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  • 1.
    Anderson, K S
    et al.
    Harvard University.
    Petersson, Stina
    Sahlgrens University Hospital.
    Wong, J
    Sahlgrens University Hospital.
    Lokko, N N
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Elevation of serum epidermal growth factor and interleukin 1 receptor antagonist in active psoriasis vulgaris2010Ingår i: BRITISH JOURNAL OF DERMATOLOGY, ISSN 0007-0963, Vol. 163, nr 5, s. 1085-1089Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Psoriatic plaques present a complex expression profile, including high levels of cytokines, chemokines and growth factors. Circulating cytokines have been suggested to reflect the activation status of the inflammatory process. Objectives To analyse 20 cytokines, chemokines and growth factors in 14 patients with psoriasis vulgaris at the start and during the course of ultraviolet B treatment. Methods A multiplex cytokine assay was used. Results We identified increased serum levels of epidermal growth factor (EGF) (mean 323 vs. 36 6 pg mL(-1), P = 0 0001), interleukin (IL)-1 receptor antagonist (mean 39 1 vs. 14 6 pg mL(-1), P = 0 02) and tumour necrosis factor-alpha (mean 7 5 vs. 4 5 pg mL(-1), P = 0 04) at baseline in patients with psoriasis compared with matched controls. None of these cytokines was correlated to the severity of the disease (Psoriasis Area and Severity Index) or decreased with phototherapy, suggesting that sources other than lesional skin contribute to the production of these cytokines. Using cluster analysis, we observed coordinate upregulation of EGF, IL-6, macrophage inflammatory protein-1 beta and vascular endothelial growth factor. Conclusions The sustained high expression of inflammatory circulating cytokines is a potential mechanism linking psoriasis with its extracutaneous comorbidities.

  • 2.
    Anderson, K S
    et al.
    Harvard Medical School, Boston, MA 02115, USA.
    Wong, J
    Harvard Medical School, Boston, MA 02115, USA.
    Polyak, K
    Harvard Medical School, Boston, MA 02115, USA.
    Aronzon, D
    Harvard Medical School, Boston, MA 02115, USA.
    Enerbäck, Charlotta
    Sahlgrenska University Hospital.
    Detection of psoriasin/S100A7 in the sera of patients with psoriasis2009Ingår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 160, nr 2, s. 325-332Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Psoriasis is a disease of dysregulated inflammation and epithelial hyperproliferation in the skin, involving both the innate and adaptive immune system. Psoriatic keratinocytes express high levels of psoriasin (S100A7), a small calcium-binding protein. OBJECTIVES: To determine if patients with active psoriasis have elevated serum levels of psoriasin and psoriasin-specific autoantibodies. METHODS: Blood was collected from 14 patients with psoriasis vulgaris at the start of narrowband ultraviolet (UV) B therapy and from 11 of these patients every 2 weeks during the course of the UVB treatment. Patient and control sera were tested for psoriasin antigen levels by sandwich enzyme-linked immunosorbent assay, and for psoriasin autoantibody titres using recombinant purified psoriasin and overlapping peptides. RESULTS: We confirmed strong and specific expression of psoriasin in psoriatic epidermis by immunohistochemistry. Systemic psoriasin antigen levels tended to be lower in patients (mean 213 ng mL(-1)) than in controls (mean 331 ng mL(-1), P = 0.308) and decreased with increasing disease severity. Psoriasin-specific autoantibodies were detected in a subset of patients with psoriasis and healthy normal donors (mean 0.347 vs. 0.255 units, P = 0.246). The epitopes recognized by the autoantibodies were mapped to an external loop domain of the molecule but did not show corresponding T-cell immunogenicity. CONCLUSIONS: Although psoriasin is overexpressed in psoriatic skin lesions, systemic levels of psoriasin tended to be lower with increasing disease severity, which may be due to the presence of psoriasin-specific autoantibodies. Neither psoriasin nor psoriasin-specific autoantibodies appear to be promising serum biomarkers for clinical psoriasis.

  • 3.
    Appelqvist, Frida
    et al.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Yhr, Maria
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Erlandson, Anna
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Martinsson, Tommy
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Deletion of the MGMT gene in familial melanoma2014Ingår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 53, nr 8, s. 703-711Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The DNA repair gene MGMT (O-6-methylguanine-DNA methyltransferase) is important for maintaining normal cell physiology and genomic stability. Alterations in MGMT play a critical role in the development of several types of cancer, including glioblastoma, lung cancer, and colorectal cancer. The purpose of this study was to explore the function of genetic alterations in MGMT and their connection with familial melanoma (FM). Using multiplex ligation-dependent probe amplification, we identified a deletion that included the MGMT gene in one of 64 families with a melanoma predisposition living in western Sweden. The mutation segregated with the disease as a heterozygous deletion in blood-derived DNA, but a homozygous deletion including the promoter region and exon 1 was seen in tumor tissue based on Affymetrix 500K and 6.0 arrays. By sequence analysis of the MGMT gene in the other 63 families with FM from western Sweden, we identified four common polymorphisms, nonfunctional, as predominantly described in previous studies. We conclude that inherited alterations in the MGMT gene might be a rare cause of FM, and we suggest that MGMT contributes to melanoma predisposition.

