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  • 1.
    Ahlgren, Kerstin M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Sundberg, Katarina
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105473-Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

  • 2.
    Ali, Abir Salwa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Federspiel, Birgitte
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Scoazec, Jean-Yves
    Inst Gustave Roussy, Villejuif, France.
    Hjortland, Geir Olav
    Univ Oslo, Oslo, Norway.
    Gronbaek, Henning
    Aarhus Univ Hosp, Aarhus, Denmark.
    Ladekarl, Morten
    Aarhus Univ Hosp, Aarhus, Denmark.
    Langer, Seppo W.
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, Lene Weber
    Odense Univ Hosp, Odense, Denmark.
    Arola, Johanna
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland.
    Osterlund, Pia
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland; Tampere Univ Hosp, Tampere, Finland.
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Bergen, Norway; Univ Bergen, Bergen, Norway.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology. Uppsala Univ, Sect Endocrine Oncol, Dept Med Sci, Uppsala, Sweden..
    Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187667Article in journal (Refereed)
    Abstract [en]

    Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

  • 3.
    Alit, Abir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 43-43Article in journal (Refereed)
  • 4.
    Antonodimitrakis, Pantelis Clewemar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Neuroendocrine tumors with syndromic vasoactive intestinal polypeptide hypersecretion: a retrospective study2017In: International Journal of Endocrine Oncology, Vol. 4, no 1, p. 9-22Article in journal (Refereed)
    Abstract [en]

    Aim: Vasoactive intestinal polypeptide producing neuroendocrine tumors are rare and cause severe hormonal symptoms. Patients/methods: Eighteen patients with vasoactive intestinal polypeptide producing neuroendocrine tumors were analyzed with reviews of medical records, radiology and tumor tissue specimens. Results: Twelve patients (67%) had liver metastases at diagnosis. Chemotherapy, somatostatin analogs and interferon were given as medical therapies. Streptozocin/5-fluorouracil produced an objective response in 40% of the evaluable patients. Somatostatin analogs gave a clinical/biochemical response in eight out of nine patients. Transarterial embolization of the liver and peptide receptor radionuclide therapy was given to refractory cases. Sixteen patients died during the observation period. The median overall survival from diagnosis was 102 months. Conclusion: Systemic chemotherapy and somatostatin analogs should be given in cases of advanced disease or for hormonal symptoms.

  • 5.
    Backlin, Carin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wiberg, K
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Monoclonal antibodies recognizing normal and neoplastic human adrenal cortex1995In: Endocr Pathol, Vol. 6, p. 21-Article in journal (Refereed)
  • 6. Borch, Kurt
    et al.
    Ahren, Bo
    Ahlman, Hakan
    Falkmer, Sture
    Granerus, Goran
    Grimelius, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Gastric carcinoids: biologic behavior and prognosis after differentiated treatment in relation to type.2005In: Ann Surg, ISSN 0003-4932, Vol. 242, no 1, p. 64-73Article in journal (Refereed)
  • 7.
    Cunningham, Janet L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Agarwal, Smriti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Tachykinins in endocrine tumors and the carcinoid syndrome2008In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 159, no 3, p. 275-282Article in journal (Refereed)
    Abstract [en]

    Objective

    A new antibody, active against the common tachykinin (TK) C-terminal. was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs).

    Method

    TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients.

    Results

    All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin-producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. In a Spearman partial rank test, the correlation of P-TK with daily diarrhea was independent of both U-5HIAA and CgA levels.

    Conclusion

    We found that TK synthesis occurs in serotonin-IR tumors and that P-TK levels are significantly correlated with symptoms of flush and diarrhea in patients with MSPCs. This is. to our knowledge, the first report demonstrating an independent correlation of P-TKs with carcinoid diarrhea, a symptom that is customarily regarded as serotonin mediated. Further investigations may present opportunities for new therapeutic possibilities.

  • 8.
    Cunningham, Janet Lynn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Agarwal, Smriti
    Christian Medical College, Vellore, India.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Malignant ileocaecal serotonin-producing carcinoid tumours: the presence of a solid growth pattern and/or Ki67 index above 1% identifies patients with a poorer prognosis2007In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, no 6, p. 747-756Article in journal (Refereed)
    Abstract [en]

    Patients with malignant serotonin-producing carcinoid tumours in the jejunum, ileum and caecum generally have long survival expectancy. In some patients, however, tumour progression is more rapid and there is a need to identify them at an early stage. The purpose of this study was to determine if histopathological characteristics and/or Ki67 and apoptotic indices are of prognostic value in cases of metastatic disease. Eighty-one patients with this tumour were included in the study; all had metastases and their survival range was 1-223 months. Five growth patterns were identified and described. For 57 patients whose tumour material was available, the Ki67 and apoptotic indices were calculated for ten randomly selected tumour areas and 'hot spots'. A Cox regression analysis was used to test if histopathology and/or Ki67 index ≥1% could identify patients whose survival might be shorter than anticipated. One of the histopathological growth patterns-the solid (non-organoid) cell pattern-was correlated to shorter survival in both primary tumours and metastases, when compared with the organoid growth patterns (hazard ratio 2.9 and 2.3, p≤0.01). In 75% of primary tumours and 67% of metastases, the average Ki67 index was<0.5%. Ki67 index in 'hot spots' ranged from 0.1 to 14%. Ki67 index ≥1%, in both primary tumour and metastases, identified patients at increased risk of shorter survival (hazard ratio 5.4 and 2.5, p≤0.01). The apoptotic index was very low in all cases. We conclude that in patients with metastazising serotonin-producing carcinoids, two independent criteria, a solid growth pattern and Ki67 index ≥1%, can be used to identify patients with a poorer prognosis. This study also showed that Ki67 index <2% cannot, as previously suggested, be used to indicate a benign progression for this tumour category.

  • 9.
    Ekeblad, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Grimfjärd, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Térèse
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Co-expression of ghrelin and its receptor in pancreatic endocrine tumours2007In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 1, p. 115-122Article in journal (Refereed)
    Abstract [en]

    Objective 

    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.

    Design 

    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.

    Results 

    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 (> 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/m2. There was no association between ghrelin or receptor expression and survival.

    Conclusions 

    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.

  • 10.
    Fryknäs, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wickenberg Bolin, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signal Processing.
    Foukakis, Theodoros
    Lee, Jia-Jing
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Höög, Anders
    Larsson, Catharina
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wallin, Göran
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molecular markers for discrimination of benign and malignant follicular thyroid tumors2006In: Tumor Biology, ISSN 1010-4283, Vol. 27, no 4, p. 211-220Article in journal (Refereed)
  • 11. Galanti, M. Rosaria
    et al.
    Hansson, Lisbeth
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Bergström, Reinhold
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Wolk, Alicja
    Hjartåker, Anette
    Lund, Eiliv
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekbom, Anders
    Diet and the risk of papillary and follicular thyroid carcinoma: A population-based case-control study in Sweden and Norway1997In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 8, no 2, p. 205-214Article in journal (Refereed)
    Abstract [en]

    A population-based case-control study was conducted in two regions of Sweden and Norway to investigate the association between dietary habits and the risk of thyroid cancer. The consumption of selected foods was reported in a self-completed food-frequency questionnaire by 246 cases with histologically confirmed papillary (n = 209) and follicular (n = 37) thyroid carcinoma, and 440 age- and gender-matched controls. Odds ratios (OR) and their 95 percent confidence interval (CI) were calculated as estimates of the relative risk using conditional logistic regression. High consumption of butter (OR = 1.6, CI = 1.1-2.5) and cheese (OR = 1.5, CI = 1.0-2.4) was associated with increased risks. Residence in areas of endemic goiter in Sweden was associated with an elevated risk, especially among women (OR = 2.5, CI = 1.3-4.9). High consumption of cruciferous vegetables was associated with increased risk only in persons who ever lived in such areas. A decreased risk was associated with consumption of iodized salt in northern Norway, and with use of iodized salt during adolescence among women (OR = 0.6, CI = 0.6-1.0). The results of this study suggest a role of diet and environment in the risk of thyroid cancer.

