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1.	Benson, Mikael, 1954, et al. (författare) A network-based analysis of the late-phase reaction of the skin. 2006 Ingår i: The Journal of allergy and clinical immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 118:1, s. 220-5 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The late-phase reaction (LPR) of the skin is an in vivo model of allergic inflammation. OBJECTIVE: We sought to identify disease-associated pathways in the LPR using a network-based analysis. METHODS: The LPR was examined by means of DNA microarray analysis of skin biopsy specimens from 10 patients with allergic rhinitis and 10 healthy control subjects. The results were further analyzed in 2 different materials consisting of nasal fluids and allergen-challenged CD4(+) T cells from patients with allergic rhinitis. RESULTS: The DNA microarray analysis revealed several genes of known relevance to allergy. The eosinophil marker Charcot-Leyden crystal protein (CLC) that encodes Charcot-Leyden crystal protein differed most in expression. A network-based analysis showed upregulation of IL-4- and CCL4-dependent pathways and downregulation of a TGF-beta-induced pathway. CCL4 is expressed by CD4(+) T cells and chemotactic for eosinophils. We hypothesized that allergen induces release of CCL4 from T(H)2 cells and that this contributes to influx of eosinophils. Further analysis showed increase of CCL4 protein in nasal fluids from allergic patients during the season. Allergen challenge of PBMCs resulted in proliferation of T(H)2 cells and increased production of CCL4 in CD4(+) T cells from allergic patients. An analysis of the DNA microarray data revealed a significant correlation between CCL4 and the eosinophil marker CLC. CONCLUSION: A network-based analysis of the LPR showed increased activity of IL-4- and CCL4- dependent pathways and downregulation of the TGF-beta-induced pathway. Allergen-induced release of CCL4 from T(H)2 cells might contribute to influx of eosinophils during the LPR. CLINICAL IMPLICATIONS: Involvement of multiple interacting pathways indicates that it might be difficult to identify one single mediator as a biomarker or drug target in allergic inflammation.
2.	Benson, Mikael, 1954, et al. (författare) Gene profiling reveals decreased expression of uteroglobin and other anti-inflammatory genes in nasal fluid cells from patients with intermittent allergic rhinitis 2005 Ingår i: Clin Exp Allergy. - : Wiley. ; 35:4, s. 473-478 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Intermittent allergic rhinitis (IAR) results from interactions between a large number of pro- and anti-inflammatory mediators. Little is known about anti-inflammatory mediators in IAR. DNA microarrays allow simultaneous analysis of the whole transcriptome in a sample. OBJECTIVE: To identify anti-inflammatory transcripts in nasal fluid cells from patients with IAR during season and from healthy controls. METHODS: Nasal lavage fluids were obtained from 15 patients with symptomatic birch/and or grass pollen-induced IAR and 28 healthy controls. RNA was extracted from the nasal fluid cells and pooled into one patient- and one control pool. These were analysed with DNA microarrays containing more than 44,927 genes and variants. RESULTS: Seventeen thousand three hundred and fifty three genes were expressed in the controls and 17 928 in the patients. One thousand five hundred and seventy nine of the genes had higher expression in patients than in controls, and 1570 had lower expression in patients. Out of 189 up-regulated inflammatory genes, 187 were pro-inflammatory and two were anti-inflammatory. These genes regulated key steps of inflammation, ranging from influx of leukocytes to immunoglobulin production. By comparison, out of 49 down-regulated inflammatory genes, 36 were pro-inflammatory and 13 were anti-inflammatory. The anti-inflammatory gene that decreased most in expression in the patients was uteroglobin (also known as Clara Cell protein 16, CC16). The nasal fluid concentrations of uteroglobin protein were significantly lower in patients than in controls, 5.43+/-1.53 and 12.93+/-2.53 ng/mL, respectively (P<0.05). CONCLUSION: IAR is associated with decreased expression of uteroglobin and other anti-inflammatory genes.
3.	Benson, Mikael, 1954, et al. (författare) Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps. 2004 Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 113:6, s. 1137-43 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Treatment with local glucocorticoids (GCs) decreases symptoms and the size of nasal polyps. This might depend on the downregulation of proinflammatory genes, as well as the upregulation of anti-inflammatory genes. OBJECTIVE: We sought to identify GC-regulated anti-inflammatory genes in nasal polyps. METHODS: Affymetrix DNA microarrays were used to analyze the expression of 22,283 genes in 4 nasal polyps before and after local treatment with fluticasone (400 microg/d). Expression of uteroglobin and mammaglobin B was analyzed with real-time PCR in 6 nasal polyps and in nasal biopsy specimens from 6 healthy control subjects. RESULTS: Two hundred three genes had changed in expression in treated polyps, and 139 had known functions: 54 genes were downregulated, and 85 were upregulated. Genes associated with inflammation constituted the largest single functional group. These genes affected key steps in inflammation (eg, immunoglobulin production; antigen processing and presentation; and the chemoattraction and activation of granulocytes, T cells, and B cells). Several proinflammatory genes were downregulated. In contrast, some anti-inflammatory genes were upregulated. The gene that increased most in terms of expression was uteroglobin. This was confirmed with real-time PCR. By contrast, expression of uteroglobin was lower in untreated polyps than in healthy nasal mucosa. Immunohistochemical investigation showed staining of uteroglobin in the epithelium and in seromucous glands in control subjects and in nasal polyps. CONCLUSION: Upregulation of anti-inflammatory genes, such as uteroglobin, might contribute to the effects of local treatment with GCs in nasal polyps.
4.	Fransson, Mattias, et al. (författare) Expression of Toll-like receptor 9 in nose, peripheral blood and bone marrow during symptomatic allergic rhinitis. 2007 Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X .- 1465-9921. ; 8 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Allergic rhinitis is an inflammatory disease of the upper airway mucosa that also affects leukocytes in bone marrow and peripheral blood. Toll-like receptor 9 (TLR9) is a receptor for unmethylated CpG dinucleotides found in bacterial and viral DNA. The present study was designed to examine the expression of TLR9 in the nasal mucosa and in leukocytes derived from different cellular compartments during symptomatic allergic rhinitis. METHODS: The study was based on 32 patients with seasonal allergic rhinitis and 18 healthy subjects, serving as controls. Nasal biopsies were obtained before and after allergen challenge. Bone marrow, peripheral blood and nasal lavage fluid were sampled outside and during pollen season. The expression of TLR9 in tissues and cells was analyzed using immunohistochemistry and flow cytometry, respectively. RESULTS: TLR9 was found in several cell types in the nasal mucosa and in different leukocyte subpopulations derived from bone marrow, peripheral blood and nasal lavage fluid. The leukocyte expression was generally higher in bone marrow than in peripheral blood, and not affected by symptomatic allergic rhinitis. CONCLUSION: The widespread expression of TLR9 in the nasal mucosa along with its rich representation in leukocytes in different compartments, demonstrate the possibility for cells involved in allergic airway inflammation to directly interact with bacterial and viral DNA.
5.	Månsson, Anne, et al. (författare) TLR3 in human eosinophils: functional effects and decreased expression during allergic rhinitis. 2010 Ingår i: International archives of allergy and immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 151:2, s. 118-28 Tidskriftsartikel (refereegranskat)abstract BACKGROUND/AIM: Viral respiratory infections are increasingly implicated in allergic exacerbations. Virus-induced activation of eosinophils through Toll-like receptors (TLRs) could be involved. The present study was designed to examine TLR3 expression in eosinophils from bone marrow (BM) and peripheral blood (PB) during symptomatic allergic rhinitis, and to evaluate the functional responsiveness of TLR3 in purified eosinophils. METHODS: BM and PB samples were obtained from healthy volunteers and patients with seasonal allergic rhinitis outside and during the pollen season. Eosinophils were analyzed for TLR3 expression by flow cytometry. Polyinosinic:polycytidylic acid [poly(I:C)], an agonist for TLR3, was used to assess its functional role in purified eosinophils and the intracellular signaling pathways involved. RESULTS: TLR3 expression was demonstrated in BM and PB eosinophils. It was higher in BM-derived than in circulating cells and it was downregulated in both compartments during symptomatic allergic rhinitis. TLR3 expression was also downregulated in the presence of interleukin (IL)-4 and IL- 5. Stimulation with poly(I:C) increased the percentage of CD11b+ cells and enhanced the secretion of IL-8, effects mediated via the p38 mitogen-activated protein kinases and nuclear factor-kappaB signaling pathways. Moreover, pretreatment with IL-5 augmented the poly(I:C)-induced IL-8 release. CONCLUSIONS: Eosinophils activated via TLR3 might be more able to home and recruit leukocytes to sites of inflammation. The decreased TLR3 expression during symptomatic allergic rhinitis and in the presence of Th2 cytokines indicates a role in allergic airway inflammation. Thus, eosinophils might function as a link between viral infections and exacerbations of allergic disease.
