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  • 151.
    Cui, Tao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Novel Circulating and Tissue Biomarkers for Small Intestine Neuroendocrine Tumors and Lung Carcinoids2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Small intestine neuroendocrine tumors (SI-NETs) and lung carcinoids (LCs) are relatively indolent tumors, which originate from neuroendocrine (NE) cells of the diffuse NE system. Metastases can spread before diagnosis. Thus, potential cures become unavailable, which entitles new biomarker development. Indeed, we aimed at developing Ma2 autoantibodies and olfactory receptor 51E1 (OR51E1) as potential novel biomarkers and exploring other candidate protein markers in patients’ serum.

    First, we established a sensitive, specific and reliable anti-Ma2 indirect ELISA to distinguish SI-NET patients from healthy controls. We detected longer progression-free and recurrence-free survivals in patients expressing low anti-Ma2 titers. Moreover, a high anti-Ma2 titer was more sensitive than chromogranin A for the risk of recurrence after radical operation of SI-NET patients.

    We then investigated OR51E1 expression in SI-NETs and LCs. OR51E1 mRNA expression, analyzed by quantitative real-time PCR, was high in microdissected SI-NET cells, in LC cell lines and in frozen LC specimens. Immunohistochemistry (IHC) showed abundant OR51E1 protein expression in SI-NETs. OR51E1 co-expressed with vesicular-monoamine-transporter-1 in the majority of normal and neoplastic enterochromaffin cells.

    Furthermore, the study on LCs revealed that OR51E1, somatostatin receptor (SSTR) 2, SSTR3, and SSTR5 are expressed in 85%, 71%, 25% and 39% of typical carcinoids (TCs), whereas in 86%, 79%, 43% and 36% of atypical carcinoids (ACs). Based on the proposed IHC scoring system, in the LC cases, where all SSTR subtypes were absent, membrane OR51E1 expression was detected in 10 out of 17 TCs and 1 out of 2 ACs. Moreover, higher OR51E1 scores were detected in 5 out of 6 OctreoScan-negative LC lesions.

    In addition, the last presented study used a novel suspension bead array, which targeted 124 unique proteins, by using Human Protein Atlas antibodies, to profile biotinylated serum samples from SI-NET patients and healthy controls. We showed 9 proteins, IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP as significant contributors to tumor classification.

    In conclusion, we proposed Ma2 autoantibodies as a sensitive circulating marker for SI-NET recurrence; OR51E1 as a candidate therapeutic target for SI-NETs; whereas as a novel diagnostic marker for LCs and 9 serum proteins as novel potential SI-NET markers.

    Delarbeten
    1. Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors
    Öppna denna publikation i ny flik eller fönster >>Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors
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    2010 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, nr 12, s. e16010-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Small intestine neuroendocrine tumors (SI-NETs) belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2) as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs. Methodology/Principal Findings: A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC), to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples. Conclusion: Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA) for the risk of recurrence after radical operation of these tumors.

     

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-140192 (URN)10.1371/journal.pone.0016010 (DOI)000285793600058 ()21209860 (PubMedID)
    Tillgänglig från: 2011-01-04 Skapad: 2011-01-04 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    2. Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas
    Öppna denna publikation i ny flik eller fönster >>Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas
    Visa övriga...
    2013 (Engelska)Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, nr 2, s. 253-261Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVE: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker.

    DESIGN: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor.

    RESULTS: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor.

    CONCLUSION: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

    Nationell ämneskategori
    Cell- och molekylärbiologi Cancer och onkologi Endokrinologi och diabetes Gastroenterologi
    Identifikatorer
    urn:nbn:se:uu:diva-205136 (URN)10.1530/EJE-12-0814 (DOI)000315577400023 ()23184910 (PubMedID)
    Tillgänglig från: 2013-08-14 Skapad: 2013-08-14 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    3. Olfactory Receptor 51E1 as a Novel Target for Diagnosis in Somatostatin Receptor Negative Lung Carcinoids
    Öppna denna publikation i ny flik eller fönster >>Olfactory Receptor 51E1 as a Novel Target for Diagnosis in Somatostatin Receptor Negative Lung Carcinoids
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    2013 (Engelska)Ingår i: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 51, s. 277-286Artikel i tidskrift (Refereegranskat) Published
    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.

    Nyckelord
    Olfactory receptor 51E1, lung carcinoids, novel target for diagnosis, somatostatin receptors, OctreoScan
    Nationell ämneskategori
    Cell- och molekylärbiologi Cancer och onkologi Endokrinologi och diabetes
    Forskningsämne
    Endokrinologi och Diabetologi; Lungmedicin; Molekylärbiologi; Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-205526 (URN)10.1530/JME-13-0144 (DOI)000329207100012 ()23969981 (PubMedID)
    Anmärkning

    De två första författarna delar första författarskapet.

    Tillgänglig från: 2013-08-29 Skapad: 2013-08-19 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    4. Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
    Öppna denna publikation i ny flik eller fönster >>Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 11, s. e81712-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background

    Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.

    Materials and methods

    Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.

    Results

    A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.

    Conclusions

    We propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.

    Nationell ämneskategori
    Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Cell- och molekylärbiologi Cancer och onkologi Endokrinologi och diabetes Gastroenterologi
    Forskningsämne
    Endokrinologi och Diabetologi; Molekylärbiologi; Molekylär bioteknik; Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-205549 (URN)10.1371/journal.pone.0081712 (DOI)000327543500120 ()
    Tillgänglig från: 2013-08-29 Skapad: 2013-08-19 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
  • 152.
    Cui, Tao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tsolakis, Apostolos V
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Cunningham, Janet L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Lind, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas2013Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, nr 2, s. 253-261Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker.

    DESIGN: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor.

    RESULTS: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor.

    CONCLUSION: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

  • 153.
    Cunha, D. A.
    et al.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Molkentin, J. D.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA..
    Bugliani, M.
    Univ Pisa, Dept Endocrinol & Metab, I-56100 Pisa, Italy..
    Marchetti, P.
    Univ Pisa, Dept Endocrinol & Metab, I-56100 Pisa, Italy..
    Eizirik, D. L.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Cnop, M.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Thrombospondin 1: a master regulator of the anti-oxidant defence in pancreatic beta cells2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S46-S46Artikel i tidskrift (Övrigt vetenskapligt)
  • 154. da Silva Xavier, Gabriela
    et al.
    Loder, Merewyn K
    McDonald, Angela
    Tarasov, Andrei I
    Carzaniga, Raffaella
    Kronenberger, Katrin
    Barg, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Rutter, Guy A
    TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells2009Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, nr 4, s. 894-905Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE:

    Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature beta-cell function and suggest a potential mechanism for its actions.

    RESEARCH DESIGN AND METHODS:

    TCF7L2 expression in rodent islets and beta-cell lines was altered using RNAi or adenoviral transduction. Beta-cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology.

    RESULTS:

    Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18–1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion.

    CONCLUSION:

    TCF7L2 is involved in maintaining expression of beta-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles.

  • 155. Dahl, A. K.
    et al.
    Reynolds, C. A.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Magnusson, P. K. E.
    Pedersen, N. L.
    Multifactorial analysis of changes in body mass index across the adult life course: a study with 65 years of follow-up2014Ingår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 38, nr 8, s. 1133-1141Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Although the negative consequences on health of being obese are well known, most adults gain weight across the lifespan. The general increase in body mass index (BMI) is mainly considered to originate from behavioral and environmental changes; however, few studies have evaluated the influence of these factors on change in BMI in the presence of genetic risk. We aimed to study the influence of multifactorial causes of change in BMI, over 65 years. METHODS AND FINDINGS: Totally, 6130 participants from TwinGene, who had up to five assessments, and 536 from the Swedish Adoption/Twin Study of Aging, who had up to 12 assessments, ranging over 65 years were included. The influence of lifestyle factors, birth cohort, cardiometabolic diseases and an individual obesity genetic risk score (OGRS) based on 32 single nucleotide polymorphisms on change in BMI was evaluated with a growth model. For both sexes, BMI increased from early adulthood to age of 65 years, after which the increase leveled off; BMI declined after age of 80 years. A higher OGRS, birth after 1925 and cardiometabolic diseases were associated with higher average BMI and a steeper increase in BMI prior to 65 years of age. Among men, few factors were identified that influence BMI trajectories in late life, whereas for women type 2 diabetes mellitus and dementia were associated with a steeper decrease in BMI after the age of 65 years. CONCLUSIONS: There are two turning points in BMI in late adulthood, one at the age of 65 years and one at the age 80 years. Factors associated with an increase in BMI in midlife were not associated with an increase in BMI after the age of 65 years. These findings indicate that the causes and consequences of change in BMI differ across the lifespan. Current health recommendations need to be adjusted accordingly.

  • 156.
    Dahlqvist, Per
    et al.
    Umea University.
    Isaksson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet.
    Bensing, Sophie
    Karolinska Institute.
    Is Adrenal Insufficiency a Rare Disease?2016Ingår i: Cortisol Excess And Insufficiency / [ed] Arvat, E; Falorni, A, KARGER , 2016, s. 106-114Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Adrenal insufficiency (AI) is a potentially life-threatening condition and it is of utmost importance to identify and adequately manage affected individuals. Diagnosis is often delayed, probably partly because diseases of the adrenal or pituitary region that cause primary AI (PAI) or central AI are relatively rare conditions. However, iatrogenic AI, i.e. the physiological downregulation of the hypothalamic-pituitary-adrenal axis and adrenal atrophy caused by glucocorticoid treatment for different inflammatory conditions is likely to be considerably more common. The type of glucocorticoid, dose and duration of treatment are factors to consider when trying to predict the risk of developing symptoms of AI. However, the considerable individual variation in the sensitivity for developing iatrogenic AI impedes prediction. In industrialized countries, autoimmune adrenalitis accounts for the majority of cases of PAI. Among children, genetic conditions - in particular congenital adrenal hyperplasia - need to be considered. Important risk groups for central AI are patients with tumours in the hypothalamic-pituitary region, moderate-to-severe traumatic head injury and patients who receive cranial radiotherapy or cytotoxic T-lymphocyte antigen 4 blockade treatment. Structured endocrine follow-up is essential in these groups. Health workers need to be attentive to these potentially fatal conditions and at-risk populations should be carefully informed about symptoms and signs of AI.

  • 157.
    Dalin, Frida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Nordling Eriksson, Gabriel
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Hallgren, Åsa
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Wahlberg, Jeanette
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Fac Hlth Sci, SE-58183 Linkoping, Sweden.
    Ekwall, Olov
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Söderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Olcén, Per
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Winqvist, Ola
    Karolinska Inst, Karolinska Univ Hosp, Translat Immunol, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Kriström, Berit
    Umea Univ, Inst Clin Sci, Pediat, SE-90736 Umea, Sweden.
    Laudius, Maria
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Isaksson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet.
    Halldin Stenlid, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Pediatrisk inflammationsforskning.
    Gustafsson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Pediatrisk inflammationsforskning.
    Gebre-Medhin, Gennet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Pediatrisk inflammationsforskning.
    Björnsdottir, Sigridur
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Janson, Annika
    Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden.
    Åkerman, Anna-Karin
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Åman, Jan
    Univ Orebro, Dept Pediat, Fac Med & Hlth, SE-70281 Orebro, Sweden.
    Duchen, Karel
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Bergthorsdottir, Ragnhildur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Lindskog, Emma
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, SE-40530 Gothenburg, Sweden.
    Landin-Olsson, Mona
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Elfving, Maria
    Lund Univ, Dept Pediat, Pediat Endocrinol, Clin Sci, SE-22362 Lund, Sweden.
    Waldenström, Erik
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study2017Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, nr 2, s. 379-389Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

    OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

    DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

    MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

    RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

    CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

  • 158.
    Dam, G.
    et al.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Grønbæk, H.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Sørbye, H.
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Thiis-Evensen, E.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Transplantat Med, Neuroendocrine Tumor Ctr Excellence, Oslo, Norway.
    Paulsson, B.
    Novartis Sverige AB, Täby, Sweden.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Jensen, C.
    Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Radiol, Copenhagen, Denmark.
    Ebbesen, D.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Radiol, Aarhus, Denmark.
    Knigge, U.
    Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Endocrinol, Copenhagen, Denmark.;Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Surg Gastroenterol, Copenhagen, Denmark.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    A Prospective Nordic Study on the Use of Chromogranin A for the Prediction of Progression in Patients with Pancreatic and Small Intestinal Neuroendocrine Tumors2018Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, nr Supplement: 1, s. 152-152Artikel i tidskrift (Övrigt vetenskapligt)
  • 159. Danaei, Goodarz
    et al.
    Fahimi, Saman
    Lu, Yuan
    Zhou, Bin
    Hajifathalian, Kaveh
    Di Cesare, Mariachiara
    Lo, Wei-Cheng
    Reis-Santos, Barbara
    Cowan, Melanie J.
    Shaw, Jonathan E.
    Bentham, James
    Lin, John K.
    Bixby, Honor
    Magliano, Dianna
    Bovet, Pascal
    Miranda, J. Jaime
    Khang, Young-Ho
    Stevens, Gretchen A.
    Riley, Leanne M.
    Ali, Mohammed K.
    Ezzati, Majid
    Abdeen, Ziad A.
    Kadir, Khalid Abdul
    Abu-Rmeileh, Niveen M.
    Acosta-Cazares, Benjamin
    Aekplakorn, Wichai
    Aguilar-Salinas, Carlos A.
    Ahmadvand, Alireza
    Al Nsour, Mohannad
    Alkerwi, Ala'a
    Amouyel, Philippe
    Andersen, Lars Bo
    Anderssen, Sigmund A.
    Andrade, Dolores S.
    Anjana, Ranjit Mohan
    Aounallah-Skhiri, Hajer
    Aris, Tahir
    Arlappa, Nimmathota
    Arveiler, Dominique
    Assah, Felix K.
    Avdicova, Maria
    Balakrishna, Nagalla
    Bandosz, Piotr
    Barbagallo, Carlo M.
    Barcelo, Alberto
    Batieha, Anwar M.
    Baur, Louise A.
    Ben Romdhane, Habiba
    Bernabe-Ortiz, Antonio
    Bhargava, Santosh K.
    Bi, Yufang
    Bjerregaard, Peter
    Bjorkelund, Cecilia
    Blake, Margaret
    Blokstra, Anneke
    Bo, Simona
    Boehm, Bernhard O.
    Boissonnet, Carlos P.
    Brajkovich, Imperia
    Breckenkamp, Juergen
    Brewster, Lizzy M.
    Brian, Garry R.
    Bruno, Graziella
    Bugge, Anna
    de Leon, Antonio Cabrera
    Can, Gunay
    Candido, Ana Paula C.
    Capuano, Vincenzo
    Carvalho, Maria J.
    Casanueva, Felipe F.
    Caserta, Carmelo A.
    Castetbon, Katia
    Chamukuttan, Snehalatha
    Chaturvedi, Nishi
    Chen, Chien-Jen
    Chen, Fangfang
    Chen, Shuohua
    Cheng, Ching-Yu
    Chetrit, Angela
    Chiou, Shu-Ti
    Cho, Yumi
    Chudek, Jerzy
    Cifkova, Renata
    Claessens, Frank
    Concin, Hans
    Cooper, Cyrus
    Cooper, Rachel
    Costanzo, Simona
    Cottel, Dominique
    Cowell, Chris
    Crujeiras, Ana B.
    D'Arrigo, Graziella
    Dallongeville, Jean
    Dankner, Rachel
    Dauchet, Luc
    de Gaetano, Giovanni
    De Henauw, Stefaan
    Deepa, Mohan
    Dehghan, Abbas
    Dhana, Klodian
    Di Castelnuovo, Augusto F.
    Djalalinia, Shirin
    Doua, Kouamelan
    Drygas, Wojciech
    Du, Yong
    Egbagbe, Eruke E.
    Eggertsen, Robert
    El Ati, Jalila
    Elosua, Roberto
    Erasmus, Rajiv T.
    Erem, Cihangir
    Ergor, Gul
    Eriksen, Louise
    la Penaa, Jorge Escobedo-De
    Fall, Caroline H.
    Farzadfar, Farshad
    Felix-Redondo, Francisco J.
    Ferguson, Trevor S.
    Fernandez-Berges, Daniel
    Ferrari, Marika
    Ferreccio, Catterina
    Finn, Joseph D.
    Foger, Bernhard
    Foo, Leng Huat
    Fouad, Heba M.
    Francis, Damian K.
    Franco, Maria do Carmo
    Franco, Oscar H.
    Frontera, Guillermo
    Furusawa, Takuro
    Gaciong, Zbigniew
    Galbarczyk, Andrzej
    Garnett, Sarah P.
    Gaspoz, Jean-Michel
    Gasull, Magda
    Gates, Louise
    Geleijnse, Johanna M.
    Ghasemain, Anoosheh
    Giampaoli, Simona
    Gianfagna, Francesco
    Giovannelli, Jonathan
    Gross, Marcela Gonzalez
    Rivas, Juan P. Gonzalez
    Gorbea, Mariano Bonet
    Gottrand, Frederic
    Grant, Janet F.
    Grodzicki, Tomasz
    Grontved, Anders
    Gruden, Grabriella
    Gu, Dongfeng
    Guan, Ong Peng
    Guerrero, Ramiro
    Guessous, Idris
    Guimaraes, Andre L.
    Gutierrez, Laura
    Hardy, Rebecca
    Kumar, Rachakulla Hari
    He, Jiang
    Heidemann, Christin
    Hihtaniemi, Ilpo Tapani
    Ho, Sai Yin
    Ho, Suzanne C.
    Hofman, Albert
    Russo, Andrea R. V.
    Hormiga, Claudia M.
    Horta, Bernardo L.
    Houti, Leila
    Hussieni, Abdullatif S.
    Huybrechts, Inge
    Hwalla, Nahla
    Iacoviello, Licia
    Iannone, Anna G.
    Ibrahim, Mohsen M.
    Ikeda, Nayu
    Ikram, M. Arfan
    Irazola, Vilma E.
    Islam, Muhammad
    Iwasaki, Masanori
    Jacobs, Jeremy M.
    Jafar, Tazeen
    Jasienska, Grazyna
    Jiang, Chao Qiang
    Jonas, Jost B.
    Joshi, Pradeep
    Kafatos, Anthony
    Kalter-Leibovici, Ofra
    Kasaeian, Amir
    Katz, Joanne
    Kaur, Prabhdeep
    Kavousi, Maryam
    Kelishadi, Roya
    Kengne, Andre P.
    Kersting, Mathilde
    Khader, Yousef Saleh
    Kiechl, Stefan
    Kim, Jeongseon
    Kiyohara, Yutaka
    Kolsteren, Patrick
    Korrovits, Paul
    Koskinen, Seppo
    Kratzer, Wolfgang
    Kromhout, Daan
    Kula, Krzysztof
    Kurjata, Pawel
    Kyobutungi, Catherine
    Lachat, Carl
    Laid, Youcef
    Lam, Tai Hing
    Landrove, Orlando
    Lanska, Vera
    Lappas, Georg
    Laxmaiah, Avula
    Leclercq, Catherine
    Lee, Jeannette
    Lee, Jeonghee
    Lehtimaki, Terho
    Lekhraj, Rampal
    Leon-Munoz, Luz M.
    Li, Yanping
    Lim, Wei-Yen
    Lima-Costa, M. Fernanda
    Lin, Hsien-Ho
    Lin, Xu
    Lissner, Lauren
    Lorbeer, Roberto
    Lozano, Jose Eugenio
    Lundqvist, Annamari
    Lytsy, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Socialmedicin.
    Ma, Guansheng
    Machado-Coelho, George L. L.
    Machi, Suka
    Maggi, Stefania
    Makdisse, Marcia
    Rao, Kodavanti Mallikharjuna
    Manios, Yannis
    Manzato, Enzo
    Margozzini, Paula
    Marques-Vidal, Pedro
    Martorell, Reynaldo
    Masoodi, Shariq R.
    Matsha, Tandi E.
    Mbanya, Jean Claude N.
    McFarlane, Shelly R.
    McGarvey, Stephen T.
    McLachlan, Stela
    McNulty, Breige A.
    Mediene-Benchekor, Sounnia
    Meirhaeghe, Aline
    Menezes, Ana Maria B.
    Merat, Shahin
    Meshram, Indrapal I.
    Mi, Jie
    Miquel, Juan Francisco
    Mohamed, Mostafa K.
    Mohammad, Kazem
    Mohan, Viswanathan
    Yusoff, Muhammad Fadhli Mohd
    Moller, Niels C.
    Molnar, Denes
    Mondo, Charles K.
    Moreno, Luis A.
    Morgan, Karen
    Moschonis, George
    Mossakowska, Malgorzata
    Mostafa, Aya
    Mota, Jorge
    Muiesan, Maria L.
    Muller-Nurasyid, Martina
    Mursu, Jaakko
    Nagel, Gabriele
    Namesna, Jana
    Nang, Ei Ei K.
    Nangia, Vinay B.
    Navarrete-Munoz, Eva Maria
    Ndiaye, Ndeye Coumba
    Nervi, Flavio
    Nguyen, Nguyen D.
    Nieto-Martinez, Ramfi S. E.
    Ning, Guang
    Ninomiya, Toshiharu
    Noale, Marianna
    Noto, Davide
    Ochoa-Aviles, Angelica M.
    Oh, Kyungwon
    Onat, Altan
    Osmond, Clive
    Otero, Johanna A.
    Palmieri, Luigi
    Panda-Jonas, Songhomitra
    Panza, Francesco
    Parsaeian, Mahboubeh
    Peixoto, Sergio Viana
    Pereira, Alexandre C.
    Peters, Annette
    Peykari, Niloofar
    Pilav, Aida
    Pitakaka, Freda
    Piwonska, Aleksandra
    Piwonski, Jerzy
    Plans-Rubio, Pedro
    Porta, Miquel
    Portegies, Marileen L. P.
    Poustchi, Hossein
    Pradeepa, Rajendra
    Price, Jacqueline F.
    Punab, Margus
    Qasrawi, Radwan F.
    Qorbani, Mostafa
    Raitakari, Olli
    Rao, Sudha Ramachandra
    Ramachandran, Ambady
    Ramos, Rafel
    Rampal, Sanjay
    Rathmann, Wolfgang
    Redon, Josep
    Reganit, Paul Ferdinand M.
    Rigo, Fernando
    Robinson, Sian M.
    Robitaille, Cynthia
    Rodriguez, Laura A.
    Rodriguez-Artalejo, Fernando
    Rodriguez-Perez, Maria del Cristo
    Rojas-Martinez, Rosalba
    Romaguera, Dora
    Rosengren, Annika
    Rubinstein, Adolfo
    Rui, Ornelas
    Ruiz-Betancourt, Blanca Sandra
    Rutkowski, Marcin
    Sabanayagam, Charumathi
    Sachdev, Harshpal S.
    Saidi, Olfa
    Sakarya, Sibel
    Salanave, Benoit
    Salonen, Jukka T.
    Salvetti, Massimo
    Sanchez-Abanto, Jose
    Nunes, Renata
    Santos, Rute
    Sardinha, Luis B.
    Scazufca, Marcia
    Schargrodsky, Herman
    Scheidt-Nave, Christa
    Shibuya, Kenji
    Shin, Youchan
    Shiri, Rahman
    Siantar, Rosalynn
    Sibai, Abla M.
    Simon, Mary
    Simons, Judith
    Simons, Leon A.
    Sjostrom, Michael
    Slowikowska-Hilczer, Jolanta
    Slusarczyk, Przemyslaw
    Smeeth, Liam
    Snijder, Marieke B.
    Solfrizzi, Vincenzo
    Sonestedt, Emily
    Soumare, Aicha
    Staessen, Jan A.
    Steene-Johannessen, Jostein
    Stehle, Peter
    Stein, Aryeh D.
    Stessman, Jochanan
    Stockl, Doris
    Stokwiszewski, Jakub
    Strufaldi, Maria Wany
    Sun, Chien-An
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Suriyawongpaisal, Paibul
    Sy, Rody G.
    Tai, E. Shyong
    Tarawneh, Mohammed
    Tarqui-Mamani, Carolina B.
    Thijs, Lutgarde
    Tolstrup, Janne S.
    Topbas, Murat
    Torrent, Maties
    Traissac, Pierre
    Trinh, Oanh T. H.
    Tulloch-Reid, Marshall K.
    Tuomainen, Tomi-Pekka
    Turley, Maria L.
    Tzourio, Christophe
    Ueda, Peter
    Ukoli, Flora M.
    Ulmer, Hanno
    Valdivia, Gonzalo
    Van Valkengoed, Irene G. M.
    Vanderschueren, Dirk
    Vanuzzo, Diego
    Vega, Tomas
    Velasquez-Melendez, Gustavo
    Veronesi, Giovanni
    Verschuren, Monique
    Vioque, Jesus
    Virtanen, Jyrki
    Visvikis-Siest, Sophie
    Viswanathan, Bharathi
    Vollenweider, Peter
    Voutilainen, Sari
    Wade, Alisha N.
    Wagner, Aline
    Walton, Janette
    Mohamud, Wan Nazaimoon Wan
    Wang, Ming-Dong
    Wang, Ya Xing
    Wannamethee, S. Goya
    Weerasekera, Deepa
    Whincup, Peter H.
    Widhalm, Kurt
    Wiecek, Andrzej
    Wilks, Rainford J.
    Willeit, Johann
    Wojtyniak, Bogdan
    Wong, Tien Yin
    Woo, Jean
    Woodward, Mark
    Wu, Aleksander Giwercman
    Wu, Frederick C.
    Wu, Shou Ling
    Xu, Haiquan
    Yang, Xiaoguang
    Ye, Xingwang
    Yoshihara, Akihiro
    Younger-Coleman, Novie O.
    Zambon, Sabina
    Zargar, Abdul Hamid
    Zdrojewski, Tomasz
    Zhao, Wenhua
    Zheng, Yingfeng
    Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331288 participants2015Ingår i: LANCET DIABETES & ENDOCRINOLOGY, ISSN 2213-8587, Vol. 3, nr 8, s. 624-637Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA(1c). We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. Methods We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA(1c) (HbA(1c) >= 6 . 5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG >= 7 . 0 mmol/L or 2hOGTT >= 11 . 1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Findings Population prevalence of diabetes based on FPG- or-2hOGTT was correlated with prevalence based on FPG alone (r= 0 . 98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA(1c) was lower than prevalence based on FPG in 42 . 8% of age-sex-survey groups and higher in another 41 . 6%; in the other 15 . 6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA(1c)-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA(1c) 6 . 5% or more had a pooled sensitivity of 52 . 8% (95% CI 51 . 3-54 . 3%) and a pooled specificity of 99 . 74% (99 . 71-99 . 78%) compared with FPG 7 . 0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30 . 5% (28 . 7-32 . 3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA(1c) versus FPG. Interpretation Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA(1c)-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test.