  • 12.
    Georgantzi, Kleopatra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Univ Hosp Solna, CCK, Stockholm, Sweden.
    Jakobson, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Christofferson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 Are Expressed in Neuroblastoma2019In: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 30, no 3, p. 173-179Article in journal (Refereed)
    Abstract [en]

    Neuroblastoma (NB), the most common extracranial cancer in childhood, exhibits neuroendocrine (NE) differentiation. Two well-established NE markers, chromogranin A (CgA) and synaptophysin (syn), are used in the histopathological diagnostics. Our aims were to explore if the NE markers synaptic vesicle protein 2 (SV2) and vesicular monoamine transporter 1 (VMAT1) and 2 (VMAT2) also are expressed in human NB and if so, evaluate their usefulness in NB histopathological diagnostics. Tumor specimens from 21 NB patients, before and/or after chemotherapy, were immunostained for CgA, syn, SV2, VMAT1, and VMAT2. Clinical data was extracted from patients' records. SV2 was highly expressed in NB, as was CgA while syn was less frequently expressed compared to the other two. Both VMATs were expressed in several NB, VMAT2 in more cases than VMAT1 and its expression was similar to syn. Chemotherapy did not affect the immunoreactivity in an obvious way. SV2 was highly expressed in NB and can thus be useful marker in NB diagnostics. VMAT1 and VMAT2 were also expressed in NB but similar to syn less reliable as tumor markers.

  • 13.
    Giandomenico, Valeria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cui, Tao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pelosi, Giuseppe
    European Institute of Oncology, Milan, Italy; University of Milan School of Medicine, Milan, Italy.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Olfactory Receptor 51E1 as a Novel Target for Diagnosis in Somatostatin Receptor Negative Lung Carcinoids2013In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 51, p. 277-286Article in journal (Refereed)
    Abstract [en]

    Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs) and 11 regional/distant metastases, and compared to OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3+, taking into account the cellular compartmentalization (membrane vs. cytoplasm) and the percentage of tumor cells (<50% vs. >50%). Our results showed that wild-type OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9/12 TCs and 7/9 ACs (p=NS). Immunohistochemically, OR51E1, SSTR2, SSTR3 and SSTR5 were detected in 85%, 71%, 25% and 39% of TCs, and in 86%, 79%, 43% and 36% of ACs, respectively. OR51E1 immunohistochemical scores were higher or equal compared to SSTRs in 79% of TCs and 86% of ACs. Furthermore, in the LC cases where all SSTR subtypes were lacking, membrane OR51E1 expression was detected in 10/17 TCs and 1/2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5/6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors.

  • 14.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Methods in neuroendocrine histopathology: a methodological overview2008In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 113, no 3, p. 243-260Article, review/survey (Refereed)
    Abstract [en]

    Light microscopy is still the main tool in diagnostic histopathology, though it does not always lead to a definitive diagnosis. It has therefore been a constant ambition to develop methods which can add further information to the diagnosis. In endocrine pathology, a major problem has been to distinguish between neuroendocrine and non-neuroendocrine tumours. The silver stains, such as the Bodian, Grimelius and Sevier-Munger methods, were the first useful "general neuroendocrine" markers. Electron microscopy can also be useful for identifying neuroendocrine tumours. A further step forward was the introduction of histochemical fluorescence methods, as these could identify biogenic amines. With the introduction of immunohistochemical techniques, tumours could be characterized in a more specific way regarding peptide hormones and biogenic amines content, proliferation factors, hormone receptors, etc. Another method, DNA cytometry, has been used mainly in predicting the prognosis. In situ hybridization can be a useful complement to the histopathological diagnosis when other methods have failed to demonstrate the neuroendocrine nature of the tumour. Some endocrine tumours, especially the well-differentiated ones, still cause diagnostic problems in predicting tumour behaviour, why further complementary methods would be of great value.

  • 15.
    Grimelius, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Silver stains demonstrating neuroendocrine cells2004In: Biotech. Histochem., Vol. 79, p. 37-44Article in journal (Refereed)
  • 16.
    Grimelius, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Biographical item: "Henry Johansson in memoriam" in Upsala Journal Of Medical Sciences, vol 122, Issue: 4, pp 260-2612017Other (Other (popular science, discussion, etc.))
  • 17.
    Grönberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Tsolakis, Apostolos V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Holmbäck, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Janson, Eva T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Ghrelin and Obestatin in Human Neuroendocrine Tumors: Expression and Effect on Obestatin Levels after Food Intake2013In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 97, no 4, p. 291-299Article in journal (Refereed)
    Abstract [en]

    Background:

    Ghrelin and obestatin are derived from the same peptide hormone precursor and are mainly produced by the gastric mucosa. Ghrelin is involved in many biological processes, whereas the physiological function of obestatin needs further investigation. The aims of the present study were to establish the incidence of ghrelin- and obestatin-immunoreactive cells in a comprehensive panel of human neuroendocrine tumors (NETs) and to investigate if blood obestatin concentrations are influenced during a standardized meal stimulation test in healthy individuals and patients with NETs.

    Materials and Methods:

    The expression of ghrelin and obestatin was investigated in NETs (n = 149) and other endocrine-related disorders (n = 3) using immunohistochemistry with specific polyclonal antibodies. Coexpression of the peptides was evaluated by double immunofluorescence. Concentrations of obestatin in blood were measured during a meal test in 6 healthy individuals and 5 patients with pancreatic NETs.

    Results:

    Ghrelin and obestatin were expressed in 14/152 and 19/152 tumor tissues, respectively, mainly representing NETs of foregut origin and in pancreatic tissue from a nesidioblastosis patient. Double immunofluorescence staining showed colocalization of the peptides. During the meal test, obestatin levels in blood were unchanged in all patients but decreased significantly in the healthy individuals.

    Conclusion:

    Only a minority of NETs express ghrelin and obestatin. However, analysis of patients with tumors originating from tissues that express the peptides in normal conditions could be of importance. The results from the meal test indicate that the hormone levels are affected by food intake in healthy individuals, whereas obestatin levels remained unchanged in pancreatic NET patients.

  • 18. Jatta, K.
    et al.
    Eliason, G.
    Portela-Gomes, G. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Caro, O.
    Nilholm, L.
    Sirjsö, A.
    Piehl-Aulin, K.
    Abdel-Halim, S. M.
    Overexpression of von Hippel-Lindau protein in skeletal muscles of patients with chronic obstructive pulmonary disease2009In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 62, no 1, p. 70-76Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation, which correlate with increased mortality. AIM: To determine the molecular mechanisms mediating decreased capillary formation in COPD. METHODS: 24 patients with COPD and 12 matching controls were recruited. Patients with COPD were classified into mild, moderate and severe groups according to GOLD (global initiative for chronic obstructive lung disease) criteria. Biopsy specimens were obtained from the tibialis anterior muscle. Fibre typing and capillary formation, together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF1alpha and HIF3alpha), vascular endothelial growth factors (VEGF-A, VEGF-B and VEGF-C isoforms) and von Hippel-Lindau (VHL) protein, were determined. VHL expression and localisation were further studied by immunohistochemistry. RESULTS: Skeletal muscle capillary formation decreased significantly with increasing disease severity. Compared with controls, a tendency to mRNA overexpression of HIF1alpha, HIF3alpha and VEGF isoforms was observed in mild and moderate COPD, which decreased at the severe stage. In contrast, skeletal muscle biopsy samples from patients with COPD exhibited significant overexpression of VHL at both the mRNA and protein level by immunohistochemistry. VHL protein was further determined to be localised to satellite cells. CONCLUSIONS: Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may have a negative effect on transduction of the hypoxic signal and may contribute to decreased capillarisation in skeletal muscles of patients with COPD.

  • 19. Kanakis, G.
    et al.
    Kaltsas, G.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Papaioannou, D.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Unusual Complication of a Pancreatic Neuroendocrine Tumor Presenting with Malignant Hypercalcemia2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 4, p. E627-E631Article in journal (Refereed)
    Abstract [en]

    Context:

    Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia but has only been described in a few cases of neuroendocrine tumors (NET).

    Objective:

    The aim of this case report is to describe the clinical syndrome, complex therapeutic interventions, and unusual complications caused by persistent PTHrP hypersecretion in a patient with a pancreatic NET.