6.	Barrenäs, Fredrik, 1981, et al. (författare) Gender differences in inflammatory proteins and pathways in seasonal allergic rhinitis 2008 Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 42:3, s. 325-329 Tidskriftsartikel (refereegranskat)
7.	Barrenäs, Fredrik, 1981, et al. (författare) Network properties of complex human disease genes identified through genome-wide association studies. 2009 Ingår i: PloS one. - San Francisco, CA San Francisco, CA, United StatesUnited States : Public Library of Science (PLoS). - 1932-6203. ; 4:11 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias. PRINCIPAL FINDINGS: We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process. CONCLUSIONS: This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.
8.	Benson, Mikael, 1954, et al. (författare) A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis. 2009 Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 64:9, s. 1286-91 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway. OBJECTIVE: To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR. METHODS: CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls. RESULTS: Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls. CONCLUSION: Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.
9.	Benson, Mikael, 1954, et al. (författare) A network-based analysis of allergen-challenged CD4+T cells from patients with allergic rhinitis 2006 Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 7:6, s. 514-521 Tidskriftsartikel (refereegranskat)abstract We performed a network-based analysis of DNA microarray data from allergen-challenged CD4 + T cells from patients with seasonal allergic rhinitis. Differentially expressed genes were organized into a functionally annotated network using the Ingenuity Knowledge Database, which is based on manual review of more than 200000 publications. The main function of this network is the regulation of lymphocyte apoptosis, a role associated with several genes of the tuber necrosis factor superfamily. The expression of TNFRSF4, one of the genes in this family, was found to be 48 times higher in allergen-challenged cells than in diluent-challenged cells. TNFRSF4 is known to inhibit apoptosis and to enhance Th2 proliferation. Examination of a different material of allergen-stimulated peripheral blood mononuclear cells showed a higher number of interleukin-4 + type 2 CD4 + T (Th2) cells in patients than in controls (P
10.	Benson, Mikael, 1954, et al. (författare) Altered levels of the soluble IL-1, IL-4 and TNF receptors, as well as the IL-1 receptor antagonist, in intermittent allergic rhinitis 2004 Ingår i: Int Arch Allergy Immunol. - : S. Karger AG. - 1018-2438 .- 1423-0097. ; 134:3, s. 227-32 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The effects of cytokines are modulated by soluble cytokine receptors (SCR) and receptor antagonists. Therefore, allergic disease may depend on altered proportions between cytokines, their SCR and receptor antagonists, rather than absolute changes in cytokine levels. Little is known about SCR in intermittent allergic rhinitis (IAR). OBJECTIVE: To examine the concentrations of SCR, i.e. sIL-1R2, sIL-4R, sIL-6R and sTNFR1, as well as the interleukin-1 receptor antagonist (IL-1Ra) in nasal fluids from allergen-challenged patients with IAR and healthy controls. METHODS: 30 patients with birch- or grass-pollen-induced IAR and 30 healthy controls were studied. In the patients nasal fluids were obtained before as well as 1 and 6 h after allergen provocation. RESULTS: Both symptom scores and rhinoscopic signs of rhinitis increased in the patients after allergen challenge. Comparisons between patients and controls showed that sIL-4R was lower in patients before and 1 and 6 h after provocation. IL-1Ra was lower before and 1 h after provocation. In addition, lower concentrations of sTNFR1 were found in patients after 1 h, while sIL-1R2 concentrations were higher after 1 h. Comparisons of patients before and after challenge showed that IL-1Ra and sTNFR1 decreased after 1 h, while sIL-1R2 increased. No significant differences were found compared to 6 h. sIL-6R did not significantly differ between the study groups. CONCLUSIONS: After allergen challenge, significant changes in the nasal fluid levels of IL-1Ra, sIL-1R2 and sTNFR1 were found. By contrast, sIL-4R remained at lower levels than in controls both before and after challenge. Since sIL-4R modulates IgE synthesis, this may play a role in the pathogenesis of IAR.
11.	Benson, Mikael, 1954, et al. (författare) [An interactive training program for students in Gothenburg. Education in pediatrics on the Internet]. : Interaktivt träningsprogram för studenter i Göteborg. Utbildning i pediatrik på internet. 1997 Ingår i: Lakartidningen. - 0023-7205. ; 94:51-52, s. 4928-30 Tidskriftsartikel (refereegranskat)
12.	Benson, Mikael, 1954, et al. (författare) Connectivity can be used to identify key genes in DNA microarray data: a study based on gene expression in nasal polyps before and after treatment with glucocorticoids 2007 Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 127:10, s. 1074-1079 Tidskriftsartikel (refereegranskat)abstract Conclusions. The presented analysis of nasal polyposis using connectivity based on the PubGene literature co-citation network demonstrates that this tool can be used to identify key genes in DNA microarray studies of human polygenic diseases. Objectives. DNA microarray studies of complex diseases may reveal differential expression of hundreds of genes. According to network theory and studies of yeast cells, genes that are connected with several other genes appear to have key regulatory roles. This study aimed to examine if this principle can be translated to DNA microarray studies of human disease, using nasal polyposis as a base for the analysis. Materials and methods. The connectivity of differentially expressed genes from a previously described microarray study of nasal polyposis before and after treatment with glucocorticoids was determined. This was done using the literature co-citation network PubGene. Results. In all, 166 genes were differentially expressed; 39 of these were previously defined as inflammatory and considered important for nasal polyposis. The connectivity of all differentially expressed genes was analysed using the PubGene literature co-citation network. Seventy-four of the 166 genes were connected to other genes. By contrast, the average number of connected genes among 100 sets of 166 randomly chosen genes was 31.5. A small number of the differentially expressed genes were highly connected, while most genes had few or no connections. This indicated a scale-free network. The most connected gene was interleukin-8, an inflammatory gene of known importance for nasal polyposis. Twenty-eight of the 74 connected genes were inflammatory (38%), compared with 11 of the 92 unconnected genes (12%), p < 0.0001. Since most evidence suggests that nasal polyps are inflammatory in their nature, this supports the hypothesis that connected genes have more disease relevance than unconnected genes.
13.	Benson, Mikael, 1954 (författare) Cytokines and their soluble receptors in nasal fluids from school children with allergic rhinitis 2000 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Allergic inflammation is associated with a shift in the balance between cytokines produced by two T helper subsets (Th1 and Th2) towards a preponderance of Th2 cells. Interleukin (IL)-4 is produced by Th2 cells and interferon-g (IFN-g) by Th1 cells. The ratio IL-4/IFN-g is often used as a marker of the balance between the cytokines. The effects of cytokines are modulated by soluble cytokine receptors (SCR). Aims: The general aim of the study was to find how Th1 and Th2 cytokines and their SCR regulate inflammatory cells and their products. For this nasal lavage fluid from school children with allergic rhinitis was examined as a local and in vivo model of allergic inflammation. A specific aim was to study the effects of topical treatment with glucocorticoids (GC) on Th1/Th2 cytokines, inflammatory cells and their products.Methods: Nasal fluids were obtained and handled in standardized ways: differential counts of inflammatory cells were measured by light microscopy, cytokine concentrations were assayed by ELISA; and eosinophil cationic protein (ECP) and IgE were determined by radioimmunoassay. Air pollen counts were determined daily by the Department of Botany in Göteborg.Material: Nasal lavage fluids from school children with allergic rhinitis and healthy controls were obtained before and during the pollen season, and from the allergic patients after treatment with a topical glucocorticoid. The study was performed during two consecutive pollen seasons, 1996 and 1997.Results: The nasal fluids were examined in a step-wise fashion, starting with Th1/Th2 cytokines. In the first study IL-4/IFN-g ratios were higher, and IFN-g levels lower in allergic patients during the pollen season compared to patients before season and compared to healthy controls. In the patients both IL-4/IFN-g ratios and IL-4 increased during the pollen season. In the second, larger, study these findings were repeated and in addition the Th2 cytokines IL-4, IL-5, and IL-10 - but not the Th1 cytokine IFN-g - were found to be higher in patients during than before the pollen season. Eosinophil counts and the levels of IgE and ECP in nasal fluid increased concurrently with development of clinical symptoms of rhinitis.In both studies IL-4 and IL-5 correlated with eosinophils, but not neutrophils, in the untreated patients with allergic rhinitis. Conversely, the neutrophil-associated chemokine IL-8 correlated with neutrophils, but not with eosinophils. In the second study the correlations between Th2 cytokines and IgE and ECP were analysed; IL-4, IL-5, IL-6 as well as IL-10 correlated with IgE and ECP.The soluble IL-4 receptor (IL-4sR), but neither IL-6sR, IL-1sR2, TNFsR1 nor TNFsR2 were found to increase in the patients during the pollen season. IL-4sR correlated with IgE and eosinophils. By contrast, none of the other soluble cytokine receptors correlated with IgE. Treatment with a topical glucocorticoid decreased the levels of IgE, ECP, and the Th2 cytokines IL-4, IL-5, IL-6, IL-10, but not IFN-g, nor the neutrophil associated cytokines IL-1b and TNF-a. In the treated patients IL-1b and TNF-a correlated with neutrophils and ECP, and IL-1b with eosinophils. Treated patients with high neutrophil counts had higher eosinophils and ECP, but not IgE, than patients with low counts.Conclusions: The results are compatible with the hypothesis that allergic rhinitis is causally related to a shift in the balance between Th1 and Th2 cytokines towards a Th2 predominance, possibly because of deficient IFN-g production. Correlation studies suggested that increase of the Th2 cytokines results in increased ECP, IgE and eosinophil counts. Theoretically the effects of the cytokines may be either inhibited or enhanced by SCR. Our findings of positive correlations between various SCR and either eosinophils, neutrophils, ECP or IgE might be explained by the existence of enhancing effects. Treatment with a topical steroid resulted in decrease of symptoms, eosinophils, ECP and IgE, but not of neutrophils. The treatment appeared to have a differential effect on cytokines, suppressing Th2 cytokines without any significant effect on the Th1 cytokine IFN-g. These effects of steroid treatment should be expected to be highly beneficial in view of the presumed, great importance of the Th1 and Th2 cytokine balance in the pathogenesis of allergic reactions.