  • 160.
    Darmanis, Spyros
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cui, Tao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Drobin, Kimi
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Schwenk, Jochen M.
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Giandomenico, Valeria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 11, s. e81712-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.

    Materials and methods

    Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.

    Results

    A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.

    Conclusions

    We propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.

  • 161.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Alexandraki, Krystallenia
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Kassi, Evanthia
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece;Univ Athens, Sch Med, Dept Biol Chem, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Angelousi, Anna
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Ragkousi, Athanasia
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Kaltsas, Gregory
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece;Univ Warwick, Clin Sci Res Labs, Warwick Med Sch, Univ Hosp, Coventry, W Midlands, England;Coventry Univ, Ctr Appl Biol & Exercise Sci, Fac Hlth & Life Sci, Coventry, W Midlands, England.
    The risk of lymph node metastases and their impact on survival in patients with appendiceal neuroendocrine neoplasms: a systematic review and meta-analysis of adult and paediatric patients2019Ingår i: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background There are no clear histopathological parameters determining the risk of lymph node (LN) metastases and appropriateness of completion prophylactic right hemicolectomy (RHC) in patients with appendiceal neuroendocrine neoplasms (ANENs). Materials and methods The PubMed, Cochrane Library, Embase, Web of Science and SCOPUS databases were searched up to November 2018. Quality/risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). Results A total of 526 articles were screened. In 11 adult and 3 paediatric studies, 602 and 77 unique patients, respectively, with ANEN and undergoing RHC, were included. The rate of LN metastases for a cutoff size >10 mm was 48.6% (vs 12.1% for lesions <10 mm) among adult patients, with an odds ratio (OR) of 4.8 (95% CI, 1.5-15.8). For 20 mm size cutoff, these figures were 61% (vs 28.2% for lesions <20 mm) with an OR of 3.2 (95% CI, 1.3-7.8). Vascular-, lymph vessel- and perineural invasions were identified as predictive factors for LN metastases in adult patients. In paediatric patients, there were no strong morphological predictors for LN metastases. The 10-year disease-specific survival (DSS) for adult patients without LN metastases was 99.2% vs 95.6% in patients with LN (OR: 0.2; 95% CI, 0.02-2.4). The complication rate of prophylactic RHC was 11.4%. Conclusions This meta-analysis demonstrates that tumour size >20 mm as well as >10 mm and/or vascular-, lymph vessel- and perineural invasions are associated with increased risk for LN metastases in adult patients with ANEN. The prognostic value of LN positivity remains to be determined in further studies with long-term follow-up.

  • 162.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Chatzelis, Eleftherios
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece;251 Hellen Air Force & VA Gen Hosp, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Papadopoulou-Marketou, Nektaria
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Linkoping, Sweden.
    Dimitriadis, Georgios K.
    Univ Hosp Coventry & Warwickshire NHS Trust, Arden Net CoE & Human Metab Res Unit HMRU, WISDEM, Coventry CV2 2DX, W Midlands, England.
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Univ Hosp Solna, CCK, R8 04, Stockholm, Sweden.
    Kaltsas, Gregory
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Endocrine paraneoplastic syndromes in patients with neuroendocrine neoplasms2019Ingår i: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 64, nr 2, s. 384-392Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Our aim was to assess the prevalence of endocrine paraneoplastic syndromes (EPNS) in neuroendocrine neoplasms (NENs) and estimate its impact on patient outcomes.

    Design: This is a retrospective analysis of 834 patients with NENs (611 gastrointestinal, 166 thoracic, 57 of unknown and various other primary origin). We included 719 consecutive NEN patients treated at EKPA-Laiko Hospital, Athens, Greece and 115 patients with lung carcinoid (LC) treated at Uppsala University Hospital, Uppsala, Sweden. EPNS diagnosis was based on standard criteria.

    Methods: Twenty-one patients with EPNS were detected: 16 with ectopic Cushing's syndrome (ECS), one with hypercalcaemia due to parathyroid hormone-related protein (PTHrP) secretion, three with hypercalcitonaemia and one patient with dual secretion of calcitonin and beta-human chorionic gonadotropin (-HCG). All tumours were well-differentiated; 10 patients had Stage IV disease at diagnosis.

    Results: The prevalence of EPNS in the Greek cohort was 1.9%, whereas that of ECS among LC patients in both centres was 6.7%. Median overall survival (OS) for patients with EPNS was 160.7 months (95%CI, 86-235.4) and median event-free survival (EFS) was 25.9 months (95%CI, 0-57.2). Patients presenting with EPNS prior to NEN diagnosis had longer EFS compared to patients with synchronous or metachronous EPNS (log-rank P=0.013). Patients with ECS of extra-thoracic origin demonstrated shorter OS and EFS compared to patients with ECS of lung or thymic origin (log-rank P=0.001 and P<0.001, respectively). LC patients with and without ECS were comparable in 5-year and 10-year OS rates (66.7% and 33.3% versus 89.8% and 60.2%, respectively; 95%CI [189.6-300.4 months], log-rank P=0.94) and in median EFS, 67 versus 183 months, 95%CI [50.5-207.5], log-rank P=0.12).

    Conclusion: EPNS are relatively rare in patients with NENs and mainly concern well-differentiated tumours of the foregut. Among patients with EPNS, LC-related ECS may not adversely affect patient outcomes when diagnosed prior to NEN and effectively been treated.