    Case Illustration:

    A 58-yr-old male patient presented with nonspecific abdominal pain and was found to have severe hypercalcemia secondary to a well-differentiated NET of the pancreas associated with extensive liver metastases. Elevated ionized calcium levels accompanied by low serum PTH and remarkably elevated PTHrP concentrations were consistent with PTHrP-related hypercalcemia that proved to be resistant to various chemotherapeutic regimens and supportive therapy. Partial control of the humoral syndrome was obtained only after the application of cytoreductive interventions and the introduction of various molecular targeted therapies. Due to persistent PTHrP action, bone disease emerged in the form of brown tumors.

    Discussion:

    The manifestation of paraneoplastic syndrome due to PTHrP hypersecretion, despite its rareness in NET, should be considered in the differential diagnosis of hypercalcemia in such tumors. Moreover, the appearance of bone lesions in this setting may be in the context of metabolic bone disease and could be misdiagnosed as bone metastases.

  • 20. Lee, Jia-Jing
    et al.
    Foukakis, Theodoros
    Hashemi, Jamileh
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wallin, Göran
    Rudduck, Christina
    Lui, Weng-Onn
    Höög, Anders
    Larsson, Catharina
    Molecular cytogenetic profiles of novel and established human anaplastic thyroid carcinoma models2007In: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 17, no 4, p. 289-301Article in journal (Refereed)
    Abstract [en]

    In this study we present two novel anaplastic thyroid carcinoma (ATC) lines (HTh 104 and HTh 112) and further characterize six frequently used ATC lines (HTh 7, HTh 74, HTh 83, C 643, KAT-4, and SW 1736). Three of the lines carried a heterozygous BRAF mutation V600E, which is in line with reports of BRAF mutations in primary ATC and papillary thyroid cancer. Several nonrandom breakpoints were identified by spectral karyotyping (SKY) and G-banding in these lines including the novel 1p36 and 17q24-25 as well as 3p21-22 and 15q26 that are also implicated in well-differentiated thyroid cancers. Comparative genomic hybridization showed frequent gain of 20q, including the UBCH10 gene in 20q13.12, which was further confirmed by array-comparative genomic hybridization and fluorescence in situ hybridization analyses. Our results concur with previous studies in both primary tumors and cell lines, indicating that gain of chromosome 20 is important in the pathogenesis of ATC and/or progression of differentiated thyroid cancers to ATC.

  • 21. Portela-Gomes, G. M.
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Selective processing of chromogranin A in rectal carcinoid tumours: An immunohistochemical study with region-specific antibodies2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 164, no 1, p. 37-37Article in journal (Other academic)
  • 22.
    Portela-Gomes, GM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Johansson, H
    Wilander, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, M
    Department of Medical Sciences.
    Chromogranin A in human neuroendocrine tumors. An immunohistochemical study with region-specific antibodies.2001In: Am. J. Surg. Pathol., Vol. 25, p. 1261-Article in journal (Refereed)
  • 23. Portela-Gomes, Guida M.
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Somatostatin Receptor Subtypes in Human Type 2 Diabetic Islets2010In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 39, no 6, p. 836-842Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES

    Somatostatin inhibits hormone release through 5 G protein-coupled somatostatin receptors (sst1-sst5). However, the role of somatostatin in islet physiology is not fully known. The immunoreactivity to sst1 to sst5 in normal human endocrine pancreas has been described. The present study reports the expression of sst1 to sst5 in human pancreatic islets with type 2 diabetes mellitus.

    METHODS

    Pancreatic autopsy specimens from individuals with type 2 diabetes mellitus and matched controls were double immunostained to demonstrate sst1 to sst5 in the major islet cell types.

    RESULTS

    Most apparent differences in type 2 diabetic islets were the lack of sst1 and sst4 in glucagon cells and sst1-3 and 4 in somatostatin cells, whereas minor changes were demonstrated in insulin cells. The pancreatic polypeptide cells showed a reversed staining pattern in diabetic islets compared with the controls.

