. (författare) Överlevnaden vid maligna gliom har ökat senaste tio åren - Analys av kvalitetsregisterdata : [Survival in malignant gliomas has increased the last decade. Analysis of quality data] 2012 Ingår i: Läkartidningen. - : Läkartidningen Förlag. - 0023-7205 .- 1652-7518. ; 109:17-18, s. 875-878 Tidskriftsartikel (refereegranskat)abstract Den årliga incidensen av högmaligna gliom, WHO grad III–IV, i Sverige är ungefär 400.Medianöverlevnaden för höggradiga gliom har ökat från 8,1 månader till 10,0 månader under det senaste decenniet i en oselekterad svensk population.För åldersgruppen 60–69 år har medianöverlevnaden ökat från 5,8 månader till 10,5 månader under denna period, dvs nästan en fördubbling.Utveckling av befintliga behandlingsmetoder, nya behandlingsstrategier och en mer aktiv inställning till terapi har sannolikt bidragit till de beskrivna överlevnadsvinsterna.
17.	Asklund, Thomas, et al. (författare) Överlevnanden vid maligna gliom har ökat senaste tio åren. Analys av kvalitetsregisterdata. 2012 Ingår i: Läkartidningen. - : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 109:17-18, s. 875-878 Tidskriftsartikel (refereegranskat)abstract The annual incidence rate of high grade malignant glioma (WHO grade III-IV) in Sweden is approximately 400 patients. The objective for the Swedish National CNS-tumor Group is to lay a foundation for research efforts and facilitate implementation and assessment of therapeutic strategies and health care for this patient group. In the analyses the diagnoses of high grade malignant gliomas are compared for the years 1999-2003, 2004-2006 and 2007-2009 for the Northern Region, the Uppsala Region and the South-east Region of Sweden, a population of 1844 patients. Survival was estimated from Kaplan-Meier survival curves, and a log-rank test was performed to assess whether the survival curves differed. The crude hazard ratio between years of diagnosis was estimated from a Cox regression model. Median survival for all patients 2004-2006 was 10.0 months (95 % confidence interval (CI) 8.9-10.9) compared to 8.1 months 1999-2003 (95 % CI 7.3-8.8). For patients 60-69 years of age almost a doubling of the survival rate has occurred during the last decade. Medan survival has increased from 5.8 months (95 % CI 5.1-7.5) 1999-2003 to 8.5 months (95 % CI 7.0-10.3) for 2004-2006 and to 10.5 months (95 % CI 9.0-12.6) for 2007-2009. Concomitant radiochemotherapy, but also the development of neurosurgical and radiotheraputic techniques and a more active therapeutic attitude, including the older patient groups, have probably contributed to the improved survival rate. A national population based registry, with a close to 100% registration compliance for important diagnostic and outcome parameters is probably an efficient instrument for evaluation of quality measures and implementation of new therapeutic strategies.
18.	Bergh, Jonas, et al. (författare) Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer : A randomised trial 2000 Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 356:9239, s. 1384-1391 Tidskriftsartikel (refereegranskat)abstract Background: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. Methods: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. Findings: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. Interpretation: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.
19.	Bergh, Jonas, et al. (författare) Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high- risk breast cancer: a randomised trial 2000 Ingår i: The Lancet. ; 356:9239, s. 1384-1391 Tidskriftsartikel (refereegranskat)
20.	Carlberg, Konstantin, et al. (författare) Integrated Single Cell and Spatial Transcriptomics Reveal Autoreactive Differentiated B Cells in Joints of Early Rheumatoid Arthritis Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Rheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of peripheral joints. Patients can be subdivided by the presence or absence of Rheumatoid Factor and anti-citrullinated protein antibodies (ACPA) in their circulation. Inflammation of the joint tissue is associated with infiltration of leukocytes from the blood, which can result in generation of lymphoid structures composed of B and T cells. Previous studies have shown that both memory B cells and antibody-secreting plasma cells populate the rheumatic joint tissue when captured from established and often long-standing disease. However, it has remained unclear, whether these cells are autoreactive and whether the associated lymphoid structures are present at the site of inflammation already at the time of diagnosis. Here, we used an integrated single cell and spatial transcriptomic approach to study B and plasma cells in synovial tissue of ACPA- and ACPA+ RA patients at this early time point. We found evidence for T cell help to B cells and presence of memory B and plasma cell pools in ACPA- as well as in ACPA+ RA. Our results demonstrated common supportive microenvironments in both patient subgroups, clonal relationships between the memory B and plasma cell pools and autoreactivity within the plasma cell compartment. These findings challenge our understanding of the dynamics of local adaptive immune responses in the RA joint of ACPA- and ACPA+ patients at the time of diagnosis, with direct implications for B and T cell targeting therapies for both patient subgroups.
21.	Eklund, Erik, et al. (författare) Proteoglycan production in disomic and trisomy 7-carrying human synovial cells. 2002 Ingår i: Matrix Biology. - 1569-1802. ; 21:4, s. 325-335 Tidskriftsartikel (refereegranskat)abstract To gain further insight into the synthesis and structure of the synovial matrix of joints, we have established cell cultures from synovial specimens and elaborated their production of hyaluronan and proteoglycans. The cultures secreted mainly the small proteoglycan decorin, but also considerable amounts of the related biglycan and the large proteoglycan versican. Only minor amounts of heparan sulfate proteoglycans were found. All cultures also had a high production of hyaluronan, which highlights the important role for normal joint function of these cells. In joint diseases, a common feature is the presence of an extra chromosome 7 (trisomy 7) in the synovial cells. To study the possible consequences of trisomy 7 on the synovial cell function, we extended our study to cultures that had been sub-cloned to contain high amounts of trisomy 7-carrying cells. These cell cultures had approximately four times more versican than their disomic counterparts in the cell culture medium, indicating that versican may be a mediator in the processes of joint destructive disorders. To find an explanation for this increase in versican, we investigated the expression/secretion of PDGF-AA and IL-6, cytokines with their genes located to chromosome 7. Indeed, both these cytokines were increased in the cultures with high frequencies of trisomy 7. We then added the two cytokines to cell cultures of disomic synovial cells, but only cells treated with IL-6 displayed an increased amount of versican. Thus, we suggest that the increased amount of versican in cultures of trisomy 7-carrying cells relates to an autocrine loop involving an increased IL-6 production.
22.	Fisher, Jane, et al. (författare) Proteome profiling of recombinant DNase therapy in reducing NETs and aiding recovery in COVID-19 patients 2021 Ingår i: Molecular and Cellular Proteomics. - : Elsevier BV. - 1535-9484 .- 1535-9476. ; 20 Tidskriftsartikel (refereegranskat)abstract Severe COVID-19 can result in pneumonia and acute respiratory failure. Accumulation of mucus in the airways is a hall mark of the disease and can result in hypoxemia. Here, we show that quantitative proteome analysis of the sputum from severe COVID-19 patients reveal high levels of neutrophil extracellular trap(s) (NETs) components, which was confirmed by microscopy. Extracellular DNA from excessive NET formation can increase sputum viscosity and can lead to acute respiratory distress syndrome (ARDS). Recombinant human DNase (rhDNase/Pulmozyme) has been shown to be beneficial in reducing sputum viscosity and improve lung function. We treated 5 COVID-19 patients presenting acute symptoms with clinically approved aerosolized Pulmozyme. No adverse reactions to the drug were seen, and improved oxygen saturation and recovery in all severely ill COVID-19 patients was observed after therapy. Immunofluorescence and proteome analysis of sputum and blood plasma samples after treatment revealed a marked reduction of NETs and a set of statistically significant proteome changes that indicate reduction of haemorrhage, plasma leakage and inflammation in the airways, and reduced systemic inflammatory state in the blood plasma of patients. Taken together, the results indicate that NETs contribute to acute respiratory failure in COVID-19 and that degrading NETs may reduce dependency on external high flow oxygen therapy in patients. Targeting NETs using rhDNase may have significant therapeutic implications in COVID-19 disease and warrants further studies.
23.	Grandfield, Kathryn, et al. (författare) Bone regeneration in hydroxyapatite scaffolds: an in vivo study in humans. 2009 Ingår i: Abstract, 22nd European Conference on Biomaterials, Lausanne, Switzerland. ; 7-11 September Konferensbidrag (refereegranskat)
24.	Grandfield, Kathryn, et al. (författare) Bone response to free form fabricated hydroxyapatite and zirconia scaffolds : a transmission electron microscopy study in the human maxilla 2012 Ingår i: Clinical Implant Dentistry and Related Research. - : Wiley. - 1523-0899 .- 1708-8208. ; 14:3, s. 461-469 Tidskriftsartikel (refereegranskat)abstract Background: Understanding the interfacial reactions to synthetic bone regenerative scaffolds in vivo is fundamental for improving osseointegration and osteogenesis. Using transmission electron microscopy, it is possible to study the biological response of hydroxyapatite (HA) and zirconia (ZrO2) scaffolds at the nanometer scale.Purpose: In this study, the bone-bonding abilities of HA and ZrO2 scaffolds produced by free-form fabrication were evaluated in the human maxilla at 3 months and 7 months.Materials and Methods: HA and ZrO2 scaffolds (ø: 3 mm) were implanted in the human maxilla, removed with surrounding bone, embedded in resin, and sectioned. A novel focused ion beam (FIB) sample preparation technique enabled the production of thin lamellae for study by scanning transmission electron microscopy.Results: Interface regions were investigated using high-angle annular dark-field imaging and energy-dispersive X-ray spectroscopy analysis. Interfacial apatite layers of 80 nm and 50 nm thickness were noted in the 3- and 7-month HA samples, respectively, and bone growth was discovered in micropores up to 10 µm into the samples.Conclusions: The absence of an interfacial layer in the ZrO2 samples suggest the formation of a direct contact with bone, while HA, which bonds through an apatite layer, shows indications of resorption with increasing implantation time. This study demonstrates the potential of HA and ZrO2 scaffolds for use as bone regenerative materials.
25.	Gustafsson, Renata, et al. (författare) Dermatan sulfate epimerase 1 deficient mice as a model for human abdominal wall defects. 2014 Ingår i: Birth Defects Research. Part A: Clinical and Molecular Teratology. - : Wiley. - 1542-0760 .- 1542-0752. ; 100:9, s. 712-720 Tidskriftsartikel (refereegranskat)abstract Dermatan sulfate (DS) is a highly sulfated polysaccharide with a variety of biological functions in extracellular matrix organization and processes such as tumorigenesis and wound healing. A distinct feature of DS is the presence of iduronic acid, produced by the two enzymes, DS-epimerase 1 and 2, which are encoded by Dse and Dsel, respectively.
26.	He, Yibo, et al. (författare) A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis. 2023 Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certainRA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.
27.	Hedman, Kristina, et al. (författare) Orimlig ökning av adhd-diagnoser 2024 Ingår i: Svenska dagbladet. - 1101-2412. Tidskriftsartikel (populärvet., debatt m.m.)abstract Sveriges neuropsykologers förening: Ökningen av adhd-diagnoser är ett samhällsproblem som inte kan lösas enbart av vården, och lösningen finns knappast i en växande mängd av utredningar, diagnoser och medicinering.
28.	Henriksson, Roger, et al. (författare) High-grade astrocytoma treated concomitantly with estramustine and radiotherapy. 2006 Ingår i: Journal of neuro-oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 78:3, s. 321-6 Tidskriftsartikel (refereegranskat)abstract Experimental and early clinical investigations have demonstrated encouraging results for estramustine in the treatment of malignant glioma. The present study is an open randomized clinical trial comparing estramustine phosphate (Estracyt) in addition to radiotherapy with radiotherapy alone as first line treatment of astrocytoma grade III and IV. The 140 patients included were in a good clinical condition with a median age of 55 years (range 22-87). Estramustine was given orally, 280 mg twice daily, as soon as the diagnosis was established, during and after the radiotherapy for a period of in total 3 months. Radiotherapy was delivered on weekdays 2 Gy daily up to 56 Gy. Eighteen patients were excluded due to misclassification, leaving 122 patients eligible for evaluation. Overall the treatment was well tolerated. Mild or moderate nausea was the most common side effect of estramustine. The minimum follow-up time was 5.2 years for the surviving patients. For astrocytoma grade III the median survival time was 10.6 (1.3-92.7) months for the radiotherapy only group and 17.3 (0.4-96.9+) months for the estramustine + radiotherapy group. In grade IV the corresponding median survival time was 12.3 (2.1-89.2) and 10.3 (0.3-91.7+) months, respectively. Median time to progress for radiotherapy only and radiotherapy and estramustin group in grade III tumours was 6.5 and 10.1 months, respectively. In grade IV tumours the corresponding figures were 5.1 and 3.3 months, respectively. Although there was a tendency for improved survival in grade III, no statistical significant differences were found between the treatment groups. No differences between the two treatment groups were evident with respect to quality of life according to the EORTC QLQ-protocol. In conclusion, this first randomized study did not demonstrate any significant improvement of using estramustine in addition to conventional radiotherapy, however, a trend for a positive response for the estramustine group was found in patients with grade III glioma.
29.	Ising, Erik, et al. (författare) Quantification of heat shock proteins in the posterior interosseous nerve among subjects with type 1 and type 2 diabetes compared to healthy controls 2023 Ingår i: Frontiers in Neuroscience. - : FRONTIERS MEDIA SA. - 1662-4548 .- 1662-453X. ; 17 Tidskriftsartikel (refereegranskat)abstract Introduction: Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 (T1D) and type 2 diabetes (T2D). No cure for DPN is available, but several potential targets have been proposed for treatment. Heat shock proteins (HSPs) are known to respond to both hyper- and hypoglycemia. DPN can be diagnosed using electrophysiology and studied using peripheral nerve biopsies.Aim: This study aimed to analyze the presence and patterns of HSPs in peripheral nerve biopsies from subjects with T1D, T2D, and healthy controls.Methods: Posterior interosseous nerves (PIN) from a total of 56 subjects with T1D (n = 9), with T2D (n = 24), and without diabetes (i.e., healthy controls, n = 23) were harvested under local anesthesia and prepared for quantitative mass spectrometry analysis. Protein intensities were associated with electrophysiology data of the ulnar nerve and morphometry of the same PIN, and differences in protein intensities between groups were analyzed.Results: In total, 32 different HSPs were identified and quantified in the nerve specimens. No statistically significant differences were observed regarding protein intensities between groups. Furthermore, protein intensities did not correlate with amplitude or conduction velocity in the ulnar nerve or with the myelinated nerve fiber density of PIN.Conclusion: Quantitative proteomics can be used to study HSPs in nerve biopsies, but no clear differences in protein quantities were observed between groups in this cohort.
30.	Ising, Erik, et al. (författare) Quantitative proteomic analysis of human peripheral nerves from subjects with type 2 diabetes 2021 Ingår i: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 38:11 Tidskriftsartikel (refereegranskat)abstract AIMS: Diabetic peripheral neuropathy (DPN) is a common and severe complication to type 2 diabetes (T2D). The pathogenesis of DPN is not fully known, but several pathways and gene polymorphisms contributing to DPN are described. DPN can be studied using nerve biopsies, but studies on the proteome of the nerve itself, and its surrounding tissue as a whole, are lacking. Studies on the posterior interosseous nerve (PIN) have proposed PIN a useful indicator of DPN.METHODS: A quantitative mass spectrometry-based proteomics analysis was made of peripheral nerves from age- and gender-matched living human male tissue donors; nine T2D subjects, with decreased sural nerve action potentials indicating DPN, and six controls without T2D, with normal electrophysiology results.RESULTS: A total of 2617 proteins were identified. Linear regression was used to discover which proteins were differentially expressed between T2D and controls. Only soft signals were found. Therefore, clustering of the 500 most variable proteins were made in order to find clusters of similar proteins in T2D subjects and healthy controls.CONCLUSIONS: This feasibility study shows, for the first time, that the use of quantitative mass spectrometry enables quantification of proteins from nerve biopsies from subjects with and without T2D, which may aid in finding biomarkers of importance to DPN development.
31.	Jarmar, Tobias, et al. (författare) High Resolution TEM Analysis of Interfaces between Biomaterials and Tissue 2006 Ingår i: Abstract, European Society for Biomaterials, Nantes. Konferensbidrag (refereegranskat)
32.	Kaczmarczyk, Aneta, 1972- (författare) Proteins of the Inter-α-inhibitor Family : Biosynthesis, Plasma Clearance and Interaction with Extracellular Matrix Components 2003 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Bikunin, a chondroitin sulfate-containing protein of 25 kDa, has protease inhibitory activity and occurs in the plasma in free and complexed form. In inter-α-inhibitor (IαI) and pre-a-inhibitor (PαI) it is covalently linked through its chondroitin sulfate (CS) chain to two or one other polypeptide of about 80 kDa – heavy chains 1 and 2 (H1, H2) and heavy chain 3 (H3) – respectively. Bikunin and the heavy chains are synthesized as precursors, which are proteolytically cleaved and assembled into IαI and PαI in the secretory pathway. The C-terminal extension (CTX) of the heavy chains seems to mediate its own cleavage and theassembly of the complexes. The heavy chains of the IαI family become transferred to hyaluronan during ovulation and inflammation.In this thesis, the biosynthesis of PαI, the plasma clearance of bikunin and the binding of IαI to collagen were studied. We found that in H3, a short segment on the N-terminal side of the CTX cleavage site is required for cleavage. Furthermore, the H3 could become linked to free CS chains primed by a xyloside, showing that the bikunin protein core is not needed for coupling. We also identified His649 as a residue essential for coupling, but not for cleavage. Bikunin labelled with a residualizing agent, 125I-tyramine cellobiose, was injected into mice to identify tissues involved in its uptake. Half of the radioactivity was recovered in the kidneys, 10% in the liver, and the rest distributed in other tissues. We determined the half-life of bikunin in rat plasma using two independent methods: injection of 125I-bikunin, or hepatectomy followed by assessing the rate of disappearance of endogenous bikunin. Both methods yielded half-time values of 5-7 minutes. Removal of the CS chain did not affect the clearance rate of bikunin.IαI and its heavy chains were found to bind to collagen with dissociation constants greater than 2 μM and 0.4-0.6 μM, respectively and this binding was independent of divalent metal ions. We suggest that the interaction of IαI with collagen may play a modulatory role in cell migration or in remodelling of the extracellular matrix.
33.	Killander, Fredrika, et al. (författare) No Increased Cardiac Mortality or Morbidity of Radiation Therapy in Breast Cancer Patients After Breast-Conserving Surgery : 20-Year Follow-up of the Randomized SweBCGRT Trial 2020 Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 107:4, s. 701-709 Tidskriftsartikel (refereegranskat)abstract PurposeRadiation therapy (RT) after breast-conserving surgery reduces locoregional recurrences and improves survival but may cause late side effects. The main purpose of this paper was to investigate long-term side effects after whole breast RT in a randomized clinical trial initiated in 1991 and to report dose-volume data based on individual 3-dimensional treatment plans for organs at risk.Methods and MaterialsThe trial included 1187 patients with T1-2 N0 breast cancer randomized to postoperative tangential whole breast RT or no further treatment. The prescription dose to the clinical target volume was 48 to 54 Gy. We present 20-year follow-up on survival, cause of death, morbidity, and later malignancies. For a cohort of patients (n = 157) with accessible computed tomography–based 3-dimensional treatment plans in Dicom-RT format, dose-volume descriptors for organs at risk were derived. In addition, these were compared with dose-volume data for a cohort of patients treated with contemporary RT techniques.ResultsThe cumulative incidence of cardiac mortality was 12.4% in the control group and 13.0% in the RT group (P = .8). There was an increase in stroke mortality: 3.4% in the control group versus 6.7% in the RT group (P = .018). Incidences of contralateral breast cancer and lung cancer were similar between groups. The median Dmean (range) heart dose for left-sided treatments was 3.0 Gy (1.1-8.1), and the corresponding value for patients treated in 2017 was 1.5 Gy (0.4-6.0).ConclusionsIn this trial, serious late side effects of whole breast RT were limited and less than previously reported in large meta-analyses. We observed no increase in cardiac mortality in irradiated patients. Doses to the heart were a median Dmean of 3.0 Gy for left-sided RT. The observed increase in stroke mortality may partly be secondary to cardiac side effects, complications to anticoagulant treatment, or to chance, rather than a direct side effect of tangential whole breast irradiation.
34.	Killander, F, et al. (författare) No increased cardiac mortality or morbidity of radiotherapy in breast cancer patients after breast conserving surgery: 20 years follow-up of the randomised x trial. 2020 Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier BV. - 1879-355X .- 0360-3016. ; 107:4, s. 701-9 Tidskriftsartikel (refereegranskat)abstract Radiotherapy (RT) after breast conserving surgery reduces loco-regional recurrences and improves survival, but may cause late side effects. The main purpose of this paper was to investigate long-term side effects after whole breast RT in a randomised clinical trial initiated in 1991 and to report dose-volume data based on individual 3D treatment plans for organs at risk (OR).The trial included 1187 T1-2 N0 breast cancer patients randomised to postoperative tangential whole breast radiotherapy or no further treatment. The prescription dose to the clinical target volume was 48-54 Gy. We present 20 year follow-up on survival, cause of death, morbidity and later malignancies. For a cohort of patients (n=157) with accessible CT-based 3D treatment plans in Dicom-RT format, dose-volume descriptors for OR were derived. In addition, these were compared with dose-volume data for a cohort of patients treated with contemporary RT techniques.The cumulative incidence of cardiac mortality was 12.4 % in the control group and 13.0 % in the RT group (P= 0.8). There was an increase in stroke mortality, 3.4 % in the control group versus 6.7 % in the RT group (P=0.018). Incidences of contra lateral breast cancer and lung cancer were similar between groups. The median Dmean (range) heart dose for left-sided treatments was 3.0 Gy (1.1-8.1) and the corresponding value for patients treated in 2017 was 1.5 Gy (0.4-6.0).In this trial serious late side effects of whole breast radiotherapy were limited and less than previously reported in large meta-analyses. We observed no increased cardiac mortality in irradiated patients with doses to the heart were median Dmean 3.0 Gy for left-sided RT. The observed increase in stroke mortality may partly be secondary to cardiac side effects, complications to anticoagulant treatment, or to chance, rather than a direct side effect of tangential whole breast irradiation.
35.	Kovács, Anikó, 1961, et al. (författare) Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes : A Long-Term Follow-Up of the SweBCG91RT Randomized Trial 2019 Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 37:14, s. 1179-87 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The effects of radiotherapy (RT) on the basis of the presence of stromal tumor infiltrating lymphocytes (TILs) have not been studied. The purpose of this study was to analyze the association of TILs with the effect of postoperative RT on ipsilateral breast tumor recurrence (IBTR) in a large randomized trial. METHODS: In the SweBCT91RT (Swedish Breast Cancer Group 91 Radiotherapy) trial, 1,178 patients with breast cancer stage I and II were randomly assigned to breast-conserving surgery plus postoperative RT or breast-conserving surgery only and followed for a median of 15.2 years. Tumor blocks were retrieved from 1,003 patients. Stromal TILs were assessed on whole-section hematoxylin-eosin-stained slides using a dichotomized cutoff of 10%. Subtypes were scored using immunohistochemistry on tissue microarray. In total, 936 patients were evaluated. RESULTS: Altogether, 670 (71%) of patients had TILs less than 10%. In a multivariable regression analysis with IBTR as dependent variable and RT, TILs, subtype, age, and grade as independent variables, RT (hazard ratio [HR], 0.42; 95% CI, 0.29 to 0.61; P < .001), high TILs (HR, 0.61; 95% CI, 0.39 to 0.96, P = .033) grade (3 v 1; HR, 2.17; 95% CI, 1.08 to 4.34; P = .029), and age (≥ 50 v < 50 years; HR, 0.55; 95% CI, 0.38 to 0.80; P = .002) were predictive of IBTR. RT was significantly beneficial in the low TILs group (HR, 0.37; 95% CI, 0.24 to 0.58; P < .001) but not in the high TILs group (HR, 0.58; 95% CI, 0.28 to 1.19; P = .138). The test for interaction between RT and TILs was not statistically significant (P = .317). CONCLUSION: This study shows that high values of TILs in the primary tumor independently seem to reduce the risk for an IBTR. Our findings further suggest that patients with breast cancer with low TILs may derive a larger benefit from RT regarding the risk of IBTR.
36.	Liedberg, Fredrik, et al. (författare) Long-term follow-up after radical cystectomy with emphasis on complications and reoperations: A Swedish population-based survey 2012 Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa Healthcare. - 0036-5599 .- 1651-2065. ; 46:1, s. 14-18 Tidskriftsartikel (refereegranskat)abstract Objective. To evaluate outcome after radical cystectomy for primary bladder cancer in a large population-based material. Material and methods. Between 1997 and 2002 all patients treated with radical cystectomy within 3 months after diagnosis of primary bladder cancer without distant metastasis were retrieved through the Swedish Bladder Cancer Registry. A follow-up questionnaire was distributed to all units where the primary registration of patients was performed. Follow-up data on recurrence date were retrieved from the patient charts and causes of death were obtained from the Swedish Cause of Death Registry until 2003. Results. During the study period radical cystectomy was performed in 39 units in Sweden, of which only five units were considered high-volume hospitals performing 10 or more procedures annually. Mean blood loss was 2300 ml (median 2000 ml) and the 90-day mortality rate was 5.7%. Blood loss was higher in high-volume units than in hospitals with lower hospital volumes, but the 90-day mortality rates were similar. During a median follow-up of 3.5 years, 24% of the patients were submitted to a reoperation. Reoperation rates were significantly higher in patients who received a continent urinary diversion (29%) compared with an ileal conduit (22%, p andlt; 0.015). Conclusions. Radical cystectomy was associated with a reoperation rate of 24% in Sweden during the study period. The reoperation rates were higher in patients receiving a continent cutaneous diversion or bladder substitution. Blood loss was higher in high-volume units; otherwise, surgical volume did not affect mortality rates, cancer-specific survival or reoperation rates.
37.	Lindgren, Erik, et al. (författare) Nondestructive Evaluation with Laser Ultrasound of Powder Bed Fusion Printed Metal Parts 2019 Konferensbidrag (refereegranskat)abstract Introduction/PurposeMany of the main advantages of 3D printing metal components, for example the possibility to manufacture components of high geometriccomplexity in small series, typically make the nondestructive quality control difficult and resource intense. A number of published studies haveproposed in-process quality control of the component, as it is built layer by layer, as a possible general approach solution to this difficulty. Previousstudies have also indicated that the non-contact nondestructive testing method laser ultrasound might be an applicable method to conduct such anin-process nondestructive evaluation of 3D printed components.MethodsIn this work laser ultrasonic nondestructive evaluation of both electron beam and laser beam powder bed fusion printed metal parts isdemonstrated. Nickel-base and Stainless Steel samples are evaluated both from a machined surface and, in order to simulate the in-process setup,from the as-printed top surface.ResultsThe laser ultrasonic evaluation results are compared to results from other material characterization methods. Designed artificial defects as well asprocess material anomalies could be detected with the proposed laser ultrasonic evaluation, both when the evaluation was performed from the asprintedtop surface as well as from the machined surface.ConclusionsWe conclude that laser ultrasound can be utilized to detect material anomalies of interest in powder bed fusion printed metal parts. Furtherresearch is required in order to better understand and improve the capability and reliability of the nondestructive evaluation method.
38.	Lindgren, Lars-Erik, 1956-, et al. (författare) Nondestructive Evaluation with Laser Ultrasound of Powder Bed Fusion Printed Metal 2019 Konferensbidrag (refereegranskat)abstract Many of the main advantages of 3D printing metal components, for example the possibility to manufacture parts of high geometric complexity in small series, typically make the nondestructive quality control difficult and resource intense. A number of published studies have proposed in-process nondestructive evaluation of the printed material, as it is built layer by layer, as a possible general approach solution to this difficulty. Previous studies have also indicated that the non-contact nondestructive testing method laser ultrasound might be an applicable method to conduct such an in-process nondestructive evaluation of 3D printed parts. Potential pros of such an ultrasonic based evaluation, as compared to more process monitoring like approaches (e.g. acoustic emission from the printing process) would for example be increased defect characterization capabilities.In this work laser ultrasonic nondestructive evaluation of both electron beam and laser beam powder bed fusion printed metal is demonstrated. Nickel-base and Stainless Steel samples are evaluated both from a machined surface and, in order to simulate the in-process setup, from the as-printed top surface.The laser ultrasonic evaluation results are then compared to results from other material characterization methods, such as light optical microscopy and X-ray inspection. Designed artificial defects as well as process material anomalies could be detected with the proposed laser ultrasonic evaluation. In some cases material defects could be detected also when the laser ultrasonic evaluation was performed from the as-printed top surface.Our results are similar to other studies that have been reported on the subject: laser ultrasound can be utilized to detect material anomalies of interest in powder bed fusion printed metal material. Further research is required in order to better understand and improve the capability and reliability of the nondestructive evaluation method.
