1,101 results on '"Holger S Willenberg"'
Search Results
52. Is steroid profiling using LC-MS/MS useful in the diagnostic work-up of primary aldosteronism?
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Graeme Eisenhofer, Jaap Deinum, Tracy Ann Williams, Mirko Peitzsch, Anna Dietz, Lars Christian Rump, Tanja Dekkers, Felix Beuschlein, Martin Reincke, Martin Bidlingmaier, Jacques W. M. Lenders, Marcus Treitl, and Holger S. Willenberg
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Oncology ,medicine.medical_specialty ,Primary aldosteronism ,business.industry ,medicine.medical_treatment ,Internal medicine ,Lc ms ms ,Medicine ,business ,medicine.disease ,Work-up ,Steroid - Published
- 2016
53. Activating mutations in CTNNB1 in aldosterone producing adenomas
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Peter Stålberg, Martin K. Walz, K. Alexander Iwen, Peyman Björklund, Rajani Maharjan, Hendrik Lehnert, Per Hellman, Bruce G. Robinson, Stan B. Sidhu, Holger S. Willenberg, Tobias Åkerström, Henning Dralle, Julian C. Y. Ip, Kenko Cupisti, Celso E. Gomez-Sanchez, and Ana Moser
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Male ,0301 basic medicine ,medicine.medical_specialty ,Beta-catenin ,Secondary hypertension ,030209 endocrinology & metabolism ,medicine.disease_cause ,Article ,03 medical and health sciences ,Exon ,chemistry.chemical_compound ,0302 clinical medicine ,Protein Domains ,Internal medicine ,KCNJ5 ,medicine ,AXIN2 ,Humans ,Aldosterone ,Wnt Signaling Pathway ,beta Catenin ,Mutation ,Multidisciplinary ,biology ,business.industry ,Wnt signaling pathway ,Exons ,medicine.disease ,Adrenal Cortex Neoplasms ,Neoplasm Proteins ,030104 developmental biology ,Endocrinology ,chemistry ,Adrenocortical Adenoma ,biology.protein ,Female ,business - Abstract
Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitute a large proportion of PA cases and represent a surgically correctable form of the disease. The WNT signaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling is mutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutations in a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. All of the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3. The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. This report provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.
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- 2016
54. Computational analysis of liquid chromatography-tandem mass spectrometric steroid profiling in NCI H295R cells following angiotensin II, forskolin and abiraterone treatment
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Peter Dieterich, Angela Hübner, Susan Richter, Ramona Jühlen, Mirko Peitzsch, Jacques W.M. Lenders, Graeme Eisenhofer, Holger S. Willenberg, Anastasios Mangelis, and Andreas Deussen
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0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Clinical Biochemistry ,Dehydroepiandrosterone ,Biochemistry ,Models, Biological ,Steroid ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Endocrinology ,Tandem Mass Spectrometry ,medicine ,Humans ,Steroid 11-beta-hydroxylase ,Molecular Biology ,Cell Proliferation ,Chromatography ,Forskolin ,Aldosterone ,Chemistry ,Adrenal cortex ,Angiotensin II ,Colforsin ,Biological Transport ,Cell Biology ,Adrenal Cortical Cell ,030104 developmental biology ,medicine.anatomical_structure ,Adrenal Cortex ,Molecular Medicine ,Androstenes ,Steroids ,Metabolic Networks and Pathways ,Chromatography, Liquid - Abstract
Item does not contain fulltext Adrenal steroid hormones, which regulate a plethora of physiological functions, are produced via tightly controlled pathways. Investigations of these pathways, based on experimental data, can be facilitated by computational modeling for calculations of metabolic rate alterations. We therefore used a model system, based on mass balance and mass reaction equations, to kinetically evaluate adrenal steroidogenesis in human adrenal cortex-derived NCI H295R cells. For this purpose a panel of 10 steroids was measured by liquid chromatographic-tandem mass spectrometry. Time-dependent changes in cell incubate concentrations of steroids - including cortisol, aldosterone, dehydroepiandrosterone and their precursors - were measured after incubation with angiotensin II, forskolin and abiraterone. Model parameters were estimated based on experimental data using weighted least square fitting. Time-dependent angiotensin II- and forskolin-induced changes were observed for incubate concentrations of precursor steroids with peaks that preceded maximal increases in aldosterone and cortisol. Inhibition of 17-alpha-hydroxylase/17,20-lyase with abiraterone resulted in increases in upstream precursor steroids and decreases in downstream products. Derived model parameters, including rate constants of enzymatic processes, appropriately quantified observed and expected changes in metabolic pathways at multiple conversion steps. Our data demonstrate limitations of single time point measurements and the importance of assessing pathway dynamics in studies of adrenal cortical cell line steroidogenesis. Our analysis provides a framework for evaluation of steroidogenesis in adrenal cortical cell culture systems and demonstrates that computational modeling-derived estimates of kinetic parameters are an effective tool for describing perturbations in associated metabolic pathways.