14.	Benson, Mikael, 1954, et al. (författare) Cytokines in nasal fluids from school children with seasonal allergic rhinitis. 1997 Ingår i: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley-Blackwell. - 0905-6157 .- 1399-3038. ; 8:3, s. 143-9 Tidskriftsartikel (refereegranskat)abstract Allergic rhinitis is a particularly good model for studies of cytokine production in vivo. In this study the occurrence of the cytokines IL-4, IL-5, IL-10 and IFN-gamma as well as the soluble receptor for IL-4 in nasal lavage fluids were assayed in 38 school children, with seasonal allergic rhinitis, and 19 healthy age-matched, non-atopic controls, using highly sensitive enzyme immunoassays. IL-4 levels in patients with seasonal allergic rhinitis were markedly increased in comparison with those in non-atopic controls or in atopic patients before the start of the pollen season. In controls, but not in the atopic patients, levels of IFN-gamma and IL-5 were significantly higher in specimens obtained during the pollen season than in those obtained outside the season. The IL-4/IFN-gamma ratios were significantly higher in atopic than in non-atopic subjects and further increased in atopic patients during the season. In addition to IL-4, elevated levels of IL-10 were observed in association with seasonal rhinitis. Following treatment with a topical steroid (budesonide) there was a statistically significant increase of the levels of soluble IL-4 receptor. These findings indicate that nonatopic and atopic individuals react to pollen exposure with distinct cytokine patterns in agreement with the Th1/Th2 concept. Topical steroids may possibly decrease inflammation by increasing the formation of soluble IL-4 receptor.
15.	Benson, Mikael, 1954, et al. (författare) DNA microarray analysis of chromosomal susceptibility regions to identify candidate genes for allergic disease: A pilot study 2004 Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 124:7, s. 813-819 Tidskriftsartikel (refereegranskat)abstract Objective-To examine whether DNA microarray analysis of chromosomal susceptibility regions for allergy can help to identify candidate genes. Material and Methods-Nasal biopsies were obtained from 23 patients with allergic rhinitis and 12 healthy controls. RNA was extracted from the biopsies and pooled into three patient and three control pools. These were then analysed in duplicate with DNA microarrays containing 12626 genes. Candidate genes were further examined in nasal biopsies (real-time polymerase chain reaction) and blood samples (single nucleotide polymorphisms) from other patients with allergic rhinitis and from controls. Results-A total of 37 differentially expressed genes were identified according to criteria involving both the size and consistency of the gene expression levels. The chromosomal location of these genes was compared with the chromosomal susceptibility regions for allergic disease. Using a statistical method, five genes were identified in these regions, including serine protease inhibitor, Kazal type, 5 (SPINK5) and HLA-DRB2. The relevance of these genes was examined in other patients with allergic rhinitis and in controls; none of the genes were differentially expressed in nasal biopsies. Moreover, no association between allergic rhinitis and SPINK5 polymorphisms was found, at either the genotype or haplotype level. Conclusions-DNA microarray analysis of chromosomal susceptibility regions did not lead to identification of candidate genes that could be validated in a new material. However, because gene polymorphisms may cause differential gene expression, further studies, including validation data, are needed to examine this approach.
16.	Benson, Mikael, 1954, et al. (författare) DNA microarray analysis of transforming growth factor-β and related transcripts in nasal biopsies from patients with allergic rhinitis 2002 Ingår i: Cytokine. ; 18:1, s. 20-25 Tidskriftsartikel (refereegranskat)abstract Decreased activity of anti-inflammatory cytokines like transforming growth factor (TGF)-β may contribute to allergic inflammation. In vivo effects of TGF-β-effects are difficult to infer from local concentrations, since TGF-β-effects depend on a complex system of regulatory proteins and receptors. Instead the effects of TGF-β might be inferred by examining TGF-β-inducible transcripts. In this study DNA microarrays were used to examine local expression of TGF-β, TGF-β-regulatory and -inducible transcripts in nasal biopsies from patients with symptomatic allergic rhinitis and healthy controls. In addition, nasal fluids were analysed with cytological and immunological methods. Nasal fluid eosinophils, albumin, eosinophil granulae proteins and IgE, but not TGF-β, were higher in patients than in controls. DNA microarray analysis of nasal mucosa showed expression of transcripts encoding TGF-β, TGF-β-regulatory proteins and -receptors at variable levels in patients and controls. By comparison, analysis of 28 TGF-β-inducible transcripts indicated that 23 of these had lower measurement values in patients than in controls, while one was higher, and the remaining four were absent in both patients and controls. In summary, TGF-β and a complex system of regulatory genes and receptors are expressed in the nasal mucosa. Low expression of TGF-β-inducible transcripts may indicate decreased TGF-β activity in allergic rhinitis. DNA microarray analysis may be a way to study cytokine effects in vivo.
17.	Benson, Mikael, 1954, et al. (författare) DNA microarrays to study gene expression in allergic airways. 2002 Ingår i: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. - : Wiley. - 0954-7894 .- 1365-2222. ; 32:2, s. 301-8 Tidskriftsartikel (refereegranskat)abstract Allergic rhinitis results from interactions between a large number of cells and mediators in different compartments of the body. DNA microarrays allow simultaneous measurement of expression of thousands of genes in the same tissue sample.
18.	Benson, Mikael, 1954, et al. (författare) Increase of the soluble IL-4 receptor (IL-4sR) and positive correlation between IL-4sR and IgE in nasal fluids from school children with allergic rhinitis. 2000 Ingår i: Allergy and asthma proceedings. - : OceanSide Publications. - 1088-5412 .- 1539-6304. ; 21:2, s. 89-95 Tidskriftsartikel (refereegranskat)abstract Soluble cytokine receptors (SCR) can either act as inhibitors, by competitively inhibiting cytokines from binding to their membrane-bound receptors, or as enhancers, by serving as cytokine carriers. We have previously found that the levels of the Th2 cytokines interleukin (IL)-4, IL-5, IL-6, and IL-10 were positively correlated to eosinophils and IgE in nasal fluids from 60 children with seasonal allergic rhinitis. In this study, nasal fluids were reexamined to analyze IL-4sR, IL-6sR, IL-1 beta, TNF-alpha, IL-1sR2, TNF-sR1, and TNFsR2 in relation to eosinophils, neutrophils, ECP, and IgE. In allergic patients IL-4sR increased significantly during the pollen season, and weak, but positive correlations with IgE and eosinophils were found (r = 0.45, P < 0.001 and r = 0.4, P < 0.001 respectively). By contrast, none of the other SCR showed increases or correlations with IgE. However, positive correlations between IL1 beta, TNF-alpha, IL-6sR, IL-1sR2, TNF-sR1, TNF-sR2, and either neutrophils or ECP were found. Also, in healthy controls, these cytokines and their receptors were positively correlated to neutrophils or ECP. Thus, increased levels of the soluble IL-4 receptor, as well as IgE, were specifically associated with allergic rhinitis, whereas all other SCR correlated with either inflammatory cells or their products, in both allergic and healthy subjects. These results may suggest that SCR in vivo act as cytokine enhancers, rather than inhibitors.