39.	Lindqvist, Jan-Erik, et al. (författare) Microstructure and functional properties of rock materials 2005 Ingår i: Proceedings ot the 10th EMABM, Paisley. Konferensbidrag (refereegranskat)
40.	Lundstedt, Dan, 1970, et al. (författare) Risk Factors of Developing Long-Lasting Breast Pain After Breast Cancer Radiotherapy. 2012 Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier BV. - 1879-355X .- 0360-3016. ; 83:1, s. 71-78 Tidskriftsartikel (refereegranskat)abstract PURPOSE: Postoperative radiotherapy decreases breast cancer mortality. However, studies have revealed a long-lasting breast pain among some women after radiotherapy. The purpose of this study was to identify risk factors that contribute to breast pain after breast cancer radiotherapy. METHODS AND MATERIALS: We identified 1,027 recurrence-free women in two cohorts of Swedish women treated for breast cancer. The women had breast-conserving surgery and postoperative radiotherapy, the breast was treated to 48 Gy in 2.4-Gy fractions or to 50 Gy in 2.0-Gy fractions. Young women received a boost of up to 16 Gy. Women with more than three lymph node metastases had locoregional radiotherapy. Systemic treatments were given according to health-care guidelines. Three to 17 years after radiotherapy, we collected data using a study-specific questionnaire. We investigated the relation between breast pain and potential risk modifiers: age at treatment, time since treatment, chemotherapy, photon energy, fractionation size, boost, loco-regional radiotherapy, axillary surgery, overweight, and smoking. RESULTS: Eight hundred seventy-seven women (85%) returned the questionnaires. Among women up to 39 years of age at treatment, 23.1% had breast pain, compared with 8.7% among women older than 60 years (RR 2.66; 95% CI 1.33-5.36). Higher age at treatment (RR 0.96; 95% CI 0.94-0.98, annual decrease) and longer time since treatment (RR 0.93; 95% CI 0.88-0.98, annual decrease) were related to a lower occurrence of breast pain. Chemotherapy increased the occurrence of breast pain (RR 1.72; 95% CI 1.19-2.47). In the multivariable model only age and time since treatment were statistically significantly related to the occurrence of breast pain. We found no statistically significant relation between breast pain and the other potential risk modifiers. CONCLUSIONS: Younger women having undergone breast-conserving surgery with postoperative radiotherapy report a higher occurrence of long-lasting breast pain compared to older women. Time since treatment may decrease the occurrence of pain.
41.	Lundstedt, Dan, 1970, et al. (författare) Symptoms 10-17 years after breast cancer radiotherapy data from the randomised SWEBCG91-RT trial 2010 Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 1879-0887 .- 0167-8140. ; 97:2, s. 281-287 Tidskriftsartikel (refereegranskat)abstract Background: Postoperative radiotherapy decreases the risk for local and improves overall survival in women with breast cancer. We have limited information on radiotherapy-induced symptoms 10-17 years after therapy. Material and methods: Between 1997 and 1997, women with lymph node-negative breast cancer were randomised in a Swedish multi-institutional trial to breast conserving surgery with or without postoperative radiotherapy. In 2007, 10-17 years after randomisation, the group included 422 recurrence-free women. We collected data with a study-specific questionnaire on eight pre-selected symptom groups. Results: Fox six symptom group (oedema in breast or arm, erysipelas, heart symptoms, lung symptoms, rib fractures, and decreased shoulder mobility) we found similar occurrence in both groups. Excess occurence after radiotherapy was observed for pain in the breast or in the skin, reported to occur "occasionally" by 38.1% of survivors having undergone radiotherapy and surgery versus 24.0% of those with surgery alone (absolute difference 14.1%; p = 0.004) and at least once a week by 10.3% of the radiotherapy group versus 1.7% (absolute difference 8.6%; p = 0.001). Daily life and analgesic use did not differ between the groups. Conclusion: Ten to 17 years after postoperative radiotherapy 1 in 12 women had weekly pain that could be attributed to radiotherapy. The symptoms did not significantly affect daily life and thus the reduced risk for local recurrence seems to outweight the risk for long-term symptoms for most women. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 97 (2010) 281-287
42.	Malmström, Erik, et al. (författare) Protein C inhibitor - a novel antimicrobial agent 2009 Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 5:12, s. e1000698- Tidskriftsartikel (refereegranskat)abstract Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity.
43.	Malmström, Erik (författare) Studies on the host response to infection in the circulatory system 2013 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Sepsis is a heterogeneous, dynamic, and complex syndrome caused by interaction between the host and the invading pathogen. It is associated with an overwhelmingly dysregulated immune response, and also immunosuppression. In spite of our improved understanding of the underlying molecular pathology, sepsis still remains a common cause of morbidity and mortality worldwide. This is reflected in the unsatisfying results obtained from numerous clinical sepsis trails and in the fact that there is no sepsis-specific treatment available today. It has been proposed that it is time to reconsider the concept of sepsis and to develop novel approaches to the study of severe infectious diseases. The main goal of this thesis was to study host-pathogen interactions in the circulatory system. The research strategy pursued consisted of two distinct parts. Firstly, I worked on elucidating individual host-pathogen interaction mechanisms regarding the close crosstalk between coagulation and the innate immune system. Secondly, I used state-of-the art mass spectrometry analysis in order to get a holistic overview of the molecular processes associated with the pathogenesis of sepsis. In the first two papers, we investigated mechanisms of host-pathogen interaction while focusing on two proteins: tissue factor (TF) and protein C inhibitor (PCI). Paper I showed that soluble M1 protein from Streptococcus pyogenes induces TF expression on monocytes and pro-coagulant activity in whole blood. Paper II demonstrated a novel antimicrobial agent, PCI, and revealed a novel mechanism for how the coagulation system participates in the host defense against bacteria. In the second part of my thesis work, I used mass spectrometry (MS) to study three different biological systems: an individual cell type, clinical plasma samples, and a mouse infection model. The aim here was to develop a testable system that would enable us to study, modify, and evaluate putative effector molecules involved in the pathogenesis of sepsis. In manuscript III, I used several mass spectrometry-based techniques to study the neutrophil proteome under conditions of health and disease, and thereby identified a neutrophil-derived protein abundance pattern in plasma samples from sepsis patients. In manuscript IV, I used SWATH-MS to generate a digital compendium of data from blood plasma samples at different stages of sepsis. This study had two important novel contributions: a deep proteome map of plasma protein dynamics during severe infections and a valuable digital data resource for future sepsis research. In manuscript V, we set out to determine the dynamic changes in protein expression in mouse plasma during severe infection and compared the results to those in human sepsis plasma, with a view to facilitating transfer and interpretation of experimental observations between the two biological systems. The two research strategies used in this thesis were complementary, since the first part provided molecular details of individual biological mechanisms and the other part gave an integrated molecular overview of many separate biological events. The use of mass spectrometry-based techniques allows us to study and integrate information from in-vitro experiments, in-vivo model systems, and clinical observations. The work described in this thesis has hopefully laid the foundation for a resource that may facilitate and improve future research on sepsis.
44.	Malmström, Erik, et al. (författare) The Long Non-Coding Antisense RNA JHDM1D-AS1 Regulates Inflammatory Responses in Human Monocytes 2022 Ingår i: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 12 Tidskriftsartikel (refereegranskat)abstract Monocytes are key players in innate immunity, with their ability to regulate inflammatory responses and combat invading pathogens. There is a growing body of evidence indicating that long non-coding RNA (lncRNA) participate in various cellular biological processes, including the innate immune response. The immunoregulatory properties of numerous lncRNAs discovered in monocytes remain largely unexplored. Here, by RNA sequencing, we identified a lncRNA JHDM1D-AS1, which was upregulated in blood monocytes obtained from patients with sepsis relative to healthy controls. JHDM1D-AS1 expression was induced in primary human monocytes exposed to Toll-like receptor ligands, such as lipopolysaccharide (LPS), or bacteria. The inducibility of JHDM1D-AS1 expression in monocytes depended, at least in part, on nuclear factor–κB activation. JHDM1D-AS1 knockdown experiments in human monocyte-derived macrophages revealed significantly enhanced expression of inflammatory mediators, before and after exposure to LPS, relative to control cells. Specifically, genes involved in inflammatory responses were upregulated (e.g., CXCL2, CXCL8, IL1RN, TREM1, TNF, and IL6), whereas genes involved in anti-inflammatory pathways were downregulated (e.g., SOCS1 and IL10RA). JHDM1D-AS1 overexpression in a pro-monocytic cell line revealed diminished pro-inflammatory responses subsequent to LPS challenge. Collectively, these findings identify JHDM1D-AS1 as a potential anti-inflammatory mediator induced in response to inflammatory stimuli.
45.	Malmström, Erik, et al. (författare) Utvärderingsverktyg supercykelvägar 2024 Ingår i: Sammanställning av referat från Transportforum 2024. - Linköping : Statens väg- och transportforskningsinstitut. ; , s. 476-477 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Region Skåne arbetar tillsammans med flera av regionens kommuner samt Trafikverket för att utveckla Supercykelvägar i Skåne. Konceptet för Supercykelvägar innebär att viktiga cykelvägar för pendlingstrafik ska utvecklas och uppgraderas samt marknadsföras för att utnyttja potentialen som finns i Skåne med fler cyklister.Under perioden vintern 2021/2022 har AFRY tagit fram ett verktyg för utvärdering av potentiella supercykelvägar. AFRY har haft uppdraget att utveckla en metod för att på ett samlat och kvantitativt sätt beskriva kvaliteter och brister för en potentiell supercykelväg. Verktyget baseras på Region Skånes koncept för supercykelvägar. Detta innefattar har fyra kvalitetsaspekter, som därefter delats in i funktionskrav. Kvalitetsaspekterna är:TillgänglighetFramkomlighetKomfortTrygghet och säkerhetDessa tidigare definierade funktionskrav har i utvecklingen av verktyget konkretiserats i indikatorer. Verktyget har tagits fram genom en process bestående av ett antal arbetsmöten tillsammans med Region Skånes representanter för supercykelvägar, där indikatorerna och hur de ska bedömas har diskuterats. Det första utkastet av verktyget skickades till väghållare av fyra potentiella supercykelvägar för test. Bedömningarna av indikatorerna baseras i största möjliga mån på planeringsriktlinjer som finns i publicerade artiklar, guider och handböcker, bland annat GCM-handboken (numera ”Mobilitet för gående, cyklister och mopedister”). Verktygets syfte är att vara korrekt och rättvis för olika supercykelvägar, och därav vara kvantifierbar. Samtidigt ska inte en omfattande bristinventering vara ett hinder för att lansera en supercykelväg. För att cykelvägen ska klassas som supercykelväg krävs det att tre särskilda indikatorer uppfylls, så kallade skall-krav, utöver att den genomsnittliga bedömningen är tillräckligt hög. Dessa indikatorer handlar bland annat om att Region Skånes vägvisningsprinciper efterföljs, samt att det finns en handlingsplan för att fortsätta utveckla supercykelvägen. Verktyget, som är i Excel-format, utvärderar cykelvägen i sin helhet på ett kvantitativt sätt utifrån hur det ser ut idag, men kan även beakta hur framtida upprustningsplaner som finns för cykelvägen kommer att slå ut i utvärderingen.