  • 163.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Edfeldt, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Norlén, Olov
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Karakatsanis, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin Onkologi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Midkine Is a New Novel Serum Biomarker in Small Intestinal Neuroendocrine Tumors (SI-NETs)2016Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, s. 45-45Artikel i tidskrift (Refereegranskat)
  • 164.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Norlén, Olov
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Karakatsanis, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Ex Vivo Activity of Cytotoxic Drugs and Targeted Agents in Small Intestinal Neuroendocrine Tumors2018Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, nr Supplement: 1, s. 189-189Artikel i tidskrift (Övrigt vetenskapligt)
  • 165.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Karapanagioti, Angeliki
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Chrysochoou, Maria
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Thomas, Dimitrios
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Sougioultzis, Stavros
    Univ Athens, Laikon Univ Hosp, Dept Pathophysiol, Gastroenterol Div, Athens, Greece.
    Karoumpalis, Loannis
    G Gennimatas Gen Hosp, Dept Gastroenterol, Athens, Greece.
    Kaltsas, Gregory A.
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Alexandraki, Krystallenia, I
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Athens, Greece.
    Recurrence and metastatic potential in Type 1 gastric neuroendocrine neoplasms2019Ingår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 91, nr 4, s. 534-543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The aim of our study was to assess clinico-pathological and biochemical parameters of Type 1 Gastric Neuroendocrine Neoplasms (GNEN1) with respect to tumours propensity for recurrence and metastasis. Methods Hospital charts of GNEN1 patients were reviewed at a single tertiary referral centre. Results We included 114 consecutive patients (74 women; age at baseline 54.5 +/- 12.7 years [mean +/- SD]) with GNEN1. All tumours (n = 114) were well differentiated; Grade 1 (G1) accounted for 56 patients (49%), whereas 46 (40%) were Grade 2 (G2) and 12 (11%) of unknown Grade. Overall follow-up encompassed 45.3 +/- 46 (mean +/- SD) months in 84 patients who were subjected to annual surveillance; 44 (52%) developed recurrence in the stomach during follow-up with 22 experiencing multiple recurrences; three (2.6%) presented with metastases in locoregional lymph nodes (n = 3) and/or the liver (n = 2); No metastasis or death was reported during follow-up. Median recurrence-free survival (RFS) was 31 months (95% CI: 7.6-54.4). Among clinico-pathological and biochemical parameters investigated, endoscopic intervention compared with surgery (P-value = .009) and higher serum-gastrin levels (s-gastrin) at baseline and first-year follow-up were associated with recurrence (P-value = .022 and .003 respectively) and also shorter RFS (log-rank P = .009 for type of intervention and .014 for s-gastrin, respectively). Receiver Operator Curve analysis of s-gastrin levels at first-year follow-up for recurrence demonstrated an area under the curve of 0.702. Conclusion Despite the relatively high prevalence of G2 tumours, endoscopically and/or surgically treated GNEN1 remains an indolent disease with a low metastatic propensity and no disease-specific mortality reported in our series. Many patients though will experience local recurrence, warranting long-term endoscopic surveillance with s-gastrin biomarker being a complementary tool in recurrence prediction.

  • 166.
    Daskalakis, Kosmas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Srirajaskanthan, Raj
    Kings Coll Hosp London, Neuroendocrine Tumour Unit, Kings Coll Hosp, KHP ENETS Ctr Excellence,Dept Gastroenterol, London SE5 9RS, England.
    Chatzellis, Eleftherios
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Alexandraki, Krystallenia
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Angelousi, Anna
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Pizanias, Michail
    Kings Coll Hosp London, Dept Liver Transplantat, Inst Liver Studies,Hepatobiliary Pancreat Surg, Kings Healthcare Partners,NHS FT, Denmark Hill, London, England.
    Randeva, Harpal
    Univ Warwick, Warwick Med Sch, Clin Sci Res Labs, Univ Hosp, Coventry, W Midlands, England;Coventry Univ, Ctr Appl Biol & Exercise Sci, Fac Hlth & Life Sci, Coventry, W Midlands, England.
    Kaltsas, Gregory
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece;Univ Warwick, Warwick Med Sch, Clin Sci Res Labs, Univ Hosp, Coventry, W Midlands, England;Coventry Univ, Ctr Appl Biol & Exercise Sci, Fac Hlth & Life Sci, Coventry, W Midlands, England.
    Weickert, Martin O.
    Univ Hosp Coventry & Warwickshire NHS Trust, ARDEN NET Ctr, European Neuroendocrine Tumour Soc ENETS, Ctr Excellence CoE, Coventry, W Midlands, England;Univ Warwick, Warwick Med Sch, Clin Sci Res Labs, Univ Hosp, Coventry, W Midlands, England;Coventry Univ, Ctr Appl Biol & Exercise Sci, Fac Hlth & Life Sci, Coventry, W Midlands, England.
    Lung Metastases in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Neoplasms: An Appraisal of the Validity of Thoracic Imaging Surveillance2019Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, nr 4, s. 308-316Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Aims: To evaluate the impact of lung metastases (LM) on overall survival (OS) in well-differentiated (WD) stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) patients along with developing surveillance strategies for thoracic imaging. Methods: Thirty-four patients with LM, from 3 centres, were identified (22 small intestine/12 pancreatic; 17 grade 1/15 grade 2/2 of unknown grade). For comparison, we used 106 stage IV WD, grade 1 and 2 GEP-NEN patients with metastatic disease confined in the abdomen. Results: LM prevalence was 4.9% (34/692). Eleven patients (32%) presented with synchronous LM whereas 23 (68%) developed metachronous LM at a median of 25 months (range 1-150 months). Patients with metachronous LM had already established liver and/or para-aortic lymph node metastases. Eighteen of 23 patients (78%) with metachronous LM exhibited concomitant progression in the abdomen. Median OS of WD GEP-NEN patients with LM was shorter than for those with stage IV disease without extra-abdominal metastases (56 [95% CI 40.6-71.6] vs. 122.7 [95% CI 70.7-174.8] months; log-rank p = 0.001). Among patients with progressive stage IV disease, the subset of patients with LM exhibited shorter OS (log-rank p = 0.005). LM were also confirmed as an independent prognostic factor for survival in multivariable analysis (HR 0.18; 95% CI 0.07-0.45; p< 0.0001). Conclusion: LM, although relatively rare in patients with WD stage IV GEP-NENs, may impact patients' outcome. The development of metachronous LM is associated with concomitant disease progression in established abdominal metastases in most patients. These patient-related parameters could be utilized for a stratified surveillance approach, mainly reserving thoracic imaging for GEP-NEN patients with progressive disease in the abdomen.

  • 167.
    De Felice, Fernanda G.
    et al.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo Meis, Rio De Janeiro, Brazil.;DOr Inst Res & Educ, Rio De Janeiro, Brazil.;Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada..
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    A Key Role of Insulin Receptors in Memory2015Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 11, s. 3653-3655Artikel i tidskrift (Övrigt vetenskapligt)
  • 168.
    Decker, Ralph
    et al.
    Univ Gothenburg, Gothenburg Pediat Growth Res Ctr, Dept Pediat, Inst Clin Sci,Sahlgrenska Acad, S-41685 Gothenburg, Sweden;MVZ Praxis Chilehaus Pediat Endocrinol Androl Int, D-20095 Hamburg, Germany.
    Albertsson-Wikland, Kerstin
    Univ Gothenburg, Dept Physiol Endocrinol, Inst Neurosci & Physiol, Sahlgrenska Acad, S-41685 Gothenburg, Sweden.
    Kriström, Berit
    Umea Univ, Dept Pediat, Inst Clin Sci, S-90187 Umea, Sweden.
    Halldin, Maria
    Karolinska Inst, Dept Womens & Childrens Hlth, Div Pediat Endocrinol, S-17177 Stockholm, Sweden.
    Gustafsson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnendokrinologisk forskning.
    Nilsson, Nils-Östen
    Halland Hosp, Dept Pediat, S-30233 Halmstad, Sweden.
    Dahlgren, Jovanna
    Univ Gothenburg, Gothenburg Pediat Growth Res Ctr, Dept Pediat, Inst Clin Sci,Sahlgrenska Acad, S-41685 Gothenburg, Sweden.
    GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children2019Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, nr 3, s. 835-844Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period.

    Objective: To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period.

    Design and Settings: Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non-GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 μg/kg/d (GHFIX)].

    Main Outcome Measures: The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUID and GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose.

    Results: For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was -0.75 ± 1.0 at 3 months (P = 0.003) and -0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02).

    Conclusions: Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ± 2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.

  • 169.
    Delle Fave, G.
    et al.
    Osped St Andrea, Dept Digest & Liver Dis, Rome, Italy.;Univ Roma La Sapienza, Dept Digest & Liver Dis, Via Grottarossa 1035, IT-00189 Rome, Italy..
    O'Toole, D.
    St Vincents Univ, NET Ctr, Dublin, Ireland.;St James Hosp, Dept Clin Med, Dublin 8, Ireland.;Univ Dublin Trinity Coll, Dublin 2, Ireland..
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Taal, B.
    Netherlands Canc Ctr, Lijnden, Netherlands..
    Ferolla, P.
    Univ Perugia, Umbria Reg Canc Network, NET Ctr, I-06100 Perugia, Italy..
    Ramage, J. K.
    Hampshire Hosp NHS Trust, Dept Gastroenterol, Winchester, Hants, England..
    Ferone, D.
    Univ Genoa, Dept Endocrine & Metab Sci, Genoa, Italy..
    Ito, T.
    Kyushu Univ Hosp, Pancreat Dis Branch, Fukuoka 812, Japan..
    Weber, W.
    Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Zheng-Pei, Z.
    Beijing Union Med Coll Hosp, Dept Endocrinol, Beijing, Peoples R China..
    De Herder, W. W.
    Erasmus MC, Div Endocrinol, Dept Internal Med, Rotterdam, Netherlands..
    Pascher, A.
    Charite, Dept Visceral & Transplant Surg, Campus Virchow Klinikum, D-13353 Berlin, Germany..
    Ruszniewski, P.
    Beaujon Hosp, Dept Gastroenterol, Clichy, France..
    ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms2016Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, nr 2, s. 119-124Artikel i tidskrift (Refereegranskat)
  • 170. Denison, H
    et al.
    Nilsson, C
    Löfgren, L
    Himmelmann, A
    Mårtensson, G
    Knutsson, M
    Al-Shurbaji, A
    Tornqvist, H
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial2014Ingår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, nr 4, s. 334-343Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM:

    Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.

    METHODS:

    Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 hours after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.

    RESULTS:

    Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at end of treatment. With AZD7687doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.

    CONCLUSIONS:

    Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

  • 171.
    Derraik, Jose G. B.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand.
    Miles, Harriet L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Chiavaroli, Valentina
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Hofman, Paul L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand.
    Idiopathic short stature and growth hormone sensitivity in prepubertal children2019Ingår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 91, nr 1, s. 110-117Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: We compared growth hormone sensitivity to an insulin-like growth factor I (IGF-I) generation test in children with idiopathic short stature (ISS) and of normal stature (NS) across the birthweight range.

    Methods: Forty-six prepubertal children (~7.1 years) born at term were studied: ISS (n = 23; 74% boys) and NS (n = 23; 57% boys). Children underwent a modified IGF-I generation test with recombinant human growth hormone (rhGH; 0.05 mg/kg/d) over four consecutive days. Hormonal concentrations were measured at baseline and day 5.

    Results: Children with idiopathic short stature were 1.90 SDS lighter (P < 0.0001) but had 4.5% more body fat (P = 0.0007) than NS children. Overall, decreasing birthweight SDS across the normal range (-1.9 to +1.5 SDS) was associated with lower percentage IGF-I response to rhGH stimulation in univariable (r = 0.45; P = 0.002) and multivariable models (β = 24.6; P = 0.006). Plasma IGF-I concentrations rose in both groups with rhGH stimulation (P < 0.0001). GHBP levels (P = 0.002) were suppressed in ISS children (-19%; P = 0.029) but increased among NS children (+18%; P = 0.028), with contrasting responses also observed for leptin and IGFBP-1. Further, the increase in insulin concentrations in response to rhGH stimulation was ~3-fold greater in NS children (142% vs 50%; P = 0.006).

    Conclusions: A progressive decrease in birthweight SDS was associated with a reduction in GH sensitivity in both NS and ISS children. Thus, the lower IGF-I response to rhGH stimulation in association with decreasing birthweight indicates that the ISS children at the lower end of the birthweight spectrum may have partial GH resistance, which may contribute to their poorer growth.

  • 172.
    Diakatou, Evanthia
    et al.
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Alexandraki, Krystallenia I.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Tsolakis, Apostolos V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Kontogeorgos, George
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Chatzellis, Eleftherios
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Leonti, Anastasia
    Alexandra Hosp, Dept Nucl Med, Athens, Greece..
    Kaltsas, Gregory A.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores2015Ingår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, nr 3, s. 420-428Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ContextThe expression of somatostatin (sstr1-5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. ObjectiveTo investigate the co-expression of sstrs, D2R in relation to pre-operative SRSs in NENs. DesignProspective two-centre study. Patients and measurementsWe analysed pre-operative SRS of 60 patients [44 with gastrointestinal (GI) NENs and 16 with lung NENs] and compared SRS results with immunohistochemical (IHC) reactivity for sstr2, sstr3, sstr5 in sample tissues from primary (n=54) and metastatic (n=27) lesions and IHC reactivity for D2R in 23 samples from primary GI-NENs lesions. ResultsSstr2 was the commonest sstr expressed (654%) and was co-expressed with sstr3 and sstr5 in 321% and 247% of the specimens, respectively. In 67 of 81 specimens (827%), there was concordance of sstr2 immunohistochemistry with SRS findings (P<0001). D2R was expressed in only 8 of 23 (348%) GI-NENs while was co-expressed with sstr2 in all cases. SRS grade, as per Krenning scale, was higher in metastatic foci, large-size (>2cm) tumours and GI-NENs, whereas sstr2 intensity was greater in GI compared to lung NENs. SRS grade showed higher correlation with sstr2 (r=06, P<0001) and D2R (r=05, P<0001) IHC intensity scores than tumour size (r=04, P<0001) and sstr3 (r=04, P<0001) intensity score. ConclusionsSstr2 IHC expression and SRS are useful tools for the diagnosis and management of NENs because they display a high concordance. IHC expression of DR2 seems to be of potential clinical significance in GI-NENs tumours.

  • 173.
    Diamanti, Klev
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Integrating multi-omics for type 2 diabetes: Data science and big data towards personalized medicine2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Type 2 diabetes (T2D) is a complex metabolic disease characterized by multi-tissue insulin resistance and failure of the pancreatic β-cells to secrete sufficient amounts of insulin. Cells recruit transcription factors (TF) to specific genomic loci to regulate gene expression that consequently affects the protein and metabolite abundancies. Here we investigated the interplay of transcriptional and translational regulation, and its impact on metabolome and phenome for several insulin-resistant tissues from T2D donors. We implemented computational tools and multi-omics integrative approaches that can facilitate the selection of candidate combinatorial markers for T2D.

    We developed a data-driven approach to identify putative regulatory regions and TF-interaction complexes. The cell-specific sets of regulatory regions were enriched for disease-related single nucleotide polymorphisms (SNPs), highlighting the importance of such loci towards the genomic stability and the regulation of gene expression. We employed a similar principle in a second study where we integrated single nucleus ribonucleic acid sequencing (snRNA-seq) with bulk targeted chromosome-conformation-capture (HiCap) and mass spectrometry (MS) proteomics from liver. We identified a putatively polymorphic site that may contribute to variation in the pharmacogenetics of fluoropyrimidines toxicity for the DPYD gene. Additionally, we found a complex regulatory network between a group of 16 enhancers and the SLC2A2 gene that has been linked to increased risk for hepatocellular carcinoma (HCC). Moreover, three enhancers harbored motif-breaking mutations located in regulatory regions of a cohort of 314 HCC cases, and were candidate contributors to malignancy.

    In a cohort of 43 multi-organ donors we explored the alternating pattern of metabolites among visceral adipose tissue (VAT), pancreatic islets, skeletal muscle, liver and blood serum samples. A large fraction of lysophosphatidylcholines (LPC) decreased in muscle and serum of T2D donors, while a large number of carnitines increased in liver and blood of T2D donors, confirming that changes in metabolites occur in primary tissues, while their alterations in serum consist a secondary event. Next, we associated metabolite abundancies from 42 subjects to glucose uptake, fat content and volume of various organs measured by positron emission tomography/magnetic resonance imaging (PET/MRI). The fat content of the liver was positively associated with the amino acid tyrosine, and negatively associated with LPC(P-16:0). The insulin sensitivity of VAT and subcutaneous adipose tissue was positively associated with several LPCs, while the opposite applied to branch-chained amino acids. Finally, we presented the network visualization of a rule-based machine learning model that predicted non-diabetes and T2D in an “unseen” dataset with 78% accuracy.

    Delarbeten
    1. Maps of context-dependent putative regulatory regions and genomic signal interactions
    Öppna denna publikation i ny flik eller fönster >>Maps of context-dependent putative regulatory regions and genomic signal interactions
    Visa övriga...
    2016 (Engelska)Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, nr 19, s. 9110-9120Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected similar to 144k putative regulatory regions among the human cell-lines, with the majority of them being similar to 300 bp. We found similar to 20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines.

    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-310761 (URN)10.1093/nar/gkw800 (DOI)000388016900012 ()27625394 (PubMedID)
    Forskningsfinansiär
    AstraZenecaVetenskapsrådetDiabetesförbundeteSSENCE - An eScience Collaboration
    Anmärkning

    De två första författarna delar förstaförfattarskapet.

    Tillgänglig från: 2016-12-19 Skapad: 2016-12-19 Senast uppdaterad: 2019-09-22Bibliografiskt granskad
    2. Single Nuclei Transcriptome Analysis of Human Liver with Integration of Proteomics and Capture Hi-C Bulk Tissue Data
    Öppna denna publikation i ny flik eller fönster >>Single Nuclei Transcriptome Analysis of Human Liver with Integration of Proteomics and Capture Hi-C Bulk Tissue Data
    Visa övriga...
    (Engelska)Ingår i: Artikel i tidskrift (Refereegranskat) Submitted
    Abstract [en]

    The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell sub-populations. In this study, we performed snRNA-seq of a liver sample to identify sub-populations of cells based on nuclear transcriptomics. In 4,282 single nuclei we detected on average 1,377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p<0.05) for 7,682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry (MS) proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r=0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidines toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We found a complex regulatory network for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.

    Nyckelord
    multi-omics; snRNA-seq; MS proteomics; TAD; HiCap; liver; DPYD; SLC2A2
    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-393431 (URN)
    Tillgänglig från: 2019-09-21 Skapad: 2019-09-21 Senast uppdaterad: 2019-09-22
    3. Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes
    Öppna denna publikation i ny flik eller fönster >>Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes
    Visa övriga...
    2019 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 9653Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.

    Ort, förlag, år, upplaga, sidor
    NATURE PUBLISHING GROUP, 2019
    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-391017 (URN)10.1038/s41598-019-45906-5 (DOI)000474222900010 ()31273253 (PubMedID)
    Forskningsfinansiär
    AstraZenecaForskningsrådet FormaseSSENCE - An eScience CollaborationDiabetesförbundetStiftelsen familjen Ernfors fond
    Tillgänglig från: 2019-08-21 Skapad: 2019-08-21 Senast uppdaterad: 2019-09-22Bibliografiskt granskad
    4. Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissues
    Öppna denna publikation i ny flik eller fönster >>Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissues
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific alterations is challenging and requires a multi-omics approach. In this study, we aimed at discovering associations of metabolites from subcutaneous adipose tissue (SAT) and plasma with the volume, the fat fraction (FF) and the insulin sensitivity (Ki) of specific tissues using [18F]FDG PET/MRI.

    Materials and Methods: In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body-mass-index (BMI) we calculated associations between parameters of whole-body FDG PET/MRI during clamp and non-targeted metabolomics profiling for SAT and blood plasma. We also used a rule-based classifier to identify a large collection of prevalent patterns of co-dependent metabolites that characterize non-diabetes (ND) and T2D.

    Results: The plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Ki in visceral adipose tissue (VAT) and SAT, was positively associated with several species of lysophospholipids while the opposite applied to branched-chain amino acids (BCAA) and their intermediates. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. On the contrary, bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Finally, we presented a transparent machine-learning model that predicted ND or T2D in “unseen” data with an accuracy of 78%.

    Conclusions: Novel associations of several metabolites from SAT and plasma with the FF, volume and insulin senstivity of various tissues throughout the body were discovered using PET/MRI and a new integrative multi-omics approach. A promising computational model that predicted ND and T2D with high certainty, suggested novel non-linear interdependencies of metabolites.

    Nyckelord
    type 2 diabetes; metabolomics; imiomics; PET/MRI; insulin resistance;
    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-393429 (URN)
    Tillgänglig från: 2019-09-21 Skapad: 2019-09-21 Senast uppdaterad: 2019-09-22
  • 174.
    Diamanti, Klev
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cavalli, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Kumar, Chanchal
    AstraZeneca, R&D BioPharmaceut, Translat Sci & Expt Med, Early Cardiovasc Renal & Metab, Gothenburg, Sweden;Karolinska Inst, AstraZeneca Integrated CardioMetab Ctr KI AZ ICMC, Dept Med, Huddinge, Sweden.
    Skrtic, Stanko
    AstraZeneca AB, Pharmaceut Technol & Dev, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden.
    Grabherr, Manfred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Komorowski, Jan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Wadelius, Claes
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes2019Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 9653Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.

  • 175.
    Diamanti, Klev
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Visvanathar, Robin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Cavalli, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Kumar, Chanchal
    Translational Science & Experimental Medicine, Early Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca; Karolinska Institute/AstraZeneca Integrated CardioMetabolic Centre (KI/AZ ICMC), Department of Medicine.
    Stanko, Stanko
    Pharmaceutical Technology & Development, AstraZeneca AB; Department of Medicine, Sahlgrenska University Hospital, Gothenburg.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wadelius, Claes
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Komorowski, Jan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissuesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific alterations is challenging and requires a multi-omics approach. In this study, we aimed at discovering associations of metabolites from subcutaneous adipose tissue (SAT) and plasma with the volume, the fat fraction (FF) and the insulin sensitivity (Ki) of specific tissues using [18F]FDG PET/MRI.

    Materials and Methods: In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body-mass-index (BMI) we calculated associations between parameters of whole-body FDG PET/MRI during clamp and non-targeted metabolomics profiling for SAT and blood plasma. We also used a rule-based classifier to identify a large collection of prevalent patterns of co-dependent metabolites that characterize non-diabetes (ND) and T2D.

    Results: The plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Ki in visceral adipose tissue (VAT) and SAT, was positively associated with several species of lysophospholipids while the opposite applied to branched-chain amino acids (BCAA) and their intermediates. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. On the contrary, bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Finally, we presented a transparent machine-learning model that predicted ND or T2D in “unseen” data with an accuracy of 78%.

    Conclusions: Novel associations of several metabolites from SAT and plasma with the FF, volume and insulin senstivity of various tissues throughout the body were discovered using PET/MRI and a new integrative multi-omics approach. A promising computational model that predicted ND and T2D with high certainty, suggested novel non-linear interdependencies of metabolites.

  • 176.
    Diderholm, Barbro
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Beardsall, Kathryn
    Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Murgatroyd, Peter
    Addenbrookes Hosp, Wellcome Trust Clin Res Facil, Cambridge, England..
    Lees, Christoph
    Rosie Matern Hosp, Dept Obstet & Gynaecol, Cambridge, England..
    Gustafsson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Dunger, David
    Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Maternal rates of lipolysis and glucose production in late pregnancy are independently related to foetal weight2017Ingår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 87, nr 3, s. 272-278Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Associations between maternal glucose levels and increased foetal growth are well established, and independent relationships with maternal weight, weight gain and insulin resistance are also observed. The relative roles of lipolysis and glucose production in the determination of these observations remain unclear. Design: We examined, through detailed physiological studies, the relationship between maternal late gestational energy substrate production (glucose and glycerol), maternal weight and weight gain, and estimated foetal size in the third trimester. Patients: Twenty-one nulliparous pregnant women, without gestational diabetes (GDM) assessed at 28 weeks with oral glucose tolerance test, were recruited. Measurements: Rates of hepatic glucose production (GPR) and rates of glycerol production (reflecting lipolysis) using [C-13(6)]-glucose and [H-2(5)]-glycerol were measured at 34-36 weeks of gestation. Respiratory quotient was assessed by indirect calorimetry and body composition by measurements of total body water (TBW; (H2O)-O-18) and body density (BODPOD). Foetal weight was estimated from ultrasound measures of biparietal diameter, femoral length and abdominal circumference. Results: At 34-36 weeks, bivariate analyses showed that GPR and lipolysis correlated with estimated foetal weight (r=.71 and .72, respectively) as well as with maternal weight, fat mass and fat-free mass, but not maternal weight gain. In multivariate analyses, rates of both glucose production (r=.42) and lipolysis (r=.47) were independently associated with foetal size explaining 63% of the variance. Conclusions: Both maternal rates of lipolysis and hepatic glucose production in late gestation are strongly related to estimated foetal weight.

  • 177.
    Dillon, J.
    et al.
    Univ Iowa, Iowa City, IA USA.
    Kulke, M.
    Dana Farber Canc Inst, Boston, MA USA.
    Warner, R.
    Icahn Sch Med Mt Sinai, New York, NY USA.
    Bergsland, E.
    Univ Calif San Francisco, San Francisco, CA USA.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    O'Dorisio, T.
    Univ Iowa, Iowa City, IA USA.
    Mckee, C.
    Lexicon Pharmaceut, The Woodlands, TX USA.
    Lapuerta, P.
    Lexicon Pharmaceut, The Woodlands, TX USA.
    Pavel, M.
    Friedrich Alexander Univ, Erlangen, Germany.
    Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Two Phase 3 Studies in Carcinoid Syndrome2018Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, nr Supplement: 1, s. 224-224Artikel i tidskrift (Övrigt vetenskapligt)
  • 178. Dimas, Antigone S.
    et al.
    Lagou, Vasiliki
    Barker, Adam
    Knowles, Joshua W.
    Maegi, Reedik
    Hivert, Marie-France
    Benazzo, Andrea
    Rybin, Denis
    Jackson, Anne U.
    Stringham, Heather M.
    Song, Ci
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Fischer-Rosinsky, Antje
    Boesgaard, Trine Wellov
    Grarup, Niels
    Abbasi, Fahim A.
    Assimes, Themistocles L.
    Hao, Ke
    Yang, Xia
    Lecoeur, Cecile
    Barroso, Ines
    Bonnycastle, Lori L.
    Boettcher, Yvonne
    Bumpstead, Suzannah
    Chines, Peter S.
    Erdos, Michael R.
    Graessler, Jurgen
    Kovacs, Peter
    Morken, Mario A.
    Narisu, Narisu
    Payne, Felicity
    Stancakova, Alena
    Swift, Amy J.
    Toenjes, Anke
    Bornstein, Stefan R.
    Cauchi, Stephane
    Froguel, Philippe
    Meyre, David
    Schwarz, Peter E. H.
    Haering, Hans-Ulrich
    Smith, Ulf
    Boehnke, Michael
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Tuomilehto, Jaakko
    Quertemous, Thomas
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Hansen, Torben
    Pedersen, Oluf
    Walker, Mark
    Pfeiffer, Andreas F. H.
    Spranger, Joachim
    Stumvoll, Michael
    Meigs, James B.
    Wareham, Nicholas J.
    Kuusisto, Johanna
    Laakso, Markku
    Langenberg, Claudia
    Dupuis, Josee
    Watanabe, Richard M.
    Florez, Jose C.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    McCarthy, Mark I.
    Prokopenko, Inga
    Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 6, s. 2158-2171Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF712, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

  • 179.
    Doroszko, Milena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Univ Turku, Inst Biomed, Turku, Finland.
    Chrusciel, Marcin
    Univ Turku, Inst Biomed, Turku, Finland.
    Stelmaszewska, Joanna
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Slezak, Tomasz
    Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA.
    Anisimowicz, Slawomir
    Ctr Gynecol & Reprod Endocrinol Artemida, Bialystok, Poland.
    Plöckinger, Ursula
    Charite Univ Med Berlin, Interdisciplinary Ctr Metab Endocrinol Diabet & M, Berlin, Germany.
    Quinkler, Marcus
    Endocrinol Charlottenburg, Berlin, Germany;Charite Univ Med Berlin, Charite Campus Mitte, Dept Clin Endocrinol, Berlin, Germany.
    Bonomi, Marco
    Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy.
    Wolczynski, Slawomir
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Huhtaniemi, Ilpo
    Univ Turku, Inst Biomed, Turku, Finland;Imperial Coll London, Fac Med, Dept Surg & Canc, London, England.
    Toppari, Jorma
    Univ Turku, Inst Biomed, Turku, Finland;Turku Univ Hosp, Dept Pediat, Turku, Finland.
    Rahman, Nafis A.
    Univ Turku, Inst Biomed, Turku, Finland;Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    GnRH antagonist treatment of malignant adrenocortical tumors2019Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, nr 1, s. 103-117Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse C alpha 1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin a promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.

  • 180.
    Drott, Carl Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Franzén, Petra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
    Ghrelin in rat pancreatic islets decreases islet blood flow2019Ingår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 317, nr 1, s. E139-E146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the epsilon-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1 alpha). exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1 alpha receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1 alpha was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats. only, also improved the peak insulin response to glucose in vivo. thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.

  • 181.
    Drott, Carl Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Franzén, Petra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ghrelin in rat pancreatic islets decreases islet blood flow and impairs insulin secretion2018Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S218-S218Artikel i tidskrift (Övrigt vetenskapligt)
  • 182.
    Drzazga, Anna
    et al.
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Kristinsson, Hjalti
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Salaga, Maciej
    Med Univ Lodz, Dept Biochem, Mazowiecka 6-8, PL-92215 Lodz, Poland.
    Zatorski, Hubert
    Med Univ Lodz, Dept Biochem, Mazowiecka 6-8, PL-92215 Lodz, Poland.
    Koziolkiewicz, Maria
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Gendaszewska-Darmach, Edyta
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lysophosphatidylcholine and its phosphorothioate analogues potentiate insulin secretion via GPR40 (FFAR1), GPR55 and GPR119 receptors in a different manner2018Ingår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 472, s. 117-125Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lysophosphatidylcholine (LPC) is an endogenous ligand for GPR119 receptor, mediating glucose-stimulated insulin secretion (GSIS). We demonstrate that LPC facilitates GSIS in MINE pancreatic beta-cell line and murine islets of Langerhans by recognizing not only GPR119 but also GPR40 (free fatty acid receptor 1) and GPR55 activated by lysophosphatidylinositol. Natural LPCs are unstable when administered in vivo limiting their therapeutic value and therefore, we present phosphorothioate LPC analogues with increased stability. All the modified LPCs under study (12:0,14:0,16:0,18:0, and 18:1) significantly enhanced GSIS. The 16:0 sulfur analogue was the most potent, evoking 2-fold accentuated GSIS compared to the native counterpart. Interestingly, LPC analogues evoked GPR40-, GPR55-and GPR119 dependent [Ca2+](i), signaling, but did not stimulate cAMP accumulation as in the case of unmodified molecules. Thus, introduction of a phosphorothioate function not only increases LPC stability but also modulates affinity towards receptor targets and evokes different signaling pathways.

  • 183.
    Dubois, Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Kharaziha, Pedram
    Chioureas, Dimitris
    Meersman, Niels
    Panaretakis, Theocharis
    Ronquist, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Malignant Cell-Derived Extracellular Vesicles Express Different Chromogranin Epitopes Compared to Prostasomes2015Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, nr 10, s. 1063-1073Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND. Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS. We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS. A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION. Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers.

  • 184.
    Dyachok, Oleg
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gylfe, Erik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ca2+-induced Ca2+ Release via Inositol 1,4,5-trisphosphate Receptors Is Amplified by Protein Kinase A and Triggers Exocytosis in Pancreatic β-Cells2004Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, nr 44, s. 45455-45461Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hormones, such as glucagon and glucagon-like peptide-1, potently amplify nutrient stimulated insulin secretion by raising cAMP. We have studied how cAMP affects Ca2+-induced Ca2+ release (CICR) in pancreatic β-cells from mice and rats and the role of CICR in secretion. CICR was observed as pronounced Ca2+ spikes on top of glucose- or depolarization-dependent rise of the cytoplasmic Ca2+ concentration ([Ca2+]i). cAMP-elevating agents strongly promoted CICR. This effect involved sensitization of the receptors underlying CICR, because many cells exhibited the characteristic Ca2+ spiking at low or even in the absence of depolarization-dependent elevation of [Ca2+]i. The cAMP effect was mimicked by a specific activator of protein kinase A in cells unresponsive to activators of cAMP-regulated guanine nucleotide exchange factor. Ryanodine pretreatment, which abolishes CICR mediated by ryanodine receptors, did not prevent CICR. Moreover, a high concentration of caffeine, known to activate ryanodine receptors independently of Ca2+, failed to mobilize intracellular Ca2+. On the contrary, a high caffeine concentration abolished CICR by interfering with inositol 1,4,5-trisphosphate receptors (IP3Rs). Therefore, the cell-permeable IP3R antagonist 2-aminoethoxydiphenyl borate blocked the cAMP-promoted CICR. Individual CICR events in pancreatic β-cells were followed by [Ca2+]i spikes in neighboring human erythroleukemia cells, used to report secretory events in the β-cells. The results indicate that protein kinase A-mediated promotion of CICR via IP3Rs is part of the mechanism by which cAMP amplifies insulin release.