    CONCLUSIONS

    In type 2 diabetes mellitus, the sst pattern differed from that of the controls in somatostatin, pancreatic polypeptide, and glucagon cells, to a minor extent in insulin cells. It is unclear whether the changes in sst patterns are primarily due to the diabetes or secondary to metabolic disturbances. However, this study may be the basis for further functional studies to evaluate the role of sst1 to sst5 in the diabetic state.

  • 24.
    Portela-Gomes, Guida M.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Department of Medical Sciences. Clinical Chemstry.
    Grimelius, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Falkmer, Ursula G.
    Falkmer, Sture
    Expression of chromogranins A, B, and C (secretogranin II), in human adrenal medulla and in benign and malignant pheochromocytomas. An immunohistochemical study with region-specific antibodies2004In: APMIS, Vol. 112, p. 663-673Article in journal (Refereed)
  • 25.
    Portela-Gomes, Guida Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 146, no 1-3, p. 117-124Article in journal (Refereed)
    Abstract [en]

    Prohormone convertases (PCs) are proteinases that cleave inactive prohormones to biologically active peptides. Seven PCs have been identified; two of them, PC1/3 and PC2, have only been localized in neuroendocrine (NE) tissues; a third, furin, in both endocrine and exocrine tissues. We have studied the immunoreactivity of PC1/3, PC2 and furin in the four major NE cell types of the human pancreas by using double immunofluorescence techniques. The study also included the expression of NE secretory protein 7B2 (secretogranin V), a member of the granin family, which influences the function of PC2. The results showed that the three PCs and 7B2 were expressed only in endocrine pancreas, furin also in exocrine cells. Insulin (B) cells harboured PC1/3 and PC2, but not furin. Glucagon (A) cells were immunoreactive to all three PCs; all glucagon cells expressed PC2, but one subpopulation showed PC1/3 immunoreactivity and another furin. Only a few somatostatin (D) cells contained PC2, but no other proconvertase. Pancreatic polypeptide (PP) cells were non-reactive to all three PCs. 7B2 occurred only in insulin and glucagon cells. A varying co-localization pattern was observed between PCs and between PCs and 7B2, with the exception of PC1/3 and furin which were not co-localized. In conclusion, our study shows that PCs are localized in insulin and glucagon cells and do seem to be important in these cell types for processing of hormone and other protein precursors, especially chromogranins, but for the two other major cell types probably other enzymes are of importance.

  • 26. Portela-Gomes, Guida Maria
    et al.
    Grimelius, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Department of Medical Sciences. Clinical Chemstry.
    Bresaola, Enrica
    Viale, Giuseppe
    Pelosi, Giuseppe
    Expression of amino acid sequences of the chromogranin A molecule and synaptic vesicle protein 2 in neuroendocrine tumors of the lung.2005In: Virchows Arch, ISSN 0945-6317, Vol. 446, no 6, p. 604-12Article in journal (Refereed)
  • 27.
    Portela-Gomes, Guida Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rorstad, Otto
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas: predominance of receptor subtype 42007In: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 18, no 2, p. 79-85Article in journal (Refereed)
    Abstract [en]

    Insulinomas constitute a subgroup of pancreatic endocrine tumors showing B cell differentiation and clinical symptoms related to inappropriate insulin secretion (WHO). Many endocrine tumors express somatostatin receptors (sstrs), which can be visualized by octreotide scintigraphy; however, about half of all insulinomas are reported to be negative. Previous immunohistochemical investigations with antibodies to sstr subtypes 1, 2, 3, and 5 have revealed differences in expression between various neuroendocrine tumors. In the present study, the immunoreactivity to all five human sstr was studied in ten benign and six malignant human insulinomas. Sstr4 was the receptor subtype most frequently expressed in both benign and malignant tumors. A difference in the immunohistochemical sstr5 expression pattern was seen between benign and malignant tumors: Three of the six malignant tumors, but none of the benign tumors, expressed sstr5. The other receptor subtypes were expressed in low numbers with no difference between benign and malignant tumors. The finding of a strong expression of sstr4 in both benign and malignant insulinomas suggests that this receptor subtype could be of importance for diagnostic and therapeutic use.