46.	Malmström, Johan, 1975, et al. (författare) Bone ingrowth in zirconia and hydroxyapatite scaffolds with identical macroporosity. 2008 Ingår i: Journal of materials science. Materials in medicine. - : Springer Science and Business Media LLC. - 0957-4530 .- 1573-4838. ; 19:9, s. 2983-92 Tidskriftsartikel (refereegranskat)abstract The role of the material composition, porosity and surface topography of scaffolds for promotion of osteogenesis and osseointegration is not fully understood. The aim of the present study was to evaluate the effects of material composition and surface topography on bone ingrowth and bone contact. Designed macroporous ceramic scaffolds of zirconia and hydroxyapatite were used. Using free form fabrication (FFF) techniques an identical macroporosity in both materials was achieved. The scaffolds were implanted in rabbit tibia (cortical bone) and femur (trabecular bone). After 6 weeks of implantation the tissue response was assessed with histology and histomorphometry. The results showed significantly more bone ingrowth and bone contact in the hydroxyapatite scaffolds compared to the zirconia scaffold. Surface topography had no significant effect on bone contact inside the macropores regardless of material. This was observed in both cortical and trabecular bone sites. The study suggests that the difference between hydroxyapatite and zirconia was due to a difference in material chemistry.
47.	Malmström, Johan, 1975, et al. (författare) Bone response inside free-form fabricated macroporous hydroxyapatite scaffolds with and without an open microporosity 2007 Ingår i: Clinical Implant Dentistry and Related Research. ; 9:2, s. 79-88 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The technique of free-form fabrication enables the production of controlled macroporous geometry inside ceramic scaffolds. Using scaffolds with identical macropore design makes it possible to study a relevant biological response linked to other specific changes of the material. PURPOSE: This study investigates the role of open micropores in hydroxyapatite (HA) scaffold during early bone healing to quantitatively ascertain whether microporosity in otherwise identical macroporous HA scaffolds can influence the bone response in rabbit tibia and femur at 6 weeks. MATERIALS AND METHODS: HA scaffolds (Ø: 3.8 mm) with and without microporosity were randomly installed in both cortical and trabecular bone sites of New Zealand White rabbits. The animals were sacrificed 6 weeks after surgery. Ground sections obtained from en bloc tissues containing scaffold and recipient bone were subjected to histological evaluation and histomorphometric analysis. RESULTS: Microscopy showed elevated amounts of bone ingrowth and bone contact inside the microporous HA (mHA) group as compared with non-mHA. CONCLUSION: The current study indicates that the presence of open scaffold microporosity in HA, as determined by the fabrication process, enhances the ability of ceramic scaffolds to promote bone ingrowth and bone contact.
48.	Malmström, Johan, et al. (författare) Guided bone regeneration using individualized ceramic sheets 2016 Ingår i: International Journal of Oral and Maxillofacial Surgery. - : Elsevier BV. - 0901-5027 .- 1399-0020. ; 45:10, s. 1246-1252 Tidskriftsartikel (refereegranskat)abstract Guided bone regeneration (GBR) describes the use of membranes to regenerate bony defects. A membrane for GBR needs to be biocompatible, cell-occlusive, non-toxic, and mouldable, and possess space-maintaining properties including stability. The purpose of this pilot study was to describe a new method of GBR using individualized ceramic sheets to perfect bone regeneration prior to implant placement; bone regeneration was assessed using traditional histology and three-dimensional (3D) volumetric changes in the bone and soft tissue. Three patients were included. After full-thickness flap reflection, the individualized ceramic sheets were fixed. The sites were left to heal for 7 months. All patients were evaluated preoperatively and at 7 months postoperative using cone beam computed tomography and 3D optical equipment. Samples of the regenerated bone and soft tissue were collected and analyzed. The bone regenerated in the entire interior volume of all sheets. Bone biopsies revealed newly formed trabecular bone with a lamellar structure. Soft tissue biopsies showed connective tissue with no signs of an inflammatory response. This was considered to be newly formed periosteum. Thus ceramic individualized sheets can be used to regenerate large volumes of bone in both vertical and horizontal directions independent of the bone defect and with good biological acceptance of the material.
49.	Malmström, Johan, 1975, et al. (författare) Trabecular bone ingrowth in inert and bioactive materials with identical macroporosity. 2004 Ingår i: Abstract, 7th World Biomaterials Congress, Sydney, Australia, 2004. Konferensbidrag (refereegranskat)
50.	Malmström, Per, et al. (författare) Breast conservation surgery, with and without radiotherapy, in women with lymph node-negative breast cancer: a randomised clinical trial in a population with access to public mammography screening. 2003 Ingår i: European journal of cancer (Oxford, England : 1990). - 0959-8049. ; 39, s. 1690- Tidskriftsartikel (refereegranskat)abstract The effect of postoperative radiotherapy after sector resection for stage I-II lymph node-negative breast cancer was evaluated in a patient population with access to public mammographical screening. 1187 women were randomised to no further treatment or postoperative radiotherapy following a standardised sector resection and axillary dissection. Radiation was administered to a dose of 48-54 Gy. Median age was 60 years, and median size of the detected tumours was 12 mm. Of the women 65% had their tumours detected by mammographical screening. The relative risk (RR) of ipsilateral breast recurrence was significantly higher in the non-irradiated patients compared with the irradiated patients, RR=3.33 (95% Confidence Interval (CI) 2.13-5.19, P<0.001). The corresponding cumulative incidence at 5 years was 14% versus 4%, respectively. Overall survival (OS) was similar, RR=1.16 (95% CI 0.81-1.65, P=0.41), with 5 year probabilities of 93 and 94%, respectively. Recurrence-free survival (RFS) at 5 years was significantly lower in the non-irradiated women, 77% versus 88% (P<0.001). Although women above 49 years of age, whose tumours were detected with mammographical screening, had the lowest rate of ipsilateral breast recurrence in this study, the cumulative incidence of such event amounted to 10% at 5 years if radiotherapy was not given. Such a recurrence rate has been considered as unacceptably high, but is, however, in the same range as that reported after lumpectomy and postoperative radiotherapy in published series.

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