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- 2016
55. Adrenogenitales Syndrom
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Holger S. Willenberg
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- 2016
56. Nebenniereninzidentalom
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Holger S. Willenberg
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- 2016
57. Adrenal Insufficiency
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Holger S. Willenberg, Stefan R. Bornstein, Matthias Gruber, and Andreas Barthel
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medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Adrenal insufficiency ,medicine ,medicine.disease ,business - Published
- 2016
58. Contributors
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Lloyd Paul Aiello, Kyriaki S. Alatzoglou, Erik K. Alexander, Carolyn A. Allan, Bruno Allolio, Nobuyuki Amino, Bradley D. Anawalt, Peter Angelos, Valerie A. Arboleda, Richard J. Auchus, Lloyd Axelrod, Rebecca S. Bahn, H.W. Gordon Baker, MD, PhD, FRACP, Shlomi Barak, Randall B. Barnes, Andreas Barthel, Murat Bastepe, Emma K. Beardsley, Paolo Beck-Peccoz, Graeme I. Bell, Wenya Linda Bi, John P. Bilezikian, Manfred Blum, Steen J. Bonnema, Stefan R. Bornstein, Roger Bouillon, Andrew J.M. Boulton, Glenn D. Braunstein, F. Richard Bringhurst, Frank J. Broekmans, Marcello D. Bronstein, Edward M. Brown, Wendy A. Brown, Serdar E. Bulun, Henry B. Burch, Henry G. Burger, Richard O. Burney, Morton G. Burt, Enrico Cagliero, Glenda G. Callender, Maria Luiza Avancini Caramori, Robert M. Carey, Tobias Carling, Francesco Cavagnini, Jerry D. Cavallerano, Etienne Challet, Shu Jin Chan, R. Jeffrey Chang, Roland D. Chapurlat, V. Krishna Chatterjee, Francesco Chiofalo, Luca Chiovato, Kyung J. Cho, Emily Christison-Lagay, Daniel Christophe, George P. Chrousos, John A. Cidlowski, David R. Clemmons, Robert V. Considine, Marco Conti, Georges Copinschi, Kyle D. Copps, Michael A. Cowley, Leona Cuttler, Mehul T. Dattani, Stephen N. Davis, Mario De Felice, Leslie J. De Groot, David M. de Kretser, Ralph A. DeFronzo, Ahmed J. Delli, Marie B. Demay, Michael C. Dennedy, Roberto Di Lauro, Rosemary Dineen, Su Ann Ding, Sean F. Dinneen, Daniel J. Drucker, Jacques E. Dumont, Kathleen M. Dungan, Ian F. Dunn, Michael J. Econs, David A. Ehrmann, Graeme Eisenhofer, Berrin Ergun-Longmire, Erica A. Eugster, Sadaf I. Farooqi, Martin Fassnacht, Bart C.J.M. Fauser, Gianfranco Fenzi, Ele Ferrannini, David M. Findlay, Courtney Anne Finlayson, Delbert A. Fisher, Isaac R. Francis, Mason W. Freeman, Lawrence A. Frohman, Mark Frydenberg, Peter J. Fuller, Jason L. Gaglia, Gianluigi Galizia, Thomas J. Gardella, Katharine C. Garvey, Harry K. Genant, Michael S. German, Evelien F. Gevers, Francesca Pecori Giraldi, Linda C. Giudice, Andrea Giustina, Anna Glasier, Francis H. Glorieux, Allison B. Goldfine, Louis J. Gooren, David F. Gordon, Karen A. Gregerson, Raymon H. Grogan, Milton D. Gross, Ashley B. Grossman, Matthias Gruber, Valeria C. Guimarães, Mark Gurnell, Nadine G. Haddad, Daniel J. Haisenleder, David J. Handelsman, John B. Hanks, Mark J. Hannon, Erika Harno, Matthias Hebrok, Mark P. Hedger, Laszlo Hegedüs, Jerrold J. Heindel, Arturo Hernandez, Maria K. Herndon, Ken K.Y. Ho, Nelson D. Horseman, Ieuan A. Hughes, Christopher J. Hupfeld, Hero K. Hussain, Valeria Iodice, Benjamin C. James, J. Larry Jameson, Glenville Jones, Nathalie Josso, Harald Jüppner, Agata Juszczak, Jeffrey Kalish, Edwin L. Kaplan, Niki Karavitaki, Monika Karczewska-Kupczewska, Ahmed Khattab, David C. Klein, Ronald Klein, Gunnar Kleinau, Michaela Koontz, John J. Kopchick, Peter Kopp, Irina Kowalska, Stephen M. Krane, Knut Krohn, Henry M. Kronenberg, Elizabeth M. Lamos, Andrea Lania, Sue Lynn Lau, Edward R. Laws, John H. Lazarus, Diana L. Learoyd, Harold E. Lebovitz, Åke Lenmark, Edward O. List, Kate Loveland, David A. Low, Paolo E. Macchia, Noel K. Maclaren, Geraldo Madeiros-Neto, Carine Maenhaut, Christa Maes, Katharina M. Main, Carl D. Malchoff, Diana M. Malchoff, Rayaz A. Malik, Susan J. Mandel, Christos S. Mantzoros, Eleftheria Maratos-Flier, Michele Marino, John C. Marshall, T. John Martin, Thomas F.J. Martin, Christopher J. Mathias, Elizabeth A. McGee, Travis McKenzie, Robert I. McLachlan, Juris J. Meier, Shlomo Melmed, Boyd E. Metzger, Heino F.L. Meyer-Bahlburg, Robert P. