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Sökning: WFRF:(Lejonklou Margareta Halin)

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1.
  • Alavian-Ghavanini, Ali, et al. (författare)
  • Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans
  • 2018
  • Ingår i: Scientific Reports. - Nature Publishing Group. - 2045-2322. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, low APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and low APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.
2.
  • Alavian-Ghavanini, Ali, et al. (författare)
  • Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans
  • 2018
  • Ingår i: Scientific Reports. - Nature Publishing Group. - 2045-2322 .- 2045-2322. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, Iow APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and Iow APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.</p>
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3.
  • Ekeblad, Sara, et al. (författare)
  • Co-expression of ghrelin and its receptor in pancreatic endocrine tumours
  • 2007
  • Ingår i: Clinical Endocrinology. - 0300-0664 .- 1365-2265. ; 66:1, s. 115-122
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Objective </strong></p><p>Expression of ghrelin has been reported in pancreatic endocrine tumours, but data on ghrelin receptor protein expression are lacking. The aim of this study was to examine the ghrelin receptor, as well as ghrelin, in a selected series of these tumours, including multiple endocrine neoplasia 1 (MEN1) associated tumours, and to correlate data with clinical features including body mass index.</p><p><strong>Design </strong></p><p>Immunohistochemical detection of ghrelin and its receptor was performed on frozen tissue from 31 tumours: 9 MEN1 and 22 sporadic. Twenty tumours were analysed by quantitative PCR. Plasma ghrelin was assessed in 26 patients.</p><p><strong>Results </strong></p><p>Twenty-one (68%) of 31 tumours showed immunoreactivity for ghrelin (8/9 MEN1) and 19/20 expressed ghrelin mRNA. Ghrelin receptor protein was detected in 21/30 (70%) tumours (4/8 MEN1), and mRNA was detected in all analysed tumours. Insulinomas had significantly higher levels of receptor mRNA than other tumours. Five patients had elevated plasma ghrelin (&gt; 2 SD above the control group mean). No significant difference in mean plasma ghrelin levels was found between patients (908 ± 569 ng/l) and controls (952 ± 164 ng/l). Mean BMI was 24·3 kg/m<sup>2</sup>. There was no association between ghrelin or receptor expression and survival.</p><p><strong>Conclusions </strong></p><p>We report the first immunohistochemical data on expression of the ghrelin receptor in pancreatic endocrine tumours: 70% of tumours in our material. Concomitant ghrelin and receptor expression was seen in 50% of tumours, indicating an autocrine loop. Ghrelin was expressed in 68% of tumours (8/9 MEN1). Despite frequent ghrelin expression, elevated circulating ghrelin is rare in these patients.</p>
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4.
  • Ekeblad, Sara, et al. (författare)
  • Gastrointestinal stromal tumors express the orexigen ghrelin
  • 2006
  • Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 13:3, s. 963-970
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Expression of the neuroendocrine marker synaptic vesicle protein 2 (SV2) has been reported in a few cases of gastrointestinal stromal tumors (GISTs). The goal of the present study was to assess the relevance of this finding and identify a possible hormone production in these tumors. We chose to study the orexigen ghrelin and its receptor, since these patients are seldom cachexic, even in advanced disease stages. We investigated ghrelin expression by means of immunohistochemistry on frozen or paraffin-embedded sections from 22 GISTs from a well-characterized patient material. Expression of the growth hormone secretagogue receptor, the ghrelin receptor, was investigated in a subset of lesions. In six tumors, mRNA levels of ghrelin, the ghrelin receptor, and SV2 were analyzed by real-time quantitative PCR. Totally 17 out of 22 tumors showed immunoreactivity for ghrelin. Five out of ten tumors were immunoreactive for the ghrelin receptor, and all of these co-expressed ghrelin. All tumors expressed ghrelin, ghrelin receptor, and SV2 mRNA. GISTs frequently express SV2, ghrelin, and its receptor, indicating the presence of autocrine/paracrine loops.</p>
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5.
  • Ekeblad, Sara, et al. (författare)
  • Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors
  • 2012
  • Ingår i: World Journal of Surgery. - 0364-2313 .- 1432-2323. ; 36:6, s. 1411-1418
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>BACKGROUND:</strong></p> <p>Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated.</p> <p><strong>METHODS:</strong></p> <p>A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed.</p> <p><strong>RESULTS:</strong></p> <p>Patients with tumors that had &lt;5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P &lt; 0.01) and with &gt;50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P &lt; 0.001). Nuclear survivin expression in &gt;50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P &lt; 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90).</p> <p><strong>CONCLUSIONS:</strong></p> <p>High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.</p>
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6.
  • Fjallskog, Marie-Louise, et al. (författare)
  • Expression of molecular targets for tyrosine kinase receptor antagonistsin malignant endocrine pancreatic tumors
  • 2003
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 9:4, s. 1469-1473
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>PURPOSE:</strong></p> <p>Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment.</p> <p><strong>EXPERIMENTAL DESIGN:</strong></p> <p>Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR).</p> <p><strong>RESULTS:</strong></p> <p>All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals.</p> <p><strong>CONCLUSIONS:</strong></p> <p>We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.</p>
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7.
  • Fjällskog, Marie-Louise, et al. (författare)
  • Expression of molecular targets for tyrosine kinase antagonists in malignant endocrine pancreatic tumors
  • 2003
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 9:4, s. 1469-1473
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>PURPOSE:</strong></p> <p>Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment.</p> <p><strong>EXPERIMENTAL DESIGN:</strong></p> <p>Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR).</p> <p><strong>RESULTS:</strong></p> <p>All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals.</p> <p><strong>CONCLUSIONS:</strong></p> <p>We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.</p>
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8.
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9.
  • Halin Lejonklou, Margareta, 1966- (författare)
  • The MEN 1 Pancreas Tumor Development and Haploinsufficiency
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Multiple Endocrine Neoplasia Type I Syndrome (MEN 1) is a monogenic autosomal dominantly inherited cancer syndrome caused by a heterozygous loss of the <em>MEN1</em> gene, predisposing for endocrine cell proliferation and tumor formation. MEN 1 carriers classically develop tumors in endocrine organs; the parathyroids, the endocrine pancreas, and the pituitary. Other organs, endocrine and non-endocrine, may also be affected. The most common cause of death in MEN 1 is pancreatic endocrine tumor (PNET), which exhibit inactivation of both <em>MEN1</em> alleles. The increased proliferation prior to loss of the wild-type allele indicates haploinsufficiency, and little is known concerning the mechanisms behind MEN 1 PNET development. The <em>MEN1 </em>protein, menin, lacking homology with other known proteins, is involved in several aspects of transcriptional regulation and chromatin organization.</p><p>We report differential expression and subcellular localization of transcription factors important in pancreatic development, in human and mouse MEN 1 pancreas, compared to non-MEN 1 pancreas. A predominantly cytoplasmic localization of Neurogenin3 and NeuroD1 was observed in tumors as well as in MEN 1 non-tumorous pancreas.</p><p>Notch signaling factor expression and localization were examined in the pancreas of a heterozygous <em>Men1</em> mouse model, and compared with that of wild-type littermates. Nuclear Hes1 was lost in tumors, concomitant to weaker Notch1 NICD expression, and further, analyzed using qPCR, it was shown that <em>Notch1</em> was less expressed in heterozygous islets compared to wild-type islets.</p><p>Performing a global gene expression array, we identified differential gene expression in five-week-old heterozygous <em>Men1</em> mouse islets, compared to islets from wild-type littermates. The array results for a subset of the differentially regulated genes were corroborated using qPCR, western blotting and <em>in situ</em> PLA. We additionally observed significantly accelerated proliferation in islets from young heterozygous animals.</p><p>It is often problematic to determine prognosis for individual patients with PNET. This is especially true in the group of patients with well differentiated endocrine carcinomas. In the absence of metastases, morphological signs of malignancy are frequently lacking. We evaluated the expression of nuclear and cytoplasmic survivin in a clinically characterized patient material (n=111), and a high nuclear survivin expression proved to be a significant negative prognostic factor for survival.</p>
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10.
  • Johansson, T, et al. (författare)
  • Lack of Nuclear Expression of Hairy and Enhancer of Split-1 (HES1) in Pancreatic Endocrine Tumors
  • 2008
  • Ingår i: Hormone and Metabolic Research. - 0018-5043 .- 1439-4286. ; 40:5, s. 354-359
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The Notch signaling cascade plays a vital role in the proliferation and differentiation of cells during pancreatic development. Cell line experiments have suggested the involvement of Notch signaling in pancreatic endocrine tumorigenesis. We investigated the expression of NOTCH1, HES1, HEY1 and ASCL1 in pancreatic endocrine tumors and compared the data to tumor phenotype including hormone production, heredity, and WHO classification. Real-time quantitative PCR and immunohistochemistry were performed on samples of 26 pancreatic endocrine tumors. For comparison, 10 specimens of macroscopically normal pancreas were analyzed using immunohistochemistry. The subcellular localization of proteins was determined. Neither hormone production, nor heredity, or WHO classification was found to be associated with the expression of these proteins. There were discrepancies between mRNA and protein expression levels. All tumors displayed ASCL1 immunoreactivity. HES1 immunoreactivity was lacking altogether in 46% of the tumors, and in the remaining lesions its expression was weak and confined to the cytoplasm. In the nontumorous pancreatic endocrine cells, weak nuclear expression of HES1 as well as of HEY1 and NOTCH1 was observed. There was a significant positive correlation between NOTCH1 and HES1 mRNA levels, but no indication that HES1 was inhibiting ASCL1 transcription was found. No nuclear expression of HES1 was found in the tumors. This lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas.</p>
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