19.	Benson, Mikael, 1954, et al. (författare) Increased expression of Vascular Endothelial Growth Factor-A in seasonal allergic rhinitis. 2002 Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 20:6, s. 268-73 Tidskriftsartikel (refereegranskat)abstract Increased vascular dilatation and permeability characterize allergic rhinitis. In this study oligonucleotide microarrays (Affymetrix HuGe95A) were used to identify differentially expressed vasoactive genes in nasal biopsies from 23 patients with symptomatic seasonal allergic rhinitis (SAR) and 12 healthy controls. RNA was extracted from the biopsies and pooled in three patient and three control pools. Out of 12,626 analysed transcripts, 39 were higher and 81 lower in the patients. Of these transcripts two have vasoactive effects: Vascular Endothelial Growth Factor-A (VEGF-A) and the Beta-1-Adrenergic Receptor. Both were higher in patients than in controls. The mean +/- SEM expression levels in arbitrary units of VEGF-A were 130 +/- 123 in the patients and 59 +/- 53 in the controls. The fold ratio in expression levels between patients/controls was 2.2. The corresponding values for the beta-1-adrenergic receptor were 129 +/- 123 in the patients and 40 +/- 31 in the controls. The fold ratio between patient/controls was 3.2. The role of VEGF-A was assessed by determining VEGF-A concentrations in nasal fluids from another 30 patients with SAR before and after allergen provocation. VEGF-A increased from 124.3 +/- 30.2 to 163.2 +/- 37.8 pg/ml after challenge, P < 0.05. In summary, oligonucleotide microarray analysis of nasal biopsies and protein analyses of nasal fluids indicate that VEGF-A may be an important mediator in SAR.
20.	Benson, Mikael, 1954, et al. (författare) Interleukin-5 and interleukin-8 in relation to eosinophils and neutrophils in nasal fluids from school children with seasonal allergic rhinitis. 1999 Ingår i: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley-Blackwell. - 0905-6157 .- 1399-3038. ; 10:3, s. 178-85 Tidskriftsartikel (refereegranskat)abstract The objectives of this study were to measure interleukins 5 and 8 (IL-5 and IL-8) in relation to eosinophils and neutrophils, in nasal lavage fluids from 60 school children with allergic rhinitis, and to determine the influence of treatment with a topical steroid (budesonide) on the levels of the two cytokines. Highly sensitive enzyme immunoassays were used to analyze IL-5 and IL-8. IL-5 levels and relative eosinophil counts in nasal lavage fluid increased significantly in patients with allergic rhinitis during the pollen season, compared with values obtained before the start of the season, and decreased significantly after treatment with budesonide. By contrast, no significant changes in IL-8 or neutrophils were found during the pollen season, nor did they decrease following treatment. In the untreated patients, IL-5 levels correlated significantly with eosinophil counts but not with neutrophil counts, whereas IL-8 levels correlated with neutrophil counts but not with eosinophil counts. After budesonide treatment, the correlation between IL-8 and neutrophils remained, and a correlation between IL-8 and eosinophils emerged. These findings support the concepts that IL-5 has a key role in regulating eosinophils and that IL-8 is important for the regulation of neutrophils. Whereas IL-5 and relative eosinophil counts are profoundly affected by topical steroid treatment, IL-8 and neutrophils are not demonstrably affected by such treatment. It is possible that neutrophils, through the release of IL-8, could be chemotactic for eosinophils in steroid-treated patients.
21.	Benson, Mikael, 1954, et al. (författare) Inverse relation between nasal fluid Clara Cell Protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. 2007 Ingår i: Allergy. - : Wiley. - 0105-4538 .- 1398-9995. ; 62:2, s. 178-83 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Decreased levels of the anti-inflammatory Clara Cell Protein 16 (CC16) are found in intermittent allergic rhinitis (IAR) and asthma. In asthma this decrease has been associated with hyperreactivity and the A38G single nucleotide polymorphism (SNP). The aim of this study was to examine if IAR is associated with signs and symptoms of rhinitis and the A38G SNP. METHODS: Nasal fluid CC16 was analyzed in 20 patients with IAR before allergen challenge and 1 and 6 h after challenge, and from 28 healthy controls. The A38G SNP was analyzed in 80 patients with IAR and 106 controls. Nasal biopsies were obtained from three subjects in each group for immunohistochemical analysis of CC16. RESULTS: In the allergen-challenged patients symptoms and rhinoscopic signs of rhinitis increased after 1 h and normalized after 6 h. In contrast, nasal fluid CC16 decreased 1 h after allergen challenge and returned to baseline after 6 h. Nasal fluid CC16 levels did not differ from controls before and 6 h after challenge. Immunohistochemical investigation showed intense CC16 staining in the nasal epithelium of both patients before season and healthy controls, but weak staining in symptomatic patients during season. No significant association between the A38G SNP and IAR was found. CONCLUSION: There was an inverse relation between nasal fluid CC16 levels and symptoms and signs of rhinitis in allergen-challenged patients with IAR. However, there was no association between IAR and the A38G SNP.
22.	Benson, Mikael, 1954, et al. (författare) Low levels of interferon-gamma in nasal fluid accompany raised levels of T-helper 2 cytokines in children with ongoing allergic rhinitis. 2000 Ingår i: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley-Blackwell. - 0905-6157 .- 1399-3038. ; 11:1, s. 20-8 Tidskriftsartikel (refereegranskat)abstract The T-helper 2 (Th2) cytokines interleukin-(IL-) 4, IL-5, IL-6, IL-10 and the Th1 cytokine IFN-gamma and their associations with eosinophil, eosinophil cationic protein (ECP) and immunoglobulin (Ig) E were studied in nasal lavage fluid from 60 school children with allergic seasonal rhinitis and 36 nonatopic healthy controls, before and during the pollen season. Eosinophil differential counts and IgE increased significantly in the patients during the pollen season. The eosinophil differential counts, ECP and IgE were all significantly higher during the season than in specimens simultaneously obtained from the nonatopic controls. Before season, the levels of ECP and IgE, but not eosinophils, were significantly higher in the patients than in the controls. During the season the nasal lavage fluid levels of IFN-gamma were significantly lower and the IL-4/IFN-gamma quotients significantly higher in the allergic than in the control children. In the allergic children, but not in the controls, the nasal fluid levels of the Th2 cytokines IL-4, IL-5 and IL-10 increased during the season, and together with IL-6, were correlated with the differential counts of eosinophils, and with the levels of ECP and IgE. These findings are compatible with the hypothesis that a deficient release of the Th1 cytokine IFN-gamma plays an important role in the pathogenesis of allergic inflammation. Regardless of whether the defective IFN-gamma secretion is primary or a consequence of suppression by other cytokines, it will in the atopic subjects enhance the release of Th2 cytokines, which in turn will facilitate the development of allergic inflammation.
23.	Benson, Mikael, 1954, et al. (författare) Network theory to understand microarray studies of complex diseases. 2006 Ingår i: Current molecular medicine. - : Bentham Science Publishers. - 1566-5240 .- 1875-5666. ; 6:6, s. 695-701 Tidskriftsartikel (refereegranskat)abstract Complex diseases, such as allergy, diabetes and obesity depend on altered interactions between multiple genes, rather than changes in a single causal gene. DNA microarray studies of a complex disease often implicate hundreds of genes in the pathogenesis. This indicates that many different mechanisms and pathways are involved. How can we understand such complexity? How can hypotheses be formulated and tested? One approach is to organize the data in network models and to analyze these in a top-down manner. Globally, networks in nature are often characterized by a small number of highly connected nodes, while the majority of nodes have few connections. The highly connected nodes serve as hubs that affect many other nodes. Such hubs have key roles in the network. In yeast cells, for example, deletion of highly connected proteins is associated with increased lethality, compared to deletion of less connected proteins. This suggests the biological relevance of networks. Moving down in the network structure, there may be sub-networks or modules with specific functions. These modules may be further dissected to analyze individual nodes. In the context of DNA microarray studies of complex diseases, gene-interaction networks may contain modules of co-regulated or interacting genes that have distinct biological functions. Such modules may be linked to specific gene polymorphisms, transcription factors, cellular functions and disease mechanisms. Genes that are reliably active only in the context of their modules can be considered markers for the activity of the modules and may thus be promising candidates for biomarkers or therapeutic targets. This review aims to give an introduction to network theory and how it can be applied to microarray studies of complex diseases.
24.	Benson, Mikael, 1954, et al. (författare) No decrease of birch pollen specific IgA and IgG in nasal fluids from cortisone treated patients with intermittent allergic rhinitis. 2004 Ingår i: Allergy. - : Wiley. - 0105-4538 .- 1398-9995. ; 59:3, s. 365-7 Tidskriftsartikel (refereegranskat)
25.	Benson, Mikael, 1954 (författare) Pathophysiological effects of glucocorticoids on nasal polyps: an update. 2005 Ingår i: Current opinion in allergy and clinical immunology. - : Lippincott Williams & Wilkins. - 1528-4050 .- 1473-6322. ; 5:1, s. 31-5 Forskningsöversikt (refereegranskat)abstract PURPOSE OF REVIEW: The exact mechanisms by which glucocorticoids exert their beneficial effects on nasal polyps are not clearly defined. Nasal polyps, asthma and allergic rhinitis share common features such as mucosal infiltration with eosinophils and mast cells as well as local IgE production. The present review is an update on the pathophysiological mechanisms of glucocorticoids on nasal polyps described during the last 2 years. RECENT FINDINGS: The reduction of leukocyte numbers in nasal polyps following glucocorticoid treatment depends on several mechanisms, for example altered balance between the two isoforms of the human glucocorticoid receptors, GRalpha and GRbeta. Another explanation may be inhibition of CD4+ T by CD8+ T cells. Increased expression of the antiinflammatory cytokine transforming growth factor beta may contribute to this. A DNA microarray study which examined the expression of some 22 000 genes showed increased expression of several antiinflammatory genes in nasal polyps after treatment with glucocorticoids. The antiinflammatory gene that increased most was uteroglobin (also known as Clara cell protein 16) which is abundantly expressed in airway secretions and thought to have an important role in regulating inflammation. SUMMARY: Glucocorticoids affect both pro and antiinflammatory pathways in nasal polyps. Upregulation of antiinflammatory genes such as transforming growth factor beta and uteroglobin may play an important role. Elucidation of these mechanisms may help us to understand not only the effects of glucocorticoids on nasal polyps, but also on related disorders such as allergic rhinitis and asthma.
26.	Benson, Mikael, 1954, et al. (författare) Pros and cons of microarray technology in allergy research 2004 Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 34:7, s. 1001-1006 Tidskriftsartikel (refereegranskat)
27.	Benson, Mikael, 1954, et al. (författare) Systembiologin kan förändra sjukvården radikalt 2007 Ingår i: Läkartidningen. - 1652-7518 .- 0023-7205. ; 104:42, s. 3037-41 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
28.	Benson, Mikael, 1954, et al. (författare) [Systems biology can radically change health care. Basis for individualized prediction, prevention and treatment] : Systembiologin kan förändra sjukvården radikalt. Ger underlag för individualiserad prediktion, prevention och behandling. 2007 Ingår i: Läkartidningen. - 0023-7205. ; 104:42, s. 3037-41 Forskningsöversikt (refereegranskat)
29.	Benson, Mikael, 1954, et al. (författare) The clinical impact of functional genomics and proteomics 2007 Ingår i: EAACI Newsletter. ; :12, s. 14-15 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
30.	Benson, Mikael, 1954, et al. (författare) Topical steroid treatment of allergic rhinitis decreases nasal fluid TH2 cytokines, eosinophils, eosinophil cationic protein, and IgE but has no significant effect on IFN-gamma, IL-1beta, TNF-alpha, or neutrophils. 2000 Ingår i: The Journal of allergy and clinical immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 106:2, s. 307-12 Tidskriftsartikel (refereegranskat)abstract Topical treatment with glucocorticoids (GCs) is known to decrease eosinophils but not neutrophils in patients with allergic rhinitis.We sought to examine whether the differential effects of GC treatment on eosinophils and neutrophils are mirrored by differential effects on T(H)1/T(H)2 cytokines and the neutrophil-associated cytokines IL-1beta and TNF-alpha.Differential counts of eosinophils and neutrophils in nasal fluids from 60 children with seasonal allergic rhinitis treated with a topical GC were examined after staining with May-Grünwald-Giemsa stain. Nasal fluid levels of IFN-gamma, IL-4, IL-6, IL-10, IL-1beta, and TNF-alpha were examined with ELISA, and IgE and eosinophil cationic protein (ECP) levels were examined with RIA.After GC treatment, there was a statistically significant decrease of the T(H)2 cytokines IL-4, IL-6, and IL-10, as well as ECP and IgE. By contrast, there were no significant changes of the levels of IFN-gamma, IL-1beta, TNF-alpha, or neutrophils. In the GC-treated patients IL-1beta and TNF-alpha levels correlated with neutrophils and ECP, and IL-1beta correlated with eosinophils. Furthermore, ECP correlated with both eosinophils and neutrophils. Neither IL-1beta nor TNF-alpha correlated with IgE. Patients with high neutrophil counts after GC treatment were found to have significantly higher eosinophil counts and ECP than patients with low counts.The beneficial effects of topical treatment with GC in patients with allergic rhinitis could be attributed to downregulation of T(H)2 cytokines, with an ensuing decrease of eosinophils, ECP, and IgE. It is possible that neutrophils could counteract the beneficial effects of GCs by releasing the proinflammatory cytokines IL-1beta and TNF-alpha.
31.	Chavali, Sreenivas, et al. (författare) MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases 2013 Ingår i: Rna-a Publication of the Rna Society. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 19:11, s. 1552-1562 Tidskriftsartikel (refereegranskat)abstract MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.
32.	Chavali, Sreenivas, et al. (författare) Network properties of human disease genes with pleiotropic effects 2010 Ingår i: BMC Systems Biology. - 1752-0509. ; 4 Tidskriftsartikel (refereegranskat)abstract The phenotypic consequence of a human disease gene is largely affected by the topological position of its protein product in the molecular interaction network. Here, we investigated the differences in properties of specific human disease genes that are associated with one phenotype and shared genes with pleiotropic effects in the context of molecular interaction networks. We find that the shared genes have an intermediate centrality between essential and specific genes. Shared genes causing phenotypically divergent diseases (phenodiv genes) are more central to those causing phenotypically similar diseases (phenosim genes). Shared genes had higher number of disease gene interactors compared to specific genes, implying a higher likelihood of finding a novel disease gene in the network neighborhood of shared genes. Specific genes are more co-expressed with their interactors than shared genes. Relatively restricted tissue co-expression with interactors appears to be a function of shared genes leading to pleiotropy. We demonstrate essential and phenodiv genes with comparable connectivities (degrees) are intra-modular and inter-modular hubs with the former highly co-expressed with their interactors contrary to the phenodiv genes. Essential genes are predominantly nuclear proteins with transcriptional regulator activities while phenodiv genes are cytoplasmic proteins involved in signal transduction. Our results demonstrate that the ability of a disease gene to influence the cellular network determines its role in manifesting different and divergent diseases.
33.	Clancy, Trevor, et al. (författare) Immunological network signatures of cancer progression and survival. 2011 Ingår i: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4:1 Tidskriftsartikel (refereegranskat)abstract ABSTRACT: BACKGROUND: The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. METHODS: To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. RESULTS: The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. CONCLUSIONS: The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides.
34.	Clermont, Gilles, et al. (författare) Bridging the gap between systems biology and medicine 2009 Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 1:9 Tidskriftsartikel (refereegranskat)abstract ABSTRACT : Systems biology has matured considerably as a discipline over the last decade, yet some of the key challenges separating current research efforts in systems biology and clinically useful results are only now becoming apparent. As these gaps are better defined, the new discipline of systems medicine is emerging as a translational extension of systems biology. How is systems medicine defined? What are relevant ontologies for systems medicine? What are the key theoretic and methodologic challenges facing computational disease modeling? How are inaccurate and incomplete data, and uncertain biologic knowledge best synthesized in useful computational models? Does network analysis provide clinically useful insight? We discuss the outstanding difficulties in translating a rapidly growing body of data into knowledge usable at the bedside. Although core-specific challenges are best met by specialized groups, it appears fundamental that such efforts should be guided by a roadmap for systems medicine drafted by a coalition of scientists from the clinical, experimental, computational, and theoretic domains.
35.	Fransson, Mattias, et al. (författare) A role for neutrophils in intermittent allergic rhinitis 2004 Ingår i: Acta Otolaryngol. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 124:5, s. 616-20 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: In patients with intermittent allergic rhinitis, allergen challenge may induce both early- and late-phase responses. The aim of this study was to examine the correlation between inflammatory cells in the nasal lavage fluid and clinical parameters following pollen challenge. MATERIAL AND METHODS: Nasal lavage fluids were obtained from 29 patients with intermittent allergic rhinitis before and 1 and 6 h after allergen provocation, representing the control, early and late phases, respectively. Symptom and rhinoscopic scores were registered on the same occasions. Inflammatory cells were determined in the nasal fluid. RESULTS: The early phase was characterized by increased symptom scores, rhinoscopic signs of oedema and secretion and neutrophilia. In the late phase, symptom scores had diminished, but the signs of ongoing secretion remained. Both the total nasal symptom score and the secretion score correlated with the number of neutrophils in lavage fluids at 1 h. The eosinophil count did not increase during the early or late phases. CONCLUSION: A single allergen provocation induces an early-phase response dominated by neutrophils, with secretion being the only clinical sign remaining during the late phase. The increase in neutrophil numbers correlated with the registration of secretory symptoms. The presented data indicate a role for neutrophils in intermittent allergic rhinitis and their relation with secretory parameters makes it intriguing to speculate that neutrophils may function as promoters of nasal secretion.
36.	Gawel, Danuta, et al. (författare) Correction: A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases (vol 11, 47, 2019) 2020 Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 12:1 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract An amendment to this paper has been published and can be accessed via the original article.
37.	Gawel, Danuta R., 1988- (författare) Identification of genes and regulators that are shared across T cell associated diseases 2018 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Genome-wide association studies (GWASs) of hundreds of diseases and millions of patients have led to the identification of genes that are associated with more than one disease. The aims of this PhD thesis were to a) identify a group of genes important in multiple diseases (shared disease genes), b) identify shared up-stream disease regulators, and c) determine how the same genes can be involved in the pathogenesis of different diseases. These aims have been tested on CD4+ T cells because they express the T helper cell differentiation pathway, which was the most enriched pathway in analyses of all disease associated genes identified with GWASs.Combining information about known gene-gene interactions from the protein-protein interaction (PPI) network with gene expression changes in multiple T cell associated diseases led to the identification of a group of highly interconnected genes that were miss-expressed in many of those diseases – hereafter called ‘shared disease genes’. Those genes were further enriched for inflammatory, metabolic and proliferative pathways, genetic variants identified by all GWASs, as well as mutations in cancer studies and known diagnostic and therapeutic targets. Taken together, these findings supported the relevance of the shared disease genes.Identification of the shared upstream disease regulators was addressed in the second project of this PhD thesis. The underlying hypothesis assumed that the determination of the shared upstream disease regulators is possible through a network model showing in which order genes activate each other. For that reason a transcription factor–gene regulatory network (TF-GRN) was created. The TF-GRN was based on the time-series gene expression profiling of the T helper cell type 1 (Th1), and T helper cell type 2 (Th2) differentiation from Native T-cells. Transcription factors (TFs) whose expression changed early during polarization and had many downstream predicted targets (hubs) that were enriched for disease associated single nucleotide polymorphisms (SNPs) were prioritised as the putative early disease regulators. These analyses identified three transcription factors: GATA3, MAF and MYB. Their predicted targets were validated by ChIP-Seq and siRNA mediated knockdown in primary human T-cells. CD4+ T cells isolated from seasonal allergic rhinitis (SAR) and multiple sclerosis (MS) patients in their non-symptomatic stages were analysed in order to demonstrate predictive potential of those three TFs. We found that those three TFs were differentially expressed in symptom-free stages of the two diseases, while their TF-GRN{predicted targets were differentially expressed during symptomatic disease stages. Moreover, using RNA-Seq data we identified a disease associated SNP that correlated with differential splicing of GATA3.A limitation of the above study is that it concentrated on TFs as main regulators in cells, excluding other potential regulators such as microRNAs. To this end, a microRNA{gene regulatory network (mGRN) of human CD4+ T cell differentiation was constructed. Within this network, we defined regulatory clusters (groups of microRNAs that are regulating groups of mRNAs). One regulatory cluster was differentially expressed in all of the tested diseases, and was highly enriched for GWAS SNPs. Although the microRNA processing machinery was dynamically upregulated during early T-cell activation, the majority of microRNA modules showed specialisation in later time-points.In summary this PhD thesis shows the relevance of shared genes and up-stream disease regulators. Putative mechanisms of why shared genes can be involved in pathogenesis of different diseases have also been demonstrated: a) differential gene expression in different diseases; b) alternative transcription factor splicing variants may affect different downstream gene target group; and c) SNPs might cause alternative splicing.
38.	Gawel, Danuta, 1988-, et al. (författare) Stor potential när genomikdatakan implementeras i klinisk rutin : [Clinical translation of genomic medicine] 2021 Ingår i: Läkartidningen. - : Sveriges Läkarförbund. - 0023-7205 .- 1652-7518. ; 118 Forskningsöversikt (refereegranskat)abstract Recent technical developments and early clinical examples support that precision medicine has potential to provide novel diagnostic and therapeutic solutions for patients with complex diseases, who are not responding to existing therapies. Those solutions will require integration of genomic data with routine clinical, imaging, sensor, biobank and registry data. Moreover, user-friendly tools for informed decision support for both patients and clinicians will be needed. While this will entail huge technical, ethical, societal and regulatory challenges, it may contribute to transforming and improving health care towards becoming predictive, preventive, personalised and participatory (4P-medicine).
39.	Guillot, Gilles, et al. (författare) Discrimination and scoring using small sets of genes for two-sample microarray data 2007 Ingår i: Mathematical Biosciences. ; 205:2, s. 195-203 Tidskriftsartikel (refereegranskat)
40.	Johansson, S., et al. (författare) Low levels of CC16 in nasal fluid of children with birch pollen-induced rhinitis 2005 Ingår i: Allergy. - : Wiley. - 0105-4538 .- 1398-9995. ; 60:5, s. 638-42 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Clara cell protein 16 (CC16; secretoglobin 1A1) is an anti-inflammatory protein mainly expressed in the epithelial cells in the airways. OBJECTIVE: To compare the levels of CC16 in nasal lavage (NAL) from children with intermittent allergic rhinitis and healthy controls and to study the effect of a local steroid. METHODS: Thirty schoolchildren with birch pollen allergy and 30 healthy controls from the same schools were included in the study. The NAL fluid was collected before the season, during the birch pollen season and, for the patients, after 1 week of treatment with a local steroid. Symptom scores were obtained on every occasion. CC16 and eosinophil cationic protein (ECP) were analyzed with enzyme-linked immunosorbent assay. RESULTS: The nasal fluid levels of CC16 were significantly lower in patients than in controls, before and during pollen season. Before the season, the median CC16 concentrations were 9.1 (range 1.1-117) microg/l in patients and 25.7 (6.1-110.2) microg/l in controls. During the season, the median CC16 concentrations in nasal fluid were 12.9 (2.3-89.7) microg/l in the allergic children and 22.0 (9.5-90.1) microg/l in the healthy controls (P = 0.0005). Symptom scores, nasal fluid eosinophils and ECP were higher in patients during the season. Treatment with a local steroid did not change the CC16 levels. CONCLUSIONS: Nasal fluid CC16 levels were lower in children with birch pollen-induced allergic rhinitis than in healthy controls both before and during the pollen season. We speculate that reduction in anti-inflammatory activity by CC16 may contribute to the pathogenesis of allergic rhinitis.
41.	Keen, Christina, et al. (författare) Bet v 1-specific IgA increases during the pollen season but not after a single allergen challenge in children with birch pollen-induced intermittent allergic rhinitis 2005 Ingår i: Pediatr Allergy Immunol. - : Wiley-Blackwell. - 0905-6157 .- 1399-3038. ; 16:3, s. 209-16 Tidskriftsartikel (refereegranskat)abstract Allergen-specific immunoglobulins of the Immunoglobulin A (IgA) type have been found in the nasal fluid of patients with allergic rhinitis. IgA may play a protective role, but there are also data which show that allergen-specific IgA can induce eosinophil degranulation. The aim of this study was to quantitate Bet v 1-specific IgA in relation to total IgA in the nasal fluid of children with birch pollen-induced intermittent allergic rhinitis and healthy controls, after allergen challenge and during the natural pollen season. Eosinophil cationic protein (ECP), Bet v 1-specific IgA and total IgA were analyzed in nasal fluids from 30 children with birch pollen-induced intermittent allergic rhinitis and 30 healthy controls. Samples were taken before the pollen season, after challenge with birch pollen and during the pollen season, before and after treatment with nasal steroids. During the pollen season, but not after nasal allergen challenge, Bet v 1-specific IgA increased in relation to total IgA in children with allergic rhinitis. No change was found in the healthy controls. The ratio of Bet v 1-specific IgA to total IgA increased from 0.1 x 10(-3) (median) to 0.5 x 10(-3) in the allergic children, p < 0.001. No change was seen after treatment with nasal steroids, although symptoms, ECP and eosinophils were reduced. In conclusion, allergen-specific IgA in relation to total IgA increases in nasal fluids during the pollen season in allergic children but not in healthy controls. These findings are compatible with the hypothesis that allergen-specific IgA plays a role in the allergic inflammation and further studies are needed to clarify the functional role of these allergen-specific antibodies.