  • 185.
    Dyachok, Oleg
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tufveson, Gunnar
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Gylfe, Erik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ca2+-induced Ca2+ release by activation of inositol 1,4,5-trisphosphate receptors in primary pancreatic β-cells2004Ingår i: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, Vol. 36, nr 1, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effect of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) inhibition on the cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in primary insulin-releasing pancreatic β-cells isolated from mice, rats and human subjects as well as in clonal rat insulinoma INS-1 cells. In Ca2+-deficient medium the individual primary β-cells reacted to the SERCA inhibitor cyclopiazonic acid (CPA) with a slow rise of [Ca2+]i followed by an explosive transient elevation. The [Ca2+]i transients were preferentially observed at low intracellular concentrations of the Ca2+ indicator fura-2 and were unaffected by pre-treatment with 100 μM ryanodine. Whereas 20 mM caffeine had no effect on basal [Ca2+]i or the slow rise in response to CPA, it completely prevented the CPA-induced [Ca2+]i transients as well as inositol 1,4,5-trisphosphate-mediated [Ca2+]i transients in response to carbachol. In striking contrast to the primary β-cells, caffeine readily mobilized intracellular Ca2+ in INS-1 cells under identical conditions, and such mobilization was prevented by ryanodine pre-treatment. The results indicate that leakage of Ca2+ from the endoplasmic reticulum after SERCA inhibition is feedback-accelerated by Ca2+-induced Ca2+ release (CICR). In primary pancreatic β-cells this CICR is due to activation of inositol 1,4,5-trisphosphate receptors. CICR by ryanodine receptor activation may be restricted to clonal β-cells.

  • 186.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Ahmad, Tanveer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Janson, Eva T
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    TCEB3C a putative tumor suppressor gene of small intestine neuroendocrine tumors2014Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, nr 2, s. 275-284Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs), formerly midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, Western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. The large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one TCEB3C gene copy. The DNA hypomethylating agent 5-aza-2'-deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease of clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.

  • 187.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Daskalakis, Kosmas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Bäcklin, Christofer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Norlén, Olov
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors2017Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, nr 2, s. 170-181Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumors are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyze 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumor tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.

  • 188.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stalberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    ACTG2 Inhibits Growth and Is Epigenetically Repressed in Small Intestinal Neuroendocrine Tumors2014Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, nr 3-4, s. 227-227Artikel i tidskrift (Övrigt vetenskapligt)
  • 189.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    A plausible role for actin gamma smooth muscle 2 (ACTG2) in small intestinal neuroendocrine tumorigenesis2016Ingår i: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 16, nr 19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from the enterochromaffin cells in the ileum and jejunum. The knowledge about genetic and epigenetic abnormalities is limited. Low mRNA expression levels of actin gamma smooth muscle 2 (ACTG2) have been demonstrated in metastases relative to primary SI-NETs. ACTG2 and microRNA-145 (miR-145) are aberrantly expressed in other cancers and ACTG2 can be induced by miR-145. The aim of this study was to investigate the role of ACTG2 in small intestinal neuroendocrine tumorigenesis.

    METHODS: Protein expression was analyzed in SI-NETs (n = 24) and in enterochromaffin cells by immunohistochemistry. The cell line CNDT2.5 was treated with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep), the selective EZH2 inhibitor EPZ-6438, or 5-aza-2'-deoxycytidine, a DNA hypomethylating agent. Cells were transfected with ACTG2 expression plasmid or miR-145. Western blotting analysis, quantitative RT-PCR, colony formation- and viability assays were performed. miR-145 expression levels were measured in tumors.

    RESULTS: Eight primary tumors and two lymph node metastases displayed variable levels of positive staining. Fourteen SI-NETs and normal enterochromaffin cells stained negatively. Overexpression of ACTG2 significantly inhibited CNDT2.5 cell growth. Treatment with DZNep or transfection with miR-145 induced ACTG2 expression (>10-fold), but no effects were detected after treatment with EPZ-6438 or 5-aza-2'-deoxycytidine. DZNep also induced miR-145 expression. SI-NETs expressed relatively low levels of miR-145, with reduced expression in metastases compared to primary tumors.

    CONCLUSIONS: ACTG2 is expressed in a fraction of SI-NETs, can inhibit cell growth in vitro, and is positively regulated by miR-145. Theoretical therapeutic strategies based on these results are discussed.

  • 190.
    Edvinsson, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Ilbäck, Nils-Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Frisk, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Thelin, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Nyström-Rosander, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Trace Element Changes in Thoracic Aortic Dissection2016Ingår i: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 169, nr 2, s. 159-163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thoracic aortic dissection is a life-threatening condition with an incompletely understood pathogenesis. Trace elements are essential for the functioning of different processes in the body, including the immune system and associated responses to infection/inflammation. Because inflammation may be part of the pathogenesis of thoracic aortic dissection, we investigated whether trace element changes associated with inflammation occur in serum and tissue samples during the disease. The study included 21 patients undergoing surgery for thoracic aortic dissection, 10 forensic autopsy specimens for tissue controls and 23 healthy blood donors for serum controls. Levels of magnesium (Mg), calcium (Ca), vanadium (V), manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), cadmium (Cd) and mercury (Hg) were measured in the aortic tissue and serum by inductively coupled plasma-mass spectrometry (ICP-MS). In the serum, Ca, V, Cu and Zn decreased, whereas Fe increased. In the tissue, Cu and Zn decreased and Fe tended to increase. The Cu/Zn ratio in the serum, a marker of infection/inflammation, did not change in the patients. Concerning trace element changes in the serum and tissue, our data do not support the hypothesis that inflammation is involved in the pathogenesis of thoracic aortic dissection.

  • 191.
    Edén, Desireé
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mokhtari, Dariush
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glucose-stimulated insulin secretion from human pancreatic islets2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr 11, s. 2563-2572Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis Patients diagnosed with type 1 or type 2 diabetes have elevated levels of coagulation factor VIIa (FVIIa) and its receptor tissue factor (TF) in their bloodstream. This may affect the fate of the beta cells. We aimed to study the effects of TF/FVIIa signalling on cytokine-induced beta cell death and islet function in vitro. Methods Human pancreatic islets and MIN-6 beta cells were used to study TF mRNA and protein expression using real-time PCR, immunoblotting and flow cytometry. The effects of TF/FVIIa on cytokine-induced beta cell death were studied in MIN-6 cells and human pancreatic islets using cell-death ELISA and propidium iodide and cleaved caspase-3 staining. Effects of TF/FVIIa on the phosphorylation of p38, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK) were investigated by immunoblotting. Glucose-stimulated insulin secretion (GSIS) from human islets was measured with an insulin ELISA. Results A combination of the cytokines IL-1 beta, TNF-alpha and IFN-gamma induced TF expression in human pancreatic islets and in beta cells. TF/FVIIa did not affect basal beta cell death but, independently of downstream coagulation activity, augmented beta cell death in response to cytokines. The effect of TF/FVIIa on cytokine-induced beta cell death was found to be dependent on the stress kinase JNK, since FVIIa addition potentiated cytokine-induced JNK activation and JNK inhibition abolished the effect of TF/FVIIa on cytokine-induced beta cell death. Moreover, TF/FVIIa signalling resulted in inhibition of GSIS from human pancreatic islets. Conclusions/interpretation These results indicate that TF/FVIIa signalling has a negative effect on beta cell function and promotes beta cell death in response to cytokines.

  • 192. Eeg-Olofsson, K
    et al.
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och klinisk epidemiologi.
    Nilsson, P M
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Svensson, A-M
    Gudbjörnsdóttir, S
    Eliasson, B
    New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR).2010Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 268, nr 5, s. 471-482Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS

    To analyse the association between glycosylated haemoglobin A1c (HbA1c) and cardiovascular disease (CVD) in patients with type 2 diabetes in the Swedish National Diabetes Register (NDR).

    METHODS

    An observational study of 18 334 patients (age 30-79 years, previous CVD in 18%, baseline HbA1c 5.0-10.9%) who were followed for 6 years (mean 5.6 years) from 1997/1998 until 2003.

    RESULTS

    Hazard ratios per 1% unit increase in baseline or updated mean HbA1c for fatal/nonfatal coronary heart disease (CHD), CVD and total mortality were 1.11-1.13, 1.10-1.11 and 1.09-1.10, respectively (all P < 0.001), adjusted for several risk factors and clinical characteristics in Cox regression. Adjusted 6-year event rates increased with higher baseline or updated mean HbA1c with no J-shaped risk curves, in all patients and also when subgrouping by shorter (mean 3 years) or longer (mean 14 years) diabetes duration, by presence or absence of previous CVD, or by treatment with oral hypoglycaemic agents (OHAs) or insulin. Risk reductions of 20% for CHD and 16% for CVD (P < 0.001) were found in patients with a baseline mean HbA1c of 6.5%, compared to those with a mean level of 7.5%. Compared to OHA-treated patients, insulin-treated patients had an increased risk of total mortality, due almost exclusively to an increased risk of non-CVD mortality, and due less to a weakly significant increased risk of fatal CVD. HbA1c was not associated with non-CVD mortality.

    CONCLUSIONS

    This observational study showed progressively increasing risks of CHD, CVD and total mortality with higher HbA1c, and no risk increase at low HbA1c levels even with longer diabetes duration, previous CVD or treatment with either insulin or OHAs. Patients achieving HbA1c <7% showed benefits for risk reduction.

  • 193. Eeg-Olofsson, K.
    et al.
    Gudbjornsdottir, S.
    Eliasson, B.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Svensson, A. -M
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Multifactorial risk factor control in clinical practice and risk of cardiovascular disease in type 2 diabetes: report from the Swedish national diabetes register2014Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, nr S1, s. S493-S493Artikel i tidskrift (Övrigt vetenskapligt)
  • 194.
    Eeg-Olofsson, K.
    et al.
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Med, S-41124 Gothenburg, Sweden..
    Ritsinger, V.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.;Reg Kronoberg, Dept Res & Dev, Vaxjo, Sweden..
    Hero, C.
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Med, S-41124 Gothenburg, Sweden..
    Saleh, N.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Lagerqvist, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Svensson, A. -M
    Norhammar, A.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Mortality by affected coronary artery vessels in 2776 patients with type 1 diabetes undergoing coronary angiography2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S577-S578Artikel i tidskrift (Övrigt vetenskapligt)
  • 195. Eeg-Olofsson, Katarina
    et al.
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och klinisk epidemiologi.
    Nilsson, Peter M
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Svensson, Ann-Marie
    Gudbjörnsdóttir, Soffia
    Eliasson, Björn
    Glycemic control and cardiovascular disease in 7,454 patients with type 1 diabetes: an observational study from the Swedish National Diabetes Register (NDR).2010Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 33, nr 7, s. 1640-1646Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE

    We assessed the association between A1C and cardiovascular diseases (CVDs) in an observational study of patients with type 1 diabetes followed for 5 years.

    RESEARCH DESIGN AND METHODS

    A total of 7,454 patients were studied from the Swedish National Diabetes Register (aged 20-65 years, diabetes duration 1-35 years, followed from 2002 to 2007).

    RESULTS

    Hazard ratios (HRs) for fatal/nonfatal coronary heart disease (CHD) per 1% unit increase in baseline or updated mean A1C at Cox regression analysis were 1.31 and 1.34 and 1.26 and 1.32, respectively, for fatal/nonfatal CVD (all P < 0.001 after adjustment for age, sex, diabetes duration, blood pressure, total and LDL cholesterol, triglycerides, BMI, smoking, and history of CVD). HRs were only slightly lower for CHD (P = 0.002) and CVD (P = 0.002-0.007) after also adjusting for albuminuria. Adjusted 5-year event rates of CHD and CVD increased progressively with higher A1C, ranging from 5 to 12%, as well as when subgrouped by shorter (1-20 years) or longer (21-35 years) duration of diabetes. A group of 4,186 patients with A1C 5-7.9% (mean 7.2) at baseline showed risk reductions of 41% (95% confidence intervals: 15-60) (P = 0.005) for fatal/nonfatal CHD and 37% (12-55) (P = 0.008) for CVD, compared with 3,268 patients with A1C 8-11.9% (mean 9.0), fully adjusted also for albuminuria.