  • 4.
    Bivik, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Carlström, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Apoptosis has a role in the disturbed homeostasis of epidermal keratinocytes in psoriasis in JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol 132, issue , pp S79-S792012Ingår i: JOURNAL OF INVESTIGATIVE DERMATOLOGY, Nature Publishing Group , 2012, Vol. 132, s. S79-S79Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 5.
    Caren, Helena
    et al.
    University of Gothenburg, Sweden.
    Erichsen, Jennie
    University of Gothenburg, Sweden.
    Olsson, Linda
    University of Gothenburg, Sweden.
    Enerbäck, Charlotta
    University of Gothenburg, Sweden.
    Sjoberg, Rose-Marie
    University of Gothenburg, Sweden.
    Abrahamsson, Jonas
    University of Gothenburg, Sweden.
    Kogner, Per
    Childhood Canc Res Unit, SE-17176 Stockholm, Sweden .
    Martinsson, Tommy
    University of Gothenburg, Sweden.
    High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors: Four cases of homozygous deletions of the CDKN2A gene2008Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, nr 353Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Neuroblastoma is a very heterogeneous pediatric tumor of the sympathetic nervous system showing clinically significant patterns of genetic alterations. Favorable tumors usually have near-triploid karyotypes with few structural rearrangements. Aggressive stage 4 tumors often have near-diploid or near-tetraploid karyotypes and structural rearrangements. Whole genome approaches for analysis of genome-wide copy number have been used to analyze chromosomal abnormalities in tumor samples. We have used array-based copy number analysis using oligonucleotide single nucleotide polymorphisms (SNP) arrays to analyze the chromosomal structure of a large number of neuroblastoma tumors of different clinical and biological subsets. Results: Ninety-two neuroblastoma tumors were analyzed with 50 K and/or 250 K SNP arrays from Affymetrix, using CNAG3.0 software. Thirty percent of the tumors harbored 1p deletion, 22% deletion of 11q, 26% had MYCN amplification and 45% 17q gain. Most of the tumors with 1p deletion were found among those with MYCN amplification. Loss of 11q was most commonly seen in tumors without MYCN amplification. In the case of MYCN amplification, two types were identified. One type displayed simple continuous amplicons; the other type harbored more complex rearrangements. MYCN was the only common gene in all cases with amplification. Complex amplification on chromosome 12 was detected in two tumors and three different overlapping regions of amplification were identified. Two regions with homozygous deletions, four cases with CDKN2A deletions in 9p and one case with deletion on 3p (the gene RBMS3) were also detected in the tumors. Conclusion: SNP arrays provide useful tools for high-resolution characterization of significant chromosomal rearrangements in neuroblastoma tumors. The mapping arrays from Affymetrix provide both copy number and allele-specific information at a resolution of 10-12 kb. Chromosome 9p, especially the gene CDKN2A, is subject to homozygous (four cases) and heterozygous deletions (five cases) in neuroblastoma tumors.

  • 6.
    Carlström, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Petersson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Lack of Evidence for Association of VEGF Polymorphisms in Swedish Patients with Psoriasis2012Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 132, nr 5, s. 1510-1513Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 7.
    Carlström, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Petersson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility2012Ingår i: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 21, nr 12, s. 932-937Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    NACHT leucine-rich repeat- and PYD-containing (NLRP)3 protein controls the inflammasome by regulating caspase-1 activity and interleukin (IL)-1 beta processing. The contribution of IL-1 beta in the pathogenesis of psoriasis is well recognized. Polymorphisms in NLRP3 and caspase recruitment domaincontaining protein (CARD)8, a negative regulator of caspase-1 activity, have been associated with susceptibility to common inflammatory diseases, such as Crohns disease and rheumatoid arthritis. To investigate the role for genetic variants in the NLRP3 inflammasome in psoriasis susceptibility. In a patient sample comprising 1988 individuals from 491 families and 1002 healthy controls, genotypes for four selected single-nucleotide polymorphisms (SNPs) in NLRP3 (three SNPs) and CARD8 (one SNP) were determined by TaqMan (R) Allelic Discrimination. Using the transmission disequilibrium test (TDT), a significant increase in the transmission of the NLRP3 rs10733113G genotype to a subgroup of patients with more widespread psoriasis was demonstrated (P = 0.015). Using logistic regression analysis in 741 patients with psoriasis and 1002 controls, the CARD8 rs2043211 genotype was significantly different in cases and controls in overall terms [OR 1.3 (1.11.5), P = 0.004] and for both genders. Our data support the hypothesis that the inflammasome plays a role in psoriasis susceptibility.

  • 8.
    Carlström, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Genetic support for a role for the inflammasome in psoriasis in BRITISH JOURNAL OF DERMATOLOGY, vol 165, issue 6, pp E2-E22011Ingår i: BRITISH JOURNAL OF DERMATOLOGY, Wiley-Blackwell , 2011, Vol. 165, nr 6, s. E2-E2Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 9.
    EINBEIGI, Zacharia
    et al.
    Sahlgrenska University Hospital.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    WALLGREN, Arne
    Sahlgrenska University Hospital.
    NORDLING, Margareta
    Sahlgrenska University Hospital.
    KARLSSON, Per
    Sahlgrenska University Hospital.
    BRCA1 gene mutations may explain more than 80% of excess numberof ovarian cancer cases after breast cancer – a population based studyfrom the Western Sweden Health Care region2010Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, s. 361-367Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM: In a previous cohort study, we showed that there was a significant variation in the frequency of ovarian cancer after having breast cancer in Sweden, with the highest risk occuring in the Western region. The present study aimed to evaluate whether the high prevalence of the founder mutation BRCA1 3171ins5 may explain the excess number of ovarian cancer.

     

     

    METHOD: Among more than 26 000 women with breast cancer in the Western Swedish Health Care Region, 159 cases were subsequently diagnosed with ovarian cancer, whereas the expected number was 96. Archived tissue material was analysed for six common Scandinavian BRCA1 and BRCA2 gene mutations.

    RESULTS: The excess number of cases was 63 (95% CI 47-77), based on person-years at risk and national incidence rates of ovarian cancer. A BRCA1 gene mutation was detected in 33 cases corresponding to 52% of the excess number. The founder mutation, BRCA1 3171ins5, was detected in 44% of the excess number. The identified mutations decreased from 45% in women less than 50 years of age at follow-up to 14% at 60+ years at follow-up. There was no obvious decrease in mutation frequency by excess numbers with age. Age at follow-up and first-degree relatives with breast and/or ovarian cancer were the best predictors of a mutation in this material.

    CONCLUSION: The founder mutation, BRCA1 3171ins5, explains the excess of ovarian cancer after breast cancer in the region. From the relative frequency of the studied mutations found at the cancer genetic counselling clinic, it is estimated that BRCA1 gene mutations are associated with about 80-85% of the excess cases. This means that a negative screening for these mutations in similar cases may have a predictive value and could strongly reduce the risk of ovarian cancer in relatives.

  • 10.
    Ekman, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Ingrid Asp Psoriasis Research Center.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Ingrid Asp Psoriasis Research Center.
    Lack of preclinical support for the efficacy of histone deacetylase inhibitors in the treatment of psoriasis.2016Ingår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 174, nr 2, s. 424-426Artikel i tidskrift (Refereegranskat)
  • 11.
    Ekman, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sigurdardottir, G
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Carlström, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Kartul, N
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Systemically elevated Th1-, Th2-and Th17-associated chemokines in psoriasis in JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol 132, issue , pp S28-S282012Ingår i: JOURNAL OF INVESTIGATIVE DERMATOLOGY, Nature Publishing Group , 2012, Vol. 132, s. S28-S28Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 12.
    Ekman, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Sigurdardottir, Gunnthorunn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Carlström, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Kartul, Natalja
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Systemically elevated Th1-, Th2- and Th17-associated chemokines in psoriasis vulgaris before and after ultraviolet B treatment2013Ingår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 93, nr 5, s. 527-531Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation.