42.	Lentini, Antonio, 1990- (författare) Dynamic regulation of DNA methylation in human T-cell biology 2019 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract T helper cells play a central role in orchestrating immune responses in humans. Upon encountering a foreign antigen, T helper cells are activated followed by a differentiation process where the cells are specialised to help combating the infection. Dysregulation of T helper cell activation, differentiation and function has been implicated in numerous diseases, including autoimmunity and cancer. Whereas gene-regulatory networks help drive T-cell differentiation, acquisition of stable cell states require heritable epigenetic signals, such as DNA methylation. Indeed, the establishment of DNA methylation patterns is a key part of appropriate T-cell differentiation but how this is regulated over time remains unknown. Methylation can be directly attached to cytosine residues in DNA to form 5-methylcytosine (5mC) but the removal of DNA methylation requires multiple enzymatic reactions, commonly initiated by the conversion into 5-hydroxymethylcytosine (5hmC), thus creating a highly complex regulatory system. This thesis aimed to investigate how DNA methylation is dynamically regulated during T-cell differentiation.To this end, we employed large-scale profiling techniques combining gene expression as well as genome-wide 5mC and 5hmC measurements to construct a time-series model of epigenetic regulation of differentiation. This revealed that early T-cell activation was accompanied by extensive genome-wide deposition of 5hmC which resulted in demethylation upon proliferation. Early DNA methylation remodelling through 5hmC was not only indicative of demethylation events during T-cell differentiation but also marked changes persisting longterm in memory T-cell subsets. These results suggest that priming of epigenetic landscapes in T-cells is initiated during early activation events, preceding any establishment of a stable lineage, which are then maintained throughout the cells lifespan. The regions undergoing remodelling were also highly enriched for genetic variants in autoimmune diseases which we show to be functional through disruption of protein binding. These variants could potentially disrupt gene-regulatory networks and the establishment of epigenetic priming, highlighting the complex interplay between genetic and epigenetic layers. In the course of this work, we discovered that a commonly used technique to study genome-wide DNA modifications, DNA immunoprecipitation (DIP)-seq, had a false discovery rate between 50-99% depending on the modification and cell type being assayed. This represented inherent technical errors related to the use of antibodies resulting in off-target binding of repetitive sequences lacking any DNA modifications. These sequences are common in mammalian genomes making robust detection of rare DNA modifications very difficult due to the high background signals. However, offtarget binding could easily be controlled for using a non-specific antibody control which greatly improved data quality and biological insight of the data. Although future studies are advised to use alternative methods where available, error correction is an acceptable alternative which will help fuel new discoveries through the removal of extensive background signals.Taken together, this thesis shows how integrative use of high-resolution epigenomic data can be used to study complex biological systems over time as well as how these techniques can be systematically characterised to identify and correct errors resulting in improved detection.
43.	Lilja, Sandra, 1989- (författare) Digital Twins : High Resolution Disease Models for Optimized Diagnosis and Treatment 2022 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract To study immune-mediated diseases, which can affect the expression of thousands of genes among many different cell types and organs, is a daunting challenge. However, for effective diagnosis and therapeutic treatment it is relevant to understand the regulatory functions of disease. In this thesis, we hypothesized that regulatory functions in complex diseases can be effectively prioritized based on so called digital twins, which are based on high-resolution single cell data in combination with network theories. More specifically, we tested if digital twins could be used on a patient-group level to prioritize cell types, genes, and/or organs based on their regulatory function in the disease progression. If this hypothesis is true, potential biomarkers and therapeutic targets can be identified for optimized diagnosis and treatment. The long-term goal is to construct digital twins for personalized medicine, to predict the optimal treatment strategies for the individual patients. Although, this is a very ambitious goal which could not be reached through this thesis, relevant steps towards it have been reached.First, we tested if high-resolution disease models based on single cell RNAsequencing (scRNA-seq) data could be used in combination with network theories, to predict and prevent disease. For this aim, we used a mouse model of antigeninduced arthritis (AIA). Based on the cell type specific genes in AIA joint, we identified a multi-cellular disease model (MCDM), including predicted cell-cell interactions. Analyzing this model, Granulocytes were identified as most central in AIA joint. The results from this centrality analysis correlated with GWAS enrichment among the cell type specific genes, as well as with the centrality analyses based on human RA, supporting our results relevance for human disease. A drug, bezafibrate, was further identified which mainly targeted shared disease modules over the central and GWAS enriched CD4+ T cells in nine of 13 analyzed human diseases. Bezafibrate treatment of our AIA mouse model resulted in a decrease in arthritis severity score as well as a decrease in T cell proliferation into the joint.Since blood is an easily available source of data, it is of interest to know it’s potential usefulness when constructing digital twins. To test if samples taken from blood are representative of the inflamed organ, we performed a meta-analysis of different samples from blood and joint of patients with rheumatoid arthritis, as well as from joint and blood Granulocytes of our AIA mouse model. Based on differentially expressed genes (DEGs) between sick and healthy samples from each dataset, we performed pathway analyses and predicted potential biomarkers and upstream regulators (URs). Comparing the lists of pathways, biomarkers, and URs between the datasets from different subsets of blood samples showed low or no similarities. However, the datasets of human bulk or mouse single cell data collected from synovial fluid or full joint showed high similarities. Furthermore, the top shared enriched pathways, predicted biomarkers, and URs from both human and mouse were to a higher degree connected to known functions of autoimmune diseases or rheumatoid arthritis, compared to the respective results from samples taken from blood. These findings indicate that inflammatory mechanisms in cells in blood and inflamed organs differ greatly, which may have important diagnostic and therapeutic implications.We next analyzed if digital twins could be used to identify the early regulatory mechanisms that are also present at the late time points. For this, we used an in vitro time series model of seasonal allergic rhinitis. Samples were taken before allergen stimulation, as well as at 12 hours, 1 day, 2 days, 3 days, 5 days, and 7 days after allergen stimulation, for scRNA-seq and MCDM construction. Multi-directional interactions including all cell types were found at all time points, even before allergen stimulation, which complicated the identification of one key regulatory cell type or gene. Instead, we found that the regulatory genes could be ranked based on their overall downstream effect over all the time points. Our top-ranked regulatory gene, PDGFB, targeted most of the cell types at all the time points, while a previously known early regulator and drug target in allergy, IL4, targeted only five cell type and time point combinations. Validation studies further showed that neutralization of PDGF-BB on allergen-stimulated PBMC from SAR patients were more effective compared to neutralization of IL-4.Finally, we tested if a digital twin including data from multiple organs could be used to understand the systemic interactional changes due to disease. For this aim, we used a systemic mouse model of arthritis, namely collagen induced arthritis (CIA). We first analyzed ten different organs, based on which we prioritized five organs with the highest number of DEGs between CIA and healthy mice, namely joint, lung, muscle, skin, and spleen. Although only joint showed signs of inflammation, many DEGs were identified in all five organs. Those changes were organized into a multi-organ multi-cellular disease model, which indicated an on/off switch of pro-/anti-inflammatory functions in joint and muscle respectively. Validation studies in human immune-mediated inflammatory diseases supported this on/off switch, where pro-inflammatory functions were mainly found in inflamed organs, while anti-inflammatory functions were found in non-inflamed organs.In conclusion, this thesis supports the potential of using high-resolution disease models for digital twin construction. Such digital twins could then be used to prioritize cell types and genes, for further prediction of diagnostic markers and therapeutic targets. Even though the identification of one key regulatory function was complicated due to multidirectional interactions, the genes could be ranked based on their relative downstream effect. For reproducible results, we found that digital twins should ideally be based on data from locally inflamed organs, while systemic models and models covering different disease stages could be useful to understand the disease progression.
44.	Melén, Erik, et al. (författare) Precisionsmedicin kan bli viktig även vid komplexa sjukdomar : [Precision medicine in complex diseases] 2021 Ingår i: Läkartidningen. - : Sveriges Läkarförbund. - 0023-7205 .- 1652-7518. ; 118 Forskningsöversikt (refereegranskat)abstract Complex diseases represent a number of common disorders such as allergic conditions, cardiovascular, metabolic and chronic inflammatory diseases. These diseases are caused by a combination of genetic, environmental and lifestyle factors. This complex etiology creates challenges when it comes to diagnostics, follow-up programs and treatment. Although exact disease mechanisms are yet to be elucidated for most complex diseases, key genetic determinants have been mapped and omics profiling has unraveled involved pathways. Using this wealth of data, precision medicine applications have started to appear also for common, complex diseases. In this article, we review current precision medicine applications from a clinical point of view and outline briefly a roadmap ahead for further clinical implementation of precision medicine in complex diseases.