  • 28. Rubio, C A
    et al.
    Grimelius, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Von Sivers, K
    Hoog, A
    Intraductal serrated adenoma of the pancreas. A case report.2005In: Anticancer Res: Intraductal serrated adenoma of the pancreas. A case report., ISSN 0250-7005, Vol. 25, no 4, p. 3099-102Article in journal (Refereed)
  • 29. Rubio, Carlos A
    et al.
    Grimelius, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Lindholm, Johan
    Hamberg, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Porwit, Anja
    Elmberger, Göran
    Hoog, Anders
    Kanter, Lena
    Eriksson, Elina
    Stemme, Sten
    Orrego, Abiel
    Saft, Leonie
    Petersson, Fredrik
    De La Torre, Manuel
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Ekström, Christina
    Åström, Kristina
    Rundgren, Åsa
    Djokic, Miroslav
    Chandanos, E
    Lenander, Claes
    Machado, Mikael
    Nilsson, Per
    Mattsson, Lars
    Reliability of the reported size of removed colorectal polyps.: Reliability of the reported size of removed colorectal polyps.2006In: Anticancer Res: Anticancer Res, ISSN 0250-7005, Vol. 26, no 6C, p. 4895-9Article in journal (Refereed)
  • 30.
    Sköldberg, Filip
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Gunnar
    Perheentupa, Jaakko
    Betterle, Corrado
    Husebye, Eystein S.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Histidine decarboxylase, a pyridoxal phosphate-dependent enzyme, is an autoantigen of gastric enterochromaffin-like cells2003In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, no 4, p. 1445-1452Article in journal (Refereed)
    Abstract [en]

    Patients with autoimmune polyendocrine syndrome type 1 often have autoantibodies against neurotransmitter synthesizing enzymes, including the pyridoxal phosphate-dependent enzymes glutamic acid decarboxylase and aromatic L-amino acid decarboxylase. Using a candidate approach, we have identified the histamine-synthesizing enzyme histidine decarboxylase, also pyridoxal phosphate dependent, as an autoantigen in this disorder. Anti-histidine decarboxylase antibodies reacting with in vitro translated antigen were found in 36/97 (37%) of autoimmune polyendocrine syndrome type 1 patients studied. The antibodies also reacted with the native enzyme in HMC-1 cell lysates and did not cross-react with the highly homologous aromatic L-amino acid decarboxylase. Anti-histidine decarboxylase antibodies were associated with a history of intestinal dysfunction (P = 0.017). Gastric and duodenal biopsies from a patient with anti-histidine decarboxylase antibodies were studied by immunohistochemistry. The oxyntic mucosa was found to lack the histamine producing enterochromaffin-like cells, suggestive of an autoimmune destruction. To our knowledge, this is the first report of autoantibodies against histidine decarboxylase and absence of gastric enterochromaffin-like cells.

  • 31.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Portela-Gomes, G M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Immunohistochemical staining of human islet cells with region-specific antibodies against secretogranins II and III2008In: Journal of Anatomy, ISSN 0021-8782, E-ISSN 1469-7580, Vol. 212, no 3, p. 229-234Article in journal (Refereed)
    Abstract [en]

    Chromogranins and secretogranins belong to the granin family of proteins, which are expressed in neuroendocrine and nervous tissue. In earlier publications we have described the development of region-specific antibodies against CgA and CgB. In this study we describe antibodies to SgII and SgIII and their usefulness for immunohistochemical staining. Peptides homologous to defined parts of secretogranins II and III were selected and synthesized. Antibodies were raised and immunostainings were performed on normal human pancreas. The SgII 154-165 (N-terminal secretoneurin), SgII 172-186 (C-terminal secretoneurin) and SgIII antibodies immunostained all insulin-immunoreactive cells, most of the glucagon cells and some of the pancreatic polypeptide cells. The SgII 225-242 antibody immunostained only the insulin-containing cells. None of the antibodies immunostained the somatostatin cells. This study is the first observation of the expression of SgIII in human tissues, where we show expression of SgIII in three of the four major islet cell types in human pancreas.

  • 32.
    Tsolakis, Apostolos V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Granerus, Goran
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Falkmer, Sture E.
    Ryhov Cty Hosp, Dept Pathol, SE-55185 Jonkoping, Sweden..
    Janson, Eva T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours2015In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, no 47, p. 13240-13249Article in journal (Refereed)
    Abstract [en]

    AIM:

    To study histidine decarboxylase (HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite.

    METHODS:

    Control tissues from fundus (n = 3) and corpus (n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours (GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2 (VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid (U-MeImAA) was determined using high-performance liquid chromatography in 27 of the 64 patients.

    RESULTS:

    In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cell population co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumours. The relative incidence of the three aforementioned markers varied in the tumours that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumours. In four patients, increased U-MeImAA excretion was detected, but only two of the patients exhibited related endocrine symptoms.

    CONCLUSION:

    Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.

  • 33.
    Tsolakis, Apostolos V
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Islam, Md Shahidul
    Expression of the coiled coil domain containing protein 116 in the pancreatic islets and endocrine pancreatic tumors2012In: Islets, ISSN 1938-2022, Vol. 4, no 5, p. 349-353Article in journal (Refereed)
    Abstract [en]

    Aims: Coiled coil domain containing protein 116 (CCDC116) is a product of the gene coiled coil domain containing 116 located on human chromosome 22. Its function has not yet been established. The present study focuses on the expression of this protein in human pancreatic islets and in the endocrine pancreatic tumors (EPTs). Methods and Results: Expression of the protein was evaluated by immunohistochemistry in endocrine pancreas from six patients and in various EPTs from 51 patients. In pancreatic islets, virtually all insulin, approx. 75% of the somatostatin, and approx. 60% of the pancreatic polypeptide (PP) cells were immunoreactive for the CCDC116 protein whereas glucagon, ghrelin and the exocrine cells were not. All insulinomas, gastrinomas, non-functioning sporadic tumors and the hereditary multihormonal EPTs were immunoreactive with variable relative incidence. Two of the three somatostatinomas, and one of the three ACTH-secreting tumors also expressed CCDC116. Conclusions: The CCDC116 protein is expressed in all islet cell types except the glucagon and ghrelin cells. Most of the EPTs also contained CCDC116 protein. These findings suggest that this protein may play some role for the above mentioned endocrine cells and tumors. Its function has to be investigated in future studies.

  • 34.
    Tsolakis, Apostolos V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Falkmer, Sture E.
    Waldum, Helge L.
    Saras, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Obestatin/ghrelin cells in normal mucosa and endocrine tumours of the stomach2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 160, no 6, p. 941-949Article in journal (Refereed)
    Abstract [en]

    Objective:

    Obestatin and ghrelin are derived from the same gene and co-expressed in the same endocrine cells. Vesicular monoamine transporter-2 (VMAT-2), a marker for enterochromaffin-like (ECL) cells, is considered to be expressed in ghrelin cells. The aim was to establish if the two peptides and the transporter are co-expressed, both in normal gastric mucosa and in gastric endocrine tumours.

    Design:

    An immunohistochemical study was performed on gastric biopsy material and on surgical specimens from 63 patients with gastric endocrine tumours and from individuals with normal gastric mucosa. Cells displaying obestatin immunoreactivity were examined regarding co-localization with ghrelin and VMAT-2. Both single- and double-immunostaining techniques were applied. Obestatin concentration in blood was measured in a subgroup of these patients. The results were correlated to various clinico-pathological parameters.

    Results:

    In the normal mucosa, obestatin/ghrelin-immunoreactive cells rarely co-expressed VMAT-2. In most tumour tissue specimens, only a fraction of neoplastic cells displayed immunoreactivity to obestatin, and these cells always co-expressed ghrelin. Neoplastic obestatin-/ ghrelin-IR cells invariably expressed VMAT-2, except for two ghrelinomas. The obestatin concentrations in blood were consistently low and did not correlate to clinico-pathological data.

    Conclusions:

    Obestatin and ghrelin immunoreactivity always occurred in the same endocrine cells in the gastric mucosa but these cells only occasionally co-expressed VMAT-2, opposite to the findings in tumours. These results indicate that endocrine cells expressing obestatin and ghrelin mainly differ from VMAT-2 expressing cells (ECL-cells) and can develop into pure ghrelinomas. Plasma concentrations of obestatin did not correlate to cellular expression.

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