  • 13.
    Ekman, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Vegfors, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis.2017Ingår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, nr 4, s. 441-448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis.

  • 14.
    Ekman, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Verma, Deepti
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Genetic variations of NLRP1: susceptibility in psoriasis2014Ingår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 171, nr 6, s. 1517-1520Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: NACHT, LRR and PYD domain-containing protein (NLRP)1 is part of the inflammasome multiprotein complex involved in the production of interleukin (IL)-1β and IL-18, two cytokines strongly implicated in psoriasis pathogenesis. Genetic variations in NLRP1 are associated with a predisposition for chronic inflammatory conditions.

    OBJECTIVES: The aim of the study was to investigate the role of genetic variation in the NLRP1 inflammasome in psoriasis susceptibility.

    MATERIAL AND METHODS: Four haplotype-tagging single-nucleotide polymorphisms (SNPs) (rs6502867, rs8079034, rs878329 and rs12150220) were investigated by TaqMan allelic discrimination in a patient sample comprising 1847 individuals from 478 families and 802 healthy controls.

    RESULTS: Using the transmission disequilibrium test, a significant increase in the transmission of the NLRP1 rs8079034C and rs878329C alleles to patients with psoriasis was demonstrated (P = 0·006 and P = 0·033, respectively). Furthermore, homozygosity for the rs878329C allele correlated with a younger age of onset. We also observed an increase in the expression of NLRP1 mRNA in the peripheral blood cells of patients with psoriasis. This was accompanied by a higher level of circulating IL-18 and appeared to be associated with the rs878329C allele.

    CONCLUSIONS: Our data support the involvement of NLRP1 and the NLRP1 inflammasome in psoriasis susceptibility and further support the role of innate immunity in psoriasis.

  • 15.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Soluble biomarkers in psoriasis2011Ingår i: EJD. European journal of dermatology, ISSN 1167-1122, E-ISSN 1952-4013, Vol. 21, nr 6, s. 844-850Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Psoriasis is a common, chronic, recurrent skin disorder, characterized by keratinocyte proliferation, T-cell activation and angiogenesis. The results of various clinical and experimental studies indicate that psoriasis is a complex, multifactorial disease with a genetic predisposition. During the past few years, many studies related to psoriasis biomarkers have been conducted. Biomarkers can relate to diagnosis, pathogenesis, prognosis, or therapeutic response. They could provide insight into disease susceptibility and natural history. The identification of biomarkers related to co-morbidities in psoriasis, such as arthritis, cardiovascular disease and the metabolic syndrome, has attracted special interest. This review presents current knowledge of soluble biomarkers in psoriasis, including cytokines, chemokines, pro-angiogenic mediators, growth factors, antimicrobial proteins, neuropeptides and markers of oxidative stress.

  • 16.
    Erlandson, Anna
    et al.
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Appelqvist, Frida
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Enerbäck, Charlotta
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Epigenetic mutations in CDKN2A in western Swedish families with hereditary malignant melanoma2008Ingår i: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 1, nr 1, s. 89-91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study aimed to identify the molecular genetic variations associated with an increased risk of hereditary malignant melanoma (HMM) in the western Swedish population. In 68 families with increased hereditary susceptibility to malignant melanoma, we previously reported a low frequency of alterations in the CDKN2A gene, which is regarded as the major melanoma predisposition gene. Among these alterations, we identified a novel mutation in 3 families (Asp108Tyr). In the present study, we focused on the possible role of heritable epimutations as a cause of the silencing of the CDKN2A gene. We used two different technical approaches to detect changes in CpG methylation in the promoter region of the CDKN2A gene; methylation-specific PCR (MSP) analysis of bisulfite-converted DNA and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). From families who tested negative for germ-line CDKN2A mutations, 64 unrelated patients with hereditary melanoma were included in the study. We showed a consistent lack of hypermethylation in the promoter region of CDKN2A in patients with HMM in our western Swedish population. A putative germ-line methylation of the CDKN2A, if any, is therefore likely to be a rare event in hereditary melanoma. This study demonstrates that there are probably additional and as yet unknown genetic factors present in western Swedish HMM families.

  • 17.
    Erlandson, Anna
    et al.
    Sahlgrens University Hospital, Sweden.
    Appelqvist, Frida
    Sahlgrens University Hospital, Sweden.
    Wennberg, Ann-Marie
    Sahlgrens University Hospital, Sweden.
    Holm, Joanna
    Sahlgrens University Hospital, Sweden.
    Enerbäck, Charlotta
    Sahlgrens University Hospital, Sweden.
    Novel CDKN2A mutations detected in western Swedish families with hereditary malignant melanoma2007Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 127, nr 6, s. 1465-1467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have examined alterations in the cyclin-dependent kinase inhibitor 2A (CDKN2A), a major melanoma predisposing gene, in a western-Swedish hereditary melanoma population comprising 107 patients from 68 families. Using sequence analysis and multiplex ligation-dependent probe amplification, we found a novel mutation (Asp108 Tyr), segregating with the disease in three families. This mutation has previously been detected as a somatic mutation in other cancers. We found a previously described Swedish founder mutation (ins113Arg) in one family and a large duplication encompassing the CDKN2A gene locus in another family. Moreover, a debated polymorphism (Ala148Thr) was found in nine families, in which the polymorphism did not segregate with the disease.

  • 18.
    Nikamo, Pernilla
    et al.
    Karolinska Institutet, Karolinska University Hospital, Stockholm.
    Cheuk, Stanley
    Karolinska Institutet, Karolinska University Hospital, Stockholm.
    Lysell, Josefin
    Karolinska Institutet, Karolinska University Hospital, Stockholm.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Bergh, Kerstin
    Karolinska Institutet, Karolinska University Hospital, Stockholm.
    Xu Landén, Ning
    Karolinska Institutet, Karolinska University Hospital, Stockholm.
    Eidsmo, Liv
    Karolinska Institutet, Karolinska University Hospital, Stockholm.
    Ståhle, Mona
    Karolinska Institutet, Karolinska University Hospital, Stockholm.
    Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells.2014Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 134, nr 6, s. 1535-1541Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most psoriasis susceptibility genes were identified in cohorts of mixed clinical phenotypes and the exploration of genes in clinical subtypes is scarce. IL-22 has an established role in host defense and in psoriasis skin pathology, reflecting the delicate balance between control of infection and immunopathology. In a case-control study, we compared the genetic association to IL22 in psoriasis onset in patients between 0-9 (n=207), 10-20 (n=394), and 21-40 (n=468) years with healthy controls (n=1,529). Logistic regression analysis revealed association to regulatory elements in the IL22 promoter confined to onset of psoriasis before puberty (odds ratio=1.45, P<0.0007). The associated variants contain putative binding sites for AhR, a potent inducer of IL-22 expression. In a luciferase assay, transcriptional activity of a high-risk gene variant resulted in 80% higher promoter activity (P=0.012) compared with a low-risk variant. Ex vivo stimulated T cells from peripheral blood were analyzed with flow cytometry. Children with psoriasis carrying a high-risk variant produced 1.7 times more IL-22 compared with low-risk variants (P=0.042). Our combined genetic and functional data support the notion that a genetic IL22 variant that promotes epithelial barrier defense is preferentially enriched in and may precipitate the onset of psoriasis at an early age.

  • 19.
    Ofverholm, Anna
    et al.
    Sahlgrens University Hospital.
    Arkblad, Eva
    Sahlgrens University Hospital.
    Skrtic, Stanko
    Sahlgrens University Hospital.
    Albertsson, Per
    Sahlgrens University Hospital.
    Shubbar, Emman
    Sahlgrens University Hospital.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene2010Ingår i: CLINICAL BIOCHEMISTRY, ISSN 0009-9120, Vol. 43, nr 3, s. 331-334Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrimidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. We here report a frequency analysis of one of the major splice-site mutations in the DPDY gene, and further two new DPYD gene variants. Design and methods: Restriction fragment length polymorphisin (RFLP) and DNA sequence analysis were performed on genomic DNA and mRNA. Results: In 400 patients that were diagnosed with cancer and were eligible for 5-FU treatment, 14 patients were found to be heterozygous for the splice-site mutation DPYD IVS14+1Gandgt;A, which corresponds to a population frequency of 3.5%. Two novel variants in the DPYD gene were identified. The first case was heterozygous for DPYD c. 1796Tandgt;C (p.M599T). In the second case, we observed heterozygosity for the splice-site mutation DPYD IVS14+17Aandgt;G. Conclusions: We report two new DPYD gene variants, of which DPYD c. 1796Tandgt;C is potentially pathogenic, whereas DPYD IVS14+17Aandgt;G is suggested as a variant without clinical significance.

  • 20.
    Petersson, S
    et al.
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Shubbar, Emman
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Enerbäck, Lennart
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Enerbäck, Charlotta
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Expression patterns of S100 proteins in melanocytes and melanocytic lesions2009Ingår i: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 19, nr 4, s. 215-225Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    S100 proteins are differentially expressed in tumours of epithelial origin. Little is known about their expression in melanocyte-derived tumours of neuroectodermal origin. We have analysed the expression of some S100 proteins in this line of lesions using SAGE Genie informatics, cell culture and human tumour tissue. The pattern of expression of six S100 proteins was investigated at both the mRNA and protein levels, using quantitative real-time PCR, western blotting and immunohistochemical analysis. No differential expression was observed with respect to S100A4, S100A7, S100A8, S100A9 and S100A11. In contrast, S100A10 was downregulated in three melanoma cell lines compared with normal melanocytes. Using SAGE informatics, two-dimensional displays of microarray expression data from the NCI60_Novartis cell lines displayed a positive correlation between the expression of S100A10 and the expression of the proliferation marker, Ki67. Our data suggest that S100A10, like its binding partners S100A7 and annexin A2, is an oxidant-sensitive protein. In addition, higher expression of S100A10 was detected in melanocyte cell lines with long projections compared with melanoma cell lines with small ripples. In a panel of 47 melanocyte-derived lesions comprising melanocytic naevi and melanomas, S100A10 was expressed to varying degrees in the melanocytic lesions. The antigen was primarily expressed in regions with a strong proliferating or differentiating capacity, especially in regions in or near the epidermis. We suggest that S100A10 may play a role in the regulation of the proliferation or early maturation sequence of melanocytic lesions, and that it merits further study as a potential biomarker of activity.

  • 21.
    Petersson, Stina
    et al.
    Sahlgrens University Hospital, Sweden.
    Bylander, Anna
    Sahlgrens University Hospital, Sweden.
    Yhr, Maria
    Sahlgrens University Hospital, Sweden.
    Enerbäck, Charlotta
    Sahlgrens University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells2007Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 7, nr 205Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 ( psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 ( calgranulin A) and S100A9 ( calgranulin B) are expressed in ductal carcinoma in situ ( DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression. Methods: We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test. Results: We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment. Conclusion: Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.

  • 22.
    Petersson, Stina
    et al.
    Sahlgrens University Hospital.
    Shubbar, E.
    Sahlgrens University Hospital.
    Yhr, M.
    Sahlgrens University Hospital.
    Kovacs, A.
    Sahlgrens University Hospital.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Loss of ICAM-1 signaling induces psoriasin (S100A7) and MUC1 in mammary epithelial cells2011Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 125, nr 1, s. 13-25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasin (S100A7), a member of the S100 gene family, is highly expressed in high-grade comedo ductal carcinoma in situ (DCIS), with a higher risk of local recurrence. Psoriasin is, therefore, a potential biomarker for DCIS with a poor prognosis. High-grade DCIS is characterized by a high proliferation rate and crowded cells, consequently, lose contact with the extracellular matrix. The aim of this study was, therefore, to elucidate the involvement of adhesion signals in the regulation of psoriasin. Protein expression was evaluated by Western blotting, flow cytometry, and immunohistochemistry, and using breast carcinoma SAGE databases available from the CGAP website. Intercellular adhesion molecule 1 (ICAM-1) was down-regulated in MCF10A cells using short hairpin RNA. We found a significant negative correlation between the expression of ICAM-1 and psoriasin, and a positive correlation between psoriasin and MUC1 in normal and DCIS SAGE libraries. In a cluster analysis of 34 adhesion molecules and 20 S100 proteins, we showed that SAGE libraries expressing the S100 proteins-psoriasin, calgranulin-A, and calgranulin-B-clustered together. Interestingly, the expression of all the three proteins correlated strongly to the oncogenic MUC1. We confirmed the negative correlation between ICAM-1 and psoriasin/MUC1, when normal and breast cancer cells were cultured in suspension and on collagen, respectively. The down-regulation of ICAM-1 by short hairpin RNA in MCF10A cells led to the induction of psoriasin, calgranulin-A, calgranulin-B, and MUC1, and we demonstrated that these up-regulations were not ROS dependent. By blocking the phospholipase C (PLC)-IP3 pathway in these cells, we showed that the induction of psoriasin diminished. The results suggest that psoriasin is an intracellular calcium-dependent target of the PLC pathway. Our findings suggest that the down-regulation of ICAM-1 in mammary epithelial cells may contribute both to the high expression of psoriasin seen in some high-grade DCIS tumors and to the induction of MUC1.

  • 23.
    Shubbar, Emman
    et al.
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    Helou, Khalil
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    Kovács, Anikó
    Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Nemes, Szilárd
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    Hajizadeh, Shahin
    Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Einbeigi, Zakaria
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    High levels of γ-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer2013Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, nr 47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Previously, we performed analysis of gene expression in 46 axillary lymph node negative tumors and identified molecular gene signatures that resulted in different clinical outcomes. The aim of this study was to determine the correlation of γ-glutamyl hydrolase (GGH), fatty acid amide hydrolase (FAAH), Pirin (PIR) and TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65 kDa (TAF5L), selected from identified gene signatures, with clinical outcomes as well as classical clinicopathological characteristics in primary invasive breast cancer patients.

    Methods

    The protein levels of GGH, FAAH, PIR and TAF5L were assessed by immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Quantitative real-time PCR (qRT-PCR) and western blot analysis were performed to verify the expression levels of the candidate biomarkers. Patient disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. The prognostic biomarkers were identified by univariate analysis with a log-rank test and by multivariate analysis with Cox proportional hazards regression models.

    Results

    The GGH and FAAH protein levels were significantly up-regulated in invasive breast cancer tumors compared with adjacent non-cancerous tissues. Furthermore, the protein levels of GGH and FAAH were significantly correlated in tumor tissues. Tumoral GGH protein expression was significantly correlated with shorter DSS and RFS. Furthermore, the protein expression of GGH was positively correlated with undifferentiated tumors (BRE grade III) and ER/PR expressing tumors. Multivariate regression analysis showed that only GGH protein expression independently predicts DSS. No such correlations were found for FAAH, PIR and TAF5L protein expression. However, elevated protein levels of FAAH were positively associated with high number of lymph node involvement and upregulated levels of PIR were positively related with lymph node metastasis. The TAF5L was pronouncedly down-regulated in primary invasive breast cancer tissues compared to matched adjacent non-cancerous tissues.

    Conclusion

    These data show for the first time that cytoplasmic GGH might play a relevant role in the development and progression of invasive breast cancer, warranting further investigations. Our findings suggest that GGH serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. The GGH may be a very attractive targeted therapy for selected patients.

  • 24.
    Shubbar, Emman
    et al.
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vegfors, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Carlström, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Petersson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation2012Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 134, nr 1, s. 71-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ, psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of vascular endothelial growth factor (VEGF) and inhibited tumor growth in vivo. The aim of the present study was to investigate whether psoriasin could have direct effects on endothelial cells. In this study we demonstrated that psoriasin increased VEGF expression in mammary epithelial cells. The treatment of endothelial cells with recombinant psoriasin increased proliferation comparable to that of recombinant VEGF protein. No change in proliferation was seen when endothelial cells were infected with psoriasin-expressing adenoviruses, suggesting that the proliferative effect of psoriasin was mediated by a specific receptor. Treatment with sRAGE, targeting the receptor for advanced glycation end products (RAGE), thus inhibited endothelial cell proliferation and tube formation enhanced by recombinant psoriasin. We showed that VEGF expression was not induced by hydrogen peroxide, when psoriasin was silenced by shRNA, which led to the hypothesis that psoriasin induces ROS. Indeed, psoriasin was shown to induce ROS in both endothelial and epithelial cells. Moreover, sRAGE inhibited the psoriasin-dependent generation of ROS in endothelial cells. Finally, treatment with antioxidant Bcl-2 protein abolished the effect of psoriasin on endothelial cell proliferation. Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.

  • 25.
    Sigurdardottir, Gunnthorunn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ståhle, Mona
    Karolinska Institutet, Stockholm .
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Systemic treatment and narrowband ultraviolet B differentially affect cardiovascular risk markers in psoriasis.2014Ingår i: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 70, nr 6, s. 1067-1075Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Psoriasis is associated with a systemic inflammation and an increased frequency of the metabolic syndrome, both of which are believed to link psoriasis to an increased risk of cardiovascular disease.

    OBJECTIVE: The study aimed to investigate the systemic expression of markers of cardiovascular risk and determine their response to ultraviolet B therapy and treatment with the tumor necrosis factor-alfa inhibitor, etanercept.

    METHODS: Six markers of cardiovascular risk were measured in 28 patients with psoriasis and 28 control subjects.

    RESULTS: Five of the 6 investigated markers were elevated in patients with psoriasis. Four of these correlated to the body mass index and waist-hip ratio, suggesting a link to the metabolic syndrome. Total plasminogen activator inhibitor-1 remained elevated independently of these factors. The levels of the investigated risk markers decreased considerably after tumor necrosis factor-alfa inhibitor treatment but remained unaffected by ultraviolet therapy.

    LIMITATIONS: A relatively limited study population and nonrandomization are limitations.

    CONCLUSION: These findings suggest that the choice of treatment in psoriasis may influence the cardiovascular risk in patients with psoriasis and the metabolic syndrome.

  • 26.
    Sigurdardottir, Gunnthorunn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Decreased Systemic Levels of Endocan-1 and CXCL16 in Psoriasis Are Restored following Narrowband UVB Treatment.2018Ingår i: Dermatology, ISSN 1018-8665, E-ISSN 1421-9832, Vol. 234, nr 5-6, s. 173-179Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In psoriasis, a common immune-mediated disease affecting 2-3% of the population worldwide, there is an increased prevalence of extracutaneous diseases including obesity, the metabolic syndrome, and cardiovascular disease. This is believed to be linked to systemic inflammation. In previous studies, we have explored various markers in plasma and serum to characterize the ongoing systemic inflammation in psoriasis patients compared to controls. We have identified several markers that were altered in psoriasis patients, but which all were unresponsive to narrowband UVB (NB-UVB) treatment.

    OBJECTIVE: The objective of the study was to evaluate the effect of NB-UVB treatment on markers of cardiovascular risk and systemic inflammation in psoriasis.

    METHODS: The levels of 17 potential biomarkers with an association with cardiovascular risk were quantitated in plasma from 37 age- and gender-matched psoriasis patients and controls at baseline and in 21 psoriasis patients after 12 weeks of NB-UVB treatment to identify a systemic treatment response.

    RESULTS: We identified the mediators endocan-1, CXCL16, and sVEGFR1, which were systemically decreased in psoriasis at baseline, as well as FABP3, FABP4, and sIL-1R1, which showed normal baseline levels. After 10-12 weeks of NB-UVB treatment, endocan-1 and CXCL16 were restored to normal levels, while sVEGFR1, FABP3, FABP4, and sIL-1R1 showed a significant reduction.

    CONCLUSION: The current study expands the number of potential biomarkers in psoriasis by including a greater number and variety of mediators, approaching the systemic inflammation from additional vantage points, including soluble immune receptors and adipocyte contribution, to provide a more complete picture of the systemic inflammatory state in psoriasis.

  • 27.
    Stuart, Philip E.
    et al.
    University of Michigan, MI 48109 USA.
    Nair, Rajan P.
    University of Michigan, MI 48109 USA.
    Tsoi, Lam C.
    University of Michigan, MI 48109 USA; University of Michigan, MI 48109 USA; University of Michigan, MI 48109 USA.
    Tejasvi, Trilokraj
    University of Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hospital, MI 48105 USA.
    Das, Sayantan
    University of Michigan, MI 48109 USA.
    Min Kang, Hyun
    University of Michigan, MI 48109 USA.
    Ellinghaus, Eva
    University of Kiel, Germany.
    Chandran, Vinod
    University of Toronto, Canada; University of Toronto, Canada.
    Callis-Duffin, Kristina
    University of Utah, UT 84132 USA.
    Ike, Robert
    University of Michigan, MI 48109 USA.
    Li, Yanming
    University of Michigan, MI 48109 USA.
    Wen, Xiaoquan
    University of Michigan, MI 48109 USA.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Gudjonsson, Johann E.
    University of Michigan, MI 48109 USA.
    Koks, Sulev
    University of Tartu, Estonia; University of Tartu, Estonia; Estonian University of Life Science, Estonia.
    Kingo, Kuelli
    University of Tartu, Estonia.
    Esko, Tonu
    University of Tartu, Estonia.
    Mrowietz, Ulrich
    University of Medical Centre Schleswig Holstein, Germany.
    Reis, Andre
    University of Erlangen Nurnberg, Germany.
    Erich Wichmann, H.
    German Research Centre Environm Heatlh, Germany; University of Munich, Germany; Technical University of Munich, Germany.
    Gieger, Christian
    German Research Centre Environm Heatlh, Germany; German Research Centre Environm Heatlh, Germany.
    Hoffmann, Per
    University of Bonn, Germany; University of Bonn, Germany.
    Noethen, Markus M.
    University of Bonn, Germany; University of Bonn, Germany.
    Winkelmann, Juliane
    Technical University of Munich, Germany; German Research Centre Environm Heatlh, Germany.
    Kunz, Manfred
    University of Leipzig, Germany.
    Moreta, Elvia G.
    St Paul Rheumatol, MN 55121 USA.
    Mease, Philip J.
    Seattle Rheumatol Associates, WA 98122 USA.
    Ritchlin, Christopher T.
    University of Rochester, NY 14623 USA.
    Bowcock, Anne M.
    University of London Imperial Coll Science Technology and Med, England.
    Krueger, Gerald G.
    University of Utah, UT 84132 USA.
    Lim, Henry W.
    Henry Ford Hospital, MI 48202 USA.
    Weidinger, Stephan
    University of Medical Centre Schleswig Holstein, Germany.
    Weichenthal, Michael
    University of Medical Centre Schleswig Holstein, Germany.
    Voorhees, John J.
    University of Michigan, MI 48109 USA.
    Rahman, Proton
    Mem University, Canada.
    Gregersen, Peter K.
    North Shore Long Isl Jewish Health Syst, NY 11030 USA.
    Franke, Andre
    University of Kiel, Germany.
    Gladman, Dafna D.
    University of Toronto, Canada; University of Toronto, Canada.
    Abecasis, Goncalo R.
    University of Michigan, MI 48109 USA.
    Elder, James T.
    University of Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hospital, MI 48105 USA.
    Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture2015Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 97, nr 6, s. 816-836Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 x 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 x 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

  • 28.
    Thunell, Lena
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Wäster, Petra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Stjernstrom, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Synnerstad, Ingrid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Rosdahl, Inger
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma2014Ingår i: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 24, nr 3, s. 190-197Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The p53 pathway regulates stress response, and variations in p53, MDM2, and MDM4 may predispose an individual to tumor development. The aim of this study was to study the impact of genetic variation on sporadic and hereditary melanoma. We have analyzed a combination of three functionally relevant variants of the p53 pathway in 258 individuals with sporadic malignant melanomas, 50 with hereditary malignant melanomas, and 799 healthy controls. Genotyping was performed by PCR-restriction fragment length polymorphism, pyrosequencing, and allelic discrimination. We found an increased risk for hereditary melanoma in MDM2 GG homozygotes, which was more pronounced among women (P=0.035). In the event of pairwise combinations of the single nucleotide polymorphisms, a risk elevation was shown for MDM2 GG homozygotes/p53 wild-type Arg in hereditary melanoma (P=0.01). Individuals with sporadic melanomas of the superficial spreading type, including melanoma in situ, showed a slightly higher frequency of the MDM2 GG genotype compared with those with nodular melanomas (P=0.04). The dysplastic nevus phenotype, present in the majority of our hereditary melanoma cases and also in some sporadic cases, further enhanced the effect of the MDM2 GG genotype on melanoma risk (P=0.005). In conclusion, the results show an association between MDM2 SNP309 and an increased risk for hereditary melanoma, especially among women. Analysis of sporadic melanoma also shows an association between MDM2 and the superficial spreading melanoma subtype, as well as an association with the presence of dysplastic nevi in sporadic melanoma.

  • 29.
    Tsoi, Lam C.
    et al.
    University of Michigan, MI 48109 USA.
    Spain, Sarah L.
    Kings Coll London, England; Wellcome Trust Sanger Institute, England.
    Ellinghaus, Eva
    University of Kiel, Germany.
    Stuart, Philip E.
    University of Michigan, MI 48109 USA.
    Capon, Francesca
    Kings Coll London, England.
    Knight, Jo
    Centre Addict and Mental Heatlh, Canada; Guys and St Thomas NHS Fdn Trust, England.
    Tejasvi, Trilokraj
    University of Michigan, MI 48109 USA.
    Kang, Hyun M.
    University of Michigan, MI 48109 USA.
    Allen, Michael H.
    Kings Coll London, England.
    Lambert, Sylviane
    University of Michigan, MI 48109 USA.
    Stoll, Stefan W.
    University of Michigan, MI 48109 USA.
    Weidinger, Stephan
    University of Kiel, Germany.
    Gudjonsson, Johann E.
    University of Michigan, MI 48109 USA.
    Koks, Sulev
    University of Tartu, Estonia; University of Tartu, Estonia.
    Kingo, Kulli
    University of Tartu, Estonia.
    Esko, Tonu
    University of Tartu, Estonia.
    Das, Sayantan
    University of Michigan, MI 48109 USA.
    Metspalu, Andres
    University of Tartu, Estonia.
    Weichenthal, Michael
    University of Kiel, Germany.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Krueger, Gerald G.
    University of Utah, UT 84132 USA.
    Voorhees, John J.
    University of Michigan, MI 48109 USA.
    Chandran, Vinod
    University of Toronto, Canada.
    Rosen, Cheryl F.
    University of Toronto, Canada.
    Rahman, Proton
    Mem University, Canada.
    Gladman, Dafna D.
    University of Toronto, Canada.
    Reis, Andre
    University of Erlangen Nurnberg, Germany.
    Nair, Rajan P.
    University of Michigan, MI 48109 USA.
    Franke, Andre
    University of Kiel, Germany.
    Barker, Jonathan N. W. N.
    Kings Coll London, England.
    Abecasis, Goncalo R.
    University of Michigan, MI 48109 USA.
    Trembath, Richard C.
    Queen Mary University of London, England.
    Elder, James T.
    University of Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hospital, MI 48105 USA.
    Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, nr 7001Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.

  • 30.
    Tuominen, Rainer
    et al.
    Karolinska Institute, Sweden .
    Jonsson, Goran
    Lund University, Sweden .
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Appelqvist, Frida
    Sahlgrens University Hospital, Sweden .
    Olsson, Hakan
    Lund University, Sweden .
    Ingvar, Christian
    Lund University, Sweden .
    Hansson, Johan
    Karolinska Institute, Sweden .
    Hoiom, Veronica
    Karolinska Institute, Sweden .
    Investigation of a putative melanoma susceptibility locus at chromosome 3q292014Ingår i: Cancer Genetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 207, nr 3, s. 70-74Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malignant melanoma, the most fatal form of skin cancer, is currently increasing in incidence in many populations. Approximately 10% of all cases occur in families with an inherited predisposition for melanoma. In Sweden, only a minor portion of such melanoma families carry a mutation in the known melanoma gene CDKN2A, and there is a need to identify additional melanoma susceptibility genes. In a recently performed genome-wide linkage screen, novel loci with suggestive evidence of linkage to melanoma were detected. In this study, we have further analyzed one region on chromosome 3q29. In all, 89 affected and 15 nonaffected family members from 42 melanoma-prone families were genotyped for 34 genetic markers. In a pooled linkage analysis of all 42 families, we detected significant evidence of linkage, with a maximum heterogeneity logarithm of odds (HLOD) score of 3.1 with 83% of the families contributing to the linkage score. The minimum critical region of linkage (defined by a 1LOD score support interval) maps to chromosome 3q29, spans 3.5 Mb of genomic sequence, and harbors 44 identified genes. Sequence variants within this region have previously been associated with cancer susceptibility. This study reports the presence of a putative novel melanoma susceptibility locus in the Swedish population, a finding that needs to be replicated in an independent study on other individuals with familial melanoma. Sequencing of genes in the region may identify novel melanoma-associated mutations.

  • 31.
    Vegfors, J
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Psoriasin (S100A7) promote VEGF expression and angiogenesis in psoriasis in JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol 132, issue , pp S10-S102012Ingår i: JOURNAL OF INVESTIGATIVE DERMATOLOGY, Nature Publishing Group , 2012, Vol. 132, s. S10-S10Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 32.
    Vegfors, Jenny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Psoriasin (S100A7) contributes to stress-induced angiogenesis in psoriasis by the regulation of angiogenic factors in keratinocytes and promotion of angiogenic properties of dermal endothelial cells2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The S100 protein psoriasin, S100A7, is highly expressed in psoriasis. Vascular modifications occur early in the development of psoriasis and angiogenesis is one of the key features in the pathogenesis of the disease. This study aims to define the angiogenic properties of psoriasin in keratinocytes and to investigate the effects on dermal endothelial cells, thereby promoting angiogenesis in psoriasis. We showed that psoriasin expression, demonstrated by qPCR, is induced by hydrogen peroxide (H2O2) in keratinocytes and by cellular stress, such as hypoxia and cobalt chloride (CoCl2). Down-regulation of psoriasin, by siRNA, decreased the H2O2-induced expression of VEGF, heparin-binding EGF-like growth factor (HB-EGF) and matrix metalloproteinase (MMP)-1, and counteracted the reduction of the anti-angiogenic factor thrombospondin (THBS)-1. Extracellularly psoriasin was found to induce cell proliferation, migration and tube formation to a similar degree as VEGF and to induce the pro-angiogenic factors VEGF and IL-8 in dermal endothelial cells. Furthermore, we demonstrated that psoriasin-induced migration was mediated by the phosphoinositide-3-kinase (PI3K) and nuclear factor-kappa beta (NF-κB) signaling pathways. In conclusion, psoriasin is induced by cellular stress conditions and amplifies H2O2-induced expression of angiogenic factors relevant for psoriasis in keratinocytes. Moreover, psoriasin contributes to key features of the angiogenic process by inducing proliferation, migration and tube formation and increasing pro-angiogenic factors in dermal endothelial cell. Altogether, our data suggest that psoriasin is promoted by oxidative stress and mediate angiogenesis in psoriasis.

  • 33.
    Vegfors, Jenny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ekman, Anna-Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Psoriasin (S100A7) is regulated by protein kinase C (PKC) and contributes to keratinocyte differentiation by regulating the expression of epidermal differentiation markers2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Psoriasis is a chronic inflammatory skin disease that is characterized by hyperproliferation and a disturbed maturation of the epidermal cells. The differentiation process of keratinocytes in active psoriatic lesions differs from that of normal epidermis, denoted by an altered expression of differentiation markers. Psoriasin, a protein which is highly expressed in psoriasis, is located within the epidermal differentiation complex (EDC), a gene cluster that contains several genes that are important in the terminal differentiation of the human epidermis. The potential role of psoriasin in keratinocyte differentiation remain however unclear. The aim of this present study was to investigate the possible involvement of psoriasin in keratinocyte differentiation. We demonstrated, by immunohistochemical staining, a gradient of psoriasin expression in the psoriatic epidermis, from an undefined or weak expression in the basal layer to an intense expression in the suprabasal differentiated layers. The expression of psoriasin was up-regulated in cultured keratinocytes in response to stimuli known to induce differentiation, such as an elevation of extracellular calcium or  12-Otetradecanoylphorbol-13-acetate (TPA). Down-regulation of psoriasin expression, by siRNA, resulted in decreased expression of the differentiation markers involucrin, desmoglein 1, transglutaminase 1 and CD24. Inhibition of protein kinase C (PKC) counteracted the calciuminduced expression of psoriasin and involucrin. In summary, our data demonstrate that psoriasin is regulated by the PKC signaling pathway and contributes to keratinocyte differentiation by the regulation of differentiation markers.

  • 34.
    Vegfors, Jenny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Petersson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Kovacs, Aniko
    Sahlgrens University Hospital, Sweden .
    Polyak, Kornelia
    Harvard University, USA .
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    The Expression of Psoriasin (S100A7) and CD24 Is Linked and Related to the Differentiation of Mammary Epithelial Cells2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasin (S100A7), a member of the S100 family of calcium-binding proteins, is highly expressed in high-grade ductal carcinoma in situ (DCIS) and in the benign hyperproliferative skin disorder psoriasis. The gene that encodes psoriasin and many other S100 genes are located within a gene cluster on chromosome region 1q21, known as the epidermal differentiation complex. This cluster contains genes for several differentiation markers that play important roles in the terminal differentiation of the epidermis. The purpose of the present study was to evaluate the role of psoriasin in the differentiation process of mammary epithelial cells. Normal mammary epithelial cells (MCF10A) cultured in confluence and suspension, conditions known to induce psoriasin expression, demonstrated a shift towards a more differentiated phenotype indicated by an increase in the expression of the luminal differentiation markers CD24 and MUC1 and the reduced expression of the breast stem cell marker CD44. The expression of psoriasin and MUC1 was most pronounced in the CD24(+)-enriched fraction of confluent MCF10A cells. The shift towards a more differentiated phenotype was abolished upon the downregulation of psoriasin using short hairpin RNA (shRNA) and small interfering RNA (siRNA). Using specific inhibitors, we showed that psoriasin and CD24 expression was regulated by reactive oxygen species (ROS) and the nuclear factor (NF)-kappa B signaling pathways. While immunohistochemical analyses of DCIS showed heterogeneity, the expression of psoriasin and CD24 showed a similar staining pattern. Our findings suggest that the expression of psoriasin is linked to the luminal differentiation marker CD24 in mammary epithelial cells. Psoriasin demonstrated an essential role in the shift towards a more differentiated CD24(+) phenotype, supporting the hypothesis that psoriasin plays a role in the differentiation of luminal mammary epithelial cells.

  • 35.
    Verma, Deepti
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Farahani, Ensieh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Synnerstad, Ingrid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Yrkes- och miljömedicin. Linköpings universitet, Hälsouniversitetet.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Rosdahl, Inger
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma2012Ingår i: Pigment Cell & Melanoma Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 25, nr 4, s. 506-513Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genetic variants of NLRP3 and NLRP1 are known to modulate levels of pro-inflammatory cytokine interleukin (IL)-1 beta. The purpose of this study was to investigate the association of NLRP3/NLRP1 polymorphisms with susceptibility and clinical features of malignant melanoma in a Swedish casecontrol study. Common variants in NLRP3/NLRP1 were investigated in sporadic malignant melanoma patients and healthy controls followed by analysis using logistic regression. NLRP3 variant (rs35829419) was significantly more common in male patients than in controls (OR, 2.22; CI, 1.273.86). Upon stratification, significant association with nodular melanoma was observed (OR, 2.89; CI, 1.336.30), which intensified in male patients (OR 4.03, CI 1.4011.59). The NLRP1 variant (rs12150220) was significantly more common in fair-skinned female patients (OR, 1.85; CI, 1.043.33) and showed strong associations with nodular melanoma (OR, 6.03; CI, 1.3325). Our data suggest that NLRP3/NLRP1 polymorphisms are associated with melanoma susceptibility; these findings warrant validation in other independent populations.

  • 36.
    Öfverholm, Anna
    et al.
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Einbeigi, Zakaria
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Manouchehrpour, Shokoufeh
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Albertsson, Per
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Skrtic, Stanko
    Department of Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Enerbäck, Charlotta
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    The ABCB1 3435 T allele does not increasethe risk of paclitaxel-induced neurotoxicity2010Ingår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 1, s. 151-154Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Paclitaxel is a frequently used anticancer drug with considerable inter-individual variability in terms of drug efficiency and toxicity. The reasons for this variability have not been fully explained. The purpose of this study was to evaluate the possible relationship between paclitaxel-induced neurotoxicity and the distribution of genetic variations with reported functional significance in the ABCB1, CYP2C8 and CYP3A4 genes that are all implicated in taxol metabolism. Women (n=36) experiencing paclitaxel-induced neurotoxicity were included in the study, and the ABCB1 G2677A/T and C3435T as well as CYP2C8*3 and CYP3A4*1b allele frequencies were determined using PCR-RFLP and DNA sequence analysis. We showed that the ABCB1 3435T allele, previously reported as a risk allele for neurotoxicity, did not correlate with the occurrence of neurotoxicity in our patient sample (Chi-square test, p=0.61). Furthermore, we showed that neither the CYP2C8*3 nor CYP3A4*1b alleles, that both lead to diminished enzyme activity, correlated with paclitaxel-induced neurotoxicity. The occurrence and variation in severity of neurotoxicity in our Swedish patient sample could therefore not be explained by the reported functional polymorphisms in

    the ABCB1, CYP2C8 and CYP3A4 genes

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