45.	Menditto, Enrica, et al. (författare) Adherence to treatment in allergic rhinitis using mobile technology : The MASK Study 2019 Ingår i: Clinical and Experimental Allergy. - : WILEY. - 0954-7894 .- 1365-2222. ; 49:4, s. 442-460 Tidskriftsartikel (refereegranskat)abstract Background: Mobile technology may help to better understand the adherence to treatment. MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centred ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries. Objectives: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App. Methods: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from 1 January 2016 to 1 August 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach. Results: A total of 12143 users were registered. A total of 6949 users reported at least one VAS data recording. Among them, 1887 users reported >= 7 VAS data. About 1195 subjects were included in the analysis of adherence. One hundred and thirty-six (11.28%) users were adherent (MPR >= 70% and PDC <= 1.25), 51 (4.23%) were partly adherent (MPR >= 70% and PDC = 1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR <70%). Of those, the largest group was non-adherent to medications and the time interval was increased in 442 (36.68%) users. Conclusion and clinical relevance: Adherence to treatment is low. The relative efficacy of continuous vs on-demand treatment for allergic rhinitis symptoms is still a matter of debate. This study shows an approach for measuring retrospective adherence based on a mobile app. This also represents a novel approach for analysing medication-taking behaviour in a real-world setting.
46.	Mobini, Reza, 1965, et al. (författare) A module-based analytical strategy to identify novel disease-associated genes shows an inhibitory role for interleukin 7 Receptor in allergic inflammation. 2009 Ingår i: BMC systems biology. - : Springer Science and Business Media LLC. - 1752-0509. ; 3 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The identification of novel genes by high-throughput studies of complex diseases is complicated by the large number of potential genes. However, since disease-associated genes tend to interact, one solution is to arrange them in modules based on co-expression data and known gene interactions. The hypothesis of this study was that such a module could be a) found and validated in allergic disease and b) used to find and validate one ore more novel disease-associated genes. RESULTS: To test these hypotheses integrated analysis of a large number of gene expression microarray experiments from different forms of allergy was performed. This led to the identification of an experimentally validated reference gene that was used to construct a module of co-expressed and interacting genes. This module was validated in an independent material, by replicating the expression changes in allergen-challenged CD4+ cells. Moreover, the changes were reversed following treatment with corticosteroids. The module contained several novel disease-associated genes, of which the one with the highest number of interactions with known disease genes, IL7R, was selected for further validation. The expression levels of IL7R in allergen challenged CD4+ cells decreased following challenge but increased after treatment. This suggested an inhibitory role, which was confirmed by functional studies. CONCLUSION: We propose that a module-based analytical strategy is generally applicable to find novel genes in complex diseases.
47.	Olsson, Maja, 1975, et al. (författare) Increased expression of aquaporin 3 in atopic eczema. 2006 Ingår i: Allergy. - : Wiley. - 0105-4538 .- 1398-9995. ; 61:9, s. 1132-7 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Dry skin in atopic eczema depends on increased water loss. The mechanisms behind this are poorly understood. The aim of this work was to identify genes that may contribute to water loss in eczema. METHODS: Affymetrix DNA microarrays U133A were used to analyse gene expression in skin biopsies from 10 patients with atopic eczema and 10 healthy controls. RESULTS: DNA microarray analysis showed up-regulation of 262 genes and down-regulation of 129 genes in atopic eczema. The known functions of these genes were analysed using Gene Ontology to identify genes that could contribute to increased water loss. This led to identification of aquaporin 3 (AQP3), which has a key role in hydrating healthy epidermis. Increased expression of AQP3 was found in eczema compared with healthy skin. This was confirmed with real-time polymerase chain reaction (P<0.001). In healthy skin, epidermal AQP3 immunoreactivity was weak and mainly found in the stratum basale. A gradient was formed with decreasing AQP3 staining in the lower layers of the stratum spinosum. By contrast, in acute and chronic atopic eczema strong AQP3 staining was found in both the stratum basale and the stratum spinosum. CONCLUSIONS: Aquaporin 3 is the predominant aquaporin in human skin. Increased expression and altered cellular distribution of AQP3 is found in eczema and this may contribute to water loss.
48.	Pedicini, Marco, et al. (författare) Combining network modeling and gene expression microarray analysis to explore the dynamics of Th1 and Th2 cell regulation. 2010 Ingår i: PLoS computational biology. - : Public Library of Science (PLoS). - 1553-7358 .- 1553-734X. ; 6:12 Tidskriftsartikel (refereegranskat)abstract Two T helper (Th) cell subsets, namely Th1 and Th2 cells, play an important role in inflammatory diseases. The two subsets are thought to counter-regulate each other, and alterations in their balance result in different diseases. This paradigm has been challenged by recent clinical and experimental data. Because of the large number of genes involved in regulating Th1 and Th2 cells, assessment of this paradigm by modeling or experiments is difficult. Novel algorithms based on formal methods now permit the analysis of large gene regulatory networks. By combining these algorithms with in silico knockouts and gene expression microarray data from human T cells, we examined if the results were compatible with a counter-regulatory role of Th1 and Th2 cells. We constructed a directed network model of genes regulating Th1 and Th2 cells through text mining and manual curation. We identified four attractors in the network, three of which included genes that corresponded to Th0, Th1 and Th2 cells. The fourth attractor contained a mixture of Th1 and Th2 genes. We found that neither in silico knockouts of the Th1 and Th2 attractor genes nor gene expression microarray data from patients with immunological disorders and healthy subjects supported a counter-regulatory role of Th1 and Th2 cells. By combining network modeling with transcriptomic data analysis and in silico knockouts, we have devised a practical way to help unravel complex regulatory network topology and to increase our understanding of how network actions may differ in health and disease.
49.	Schoenrock, A., et al. (författare) Efficient prediction of human protein-protein interactions at a global scale 2014 Ingår i: Bmc Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 15 Tidskriftsartikel (refereegranskat)abstract Background: Our knowledge of global protein-protein interaction (PPI) networks in complex organisms such as humans is hindered by technical limitations of current methods. Results: On the basis of short co-occurring polypeptide regions, we developed a tool called MP-PIPE capable of predicting a global human PPI network within 3 months. With a recall of 23% at a precision of 82.1%, we predicted 172,132 putative PPIs. We demonstrate the usefulness of these predictions through a range of experiments. Conclusions: The speed and accuracy associated with MP-PIPE can make this a potential tool to study individual human PPI networks (from genomic sequences alone) for personalized medicine.
50.	Söderholm, Simon, 1986- (författare) Exploring the tissue-specific nature of the Wnt cell signaling system : The complex world of cell communication and the search for the Achilles heel of cancer 2023 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The Wnt signaling pathway is a biological mechanism for cell-cell communication found across all species of the animal kingdom. This pathway plays a major role in virtually all stages of embryonic development, and it governs central aspects of stem cell biology, regeneration, and tissue homeostasis. In addition, dysregulation of the pathway is associated with developmental malformations and several forms of sever cancer. However, it is still not fully understood how Wnt signaling can mediate such a variety of processes and outcomes. How is a single pathway, which according to the current models is described as a mostly linear cascade of events, able to induce diverging responses in different biological contexts? Finding an answer to this question would not only satisfy scientific curiosity but could also have clinical significance. Given the importance of Wnt signaling in normal tissue function, therapeutically targeting the pathway has historically proven to be difficult. Thus, a better understanding of the tissue-specific properties of the pathway could help us uncover a way to distinguish disease-related cells from healthy cells and identify new targets whose inhibition could impair disease while avoiding detrimental effects on normal tissue function. This thesis represents four years of research that aims to address the knowledge gaps outlined above. Specifically, the work has been focusing on exploring the time- and tissue-specific properties of Wnt signaling by assessing the genome-wide consequences of perturbing this pathway in different model systems. Through this work, we have revealed further instances of disconnection between classical Wnt components, challenging the current established models of how Wnt signaling operates. Furthermore, we demonstrate that the cellular response to Wnt activation occur in a time-dependent manner, with different responsive patterns in different cell types, and even heterogeneously across cells in an otherwise homogenous cell population, contributing to the emerging notion of context-specific Wnt signaling. Finally, we identify a new tissue-specific player in Wnt-mediated transcriptional regulation, which holds promise as a possible therapeutic target in the continuing battle against cancer. In summary, the scientific results presented in this thesis extend our current knowledge of the Wnt signaling pathway by highlighting context-specific aspects that could help explain how this fundamental process adopts different regulatory avenues. This, in turn, could prove important for our ability to identify and ultimately combat disease-specific traits, including finding the Achilles heel of cancer.

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