    CONCLUSIONS

    This observational study of patients in modern everyday clinical practice demonstrates progressively increasing risks for CHD and CVD with higher A1C, independently of traditional risk factors, with no J-shaped risk curves. A baseline mean A1C of 7.2% showed considerably reduced risks of CHD and CVD compared with A1C 9.0%, emphasizing A1C as a strong independent risk factor in type 1 diabetes.

  • 196. Eeg-Olofsson, Katarina
    et al.
    Gudbjornsdottir, Soffia
    Eliasson, Bjorn
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    The triglycerides-to-HDL-cholesterol ratio and cardiovascular disease risk in obese patients with type 2 diabetes: An observational study from the Swedish National Diabetes Register (NDR)2014Ingår i: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 106, nr 1, s. 136-144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: Assessing the association between BMI and risk of coronary heart disease (CHD), cardiovascular disease (CVD) and mortality in patients with type 2 diabetes, also with regard to higher or lower levels of the ratio triglycerides-to-HDL-cholesterol (TG:HDL). Methods: 54,061 patients with BMI >= 18.5 kg/m(2), mean age and duration 61.5 +/- 8 and 6.9 +/- 6 years, 59% males, 14% with CVD history, from the Swedish National Diabetes Register, followed for mean 4.8 years. Results: Adjusting at Cox regression for non-BMI-linked (age, sex, smoking, CVD history) and BMI-linked (blood lipids, blood pressure, HbA1c, albuminuria) covariates, hazard ratios (HR) for fatal/nonfatal CHD and CVD were mainly increased with prominent obesity (BMI >= 35 kg/m(2)), 1.19 (p = 0.01) and 1.17 (p = 0.009), compared to normal weight (BMI 18.5-24.9 kg/m(2)), although increased also with obesity (BMI 30-34.9 kg/m(2)), 1.34 and 1.30 (p < 0.001), when adjusting only for non-BMI-linked covariates. Stratifying by 75th percentile of TG: HDL, with normal weight and TG: HDL < 1.9 as reference, obese and prominently obese with TG: HDL >= 1.9 had considerably increased HR around 1.7 for fatal/nonfatal CHD and 1.6 for CVD (p < 0.001), while obese and prominently obese with TG: HDL < 1.9 only had HR 1.2-1.3 for CHD and CVD (p 0.003-<0.01). Conclusion: Obese T2D patients with high TG: HDL, associated with increased insulin resistance, had considerably increased risk of CHD and CVD.

  • 197.
    Eeg-Olofsson, Katarina
    et al.
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Med Prod Agcy, Uppsala, Sweden..
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Eliasson, Bjorn
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Svensson, Ann-Marie
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Considerably decreased risk of cardiovascular disease with combined reductions in HbA1c, blood pressure and blood lipids in type 2 diabetes: Report from the Swedish National Diabetes Register2016Ingår i: Diabetes & Vascular Disease Research, ISSN 1479-1641, E-ISSN 1752-8984, Vol. 13, nr 4, s. 268-277Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Assess the effect of risk factors changes on risk for cardiovascular disease and mortality in patients with type 2 diabetes selected from the Swedish National Diabetes Register. Methods: Observational study of 13,477 females and males aged 30-75years, with baseline HbA1c 41-67mmol/mol, systolic blood pressure 122-154mmHg and ratio non-HDL:HDL 1.7-4.1, followed for mean 6.5years until 2012. Four groups were created: a reference group (n=6757) with increasing final versus baseline HbA1c, systolic blood pressure and non-HDL:HDL cholesterol during the study period, and three groups with decreasing HbA1c (n=1925), HbA1c and systolic blood pressure (n=2050) or HbA1c and systolic blood pressure and non-HDL:HDL (n=2745). Results: Relative risk reduction for fatal/nonfatal cardiovascular disease was 35% with decrease in HbA1c only (mean 6 to final 49mmol/mol), 56% with decrease in HbA1c and systolic blood pressure (mean 12 to final 128mmHg) and 75% with combined decreases in HbA1c, systolic blood pressure and non-HDL:HDL (mean 0.8 to final 2.1), all p<0.001 adjusting for clinical characteristics, other risk factors, treatments and previous cardiovascular disease. Similar risk reductions were found for fatal/nonfatal coronary heart disease, fatal cardiovascular disease, all-cause mortality and also in a subgroup of 3038 patients with albuminuria. Conclusion: Considerable risk reductions for cardiovascular disease and mortality were seen with combined long-term risk factor improvement.

  • 198.
    Ehrlund, Anna
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Mejhert, Niklas
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Bjork, Christel
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Andersson, Robin
    Univ Copenhagen, Dept Biol, Bioinformat Ctr, Copenhagen, Denmark;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Kulyte, Agne
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Astrom, Gaby
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Itoh, Masayoshi
    RIKEN Prevent Med & Diag Innovat Program, Wako, Saitama, Japan;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Kawaji, Hideya
    RIKEN Prevent Med & Diag Innovat Program, Wako, Saitama, Japan;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Lassmann, Timo
    Telethon Kids Inst, Perth, WA, Australia;Univ Western Australia, Perth, WA, Australia;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Daub, Carsten O.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;Karolinska Inst, Sci Life Lab, Stockholm, Sweden.
    Carninci, Piero
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Forrest, Alistair R. R.
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Hayashizaki, Yoshihide
    RIKEN Prevent Med & Diag Innovat Program, Wako, Saitama, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Sandelin, Albin
    Univ Copenhagen, Dept Biol, Bioinformat Ctr, Copenhagen, Denmark;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Ryden, Mikael
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Laurencikiene, Jurga
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Arner, Peter
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Arner, Erik
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;Karolinska Inst, Dept Med, Stockholm, Sweden;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Transcriptional Dynamics During Human Adipogenesis and Its Link to Adipose Morphology and Distribution2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 1, s. 218-230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    White adipose tissue (WAT) can develop into several phenotypes with different pathophysiological impact on type 2 diabetes. To better understand the adipogenic process, the transcriptional events that occur during in vitro differentiation of human adipocytes were investigated and the findings linked to WAT phenotypes. Single molecule transcriptional profiling provided a detailed map of the expressional changes of genes, enhancers, and long noncoding RNAs, where different types of transcripts share common dynamics during differentiation. Common signatures include early downregulated, transient, and late induced transcripts, all of which are linked to distinct developmental processes during adipogenesis. Enhancers expressed during adipogenesis overlap significantly with genetic variants associated with WAT distribution. Transiently expressed and late induced genes are associated with hypertrophic WAT (few but large fat cells), a phenotype closely linked to insulin resistance and type 2 diabetes. Transcription factors that are expressed early or transiently affect differentiation and adipocyte function and are controlled by several well-known upstream regulators such as glucocorticosteroids, insulin, cAMP, and thyroid hormones. Taken together, our results suggest a complex but highly coordinated regulation of adipogenesis.

  • 199. Ekström, N.
    et al.
    Miftaraj, M.
    Svensson, A. -M
    Sundell, K. Andersson
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gudbjörnsdottir, S.
    Eliasson, B.
    Glucose-lowering treatment and clinical results in 163 121 patients with type 2 diabetes: an observational study from the Swedish national diabetes register2012Ingår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, nr 8, s. 717-726Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: To analyse clinical characteristics and treatment results in unselected type 2 diabetes mellitus (T2DM) patients, with non-pharmacological treatment as well as the most commonly used pharmacological glucose-lowering treatment regimens, in everyday clinical practice. Methods: In this population-based cross-sectional study, information was linked from the Swedish National Diabetes Register, Prescribed Drug Register and Patient Register. T2DM patients with non-pharmacological treatment and T2DM patients continuously using the 12 most common pharmacological treatment regimens were included in the study (n = 163121). Results: There were statistically significant differences in clinical characteristics between the groups. Patients with insulin-based treatment regimens had the longest duration of diabetes and more cardiovascular risk factors than the T2DM-population in general. The proportion of patients reaching HbA1c =7% varied between 70.1% (metformin) and 25.0% [premixed insulin (PMI) + SU) in patients with pharmacological treatment. 84.8% of the patients with non-pharmacological treatment reached target. Compared to patients on metformin, patients on other pharmacological treatments had a lower likelihood, with hazard ratios ranging from 0.58; 95% confidence interval (CI), 0.540.63 to 0.97;0.940.99, of having HbA1c =7% (adjusted for covariates). Patients on insulin-based treatments had the lowest likelihood, while non-pharmacological treatment was associated with an increased likelihood of having HbA1c =7%. Conclusion: This nation-wide study shows insufficiently reached treatment goals for haemoglobin A1c (HbA1c) in all treatment groups. Patients on insulin-based treatment regimens had the longest duration of diabetes, more cardiovascular risk factors and the highest proportions of patients not reaching HbA1c target.

  • 200. Ekström, Nils
    et al.
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Eliasson, Björn
    Fhärm, Eva
    Rolandsson, Olov
    Miftaraj, Mervete
    Svensson, Ann-Marie
    Gudbjörnsdottir, Soffia
    Aspirin treatment and risk of first incident cardiovascular diseases in patients with type 2 diabetes: an observational study from the Swedish National Diabetes Register.2013Ingår i: BMJ open, ISSN 2044-6055, Vol. 3, nr 4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: To investigate the benefits and risks associated with aspirin treatment in patients with type 2 diabetes and no previous cardiovascular disease (CVD) in clinical practice.

    DESIGN: Population-based cohort study between 2005 and 2009, mean follow-up 3.9 years.

    SETTING: Hospital outpatient clinics and primary care in Sweden.

    PARTICIPANTS: Men and women with type 2 diabetes, free from CVD, including atrial fibrillation and congestive heart failure, at baseline, registered in the Swedish National Diabetes Register, with continuous low-dose aspirin treatment (n=4608) or no aspirin treatment (n=14 038).

    MAIN OUTCOME MEASURES: Risks of CVD, coronary heart disease (CHD), stroke, mortality and bleedings, associated with aspirin compared with no aspirin, were analysed in all patients and in subgroups by gender and estimated cardiovascular risk. Propensity scores were used to adjust for several baseline risk factors and characteristics at Cox regression, and the effect of unknown covariates was evaluated in a sensitivity analysis.

    RESULTS: There was no association between aspirin use and beneficial effects on risks of CVD or death. Rather, there was an increased risk of non-fatal/fatal CHD associated with aspirin; HR 1.19 (95% CI 1.01 to 1.41), p=0.04. The increased risk of cardiovascular outcomes associated with aspirin was seen when analysing women separately; HR 1.41 (95% CI 1.07 to 1.87), p=0.02, and HR 1.28 (95% CI 1.01 to 1.61), p=0.04, for CHD and CVD, respectively, but not for men separately. There was a trend towards increased risk of a composite of bleedings associated with aspirin, n=157; HR 1.41 (95% CI 0.99 to 1.99).

    CONCLUSIONS: The results support the trend towards more restrictive use of aspirin in patients with type 2 diabetes and no previous CVD. More research is needed to explore the differences in aspirin's effects in women and men.

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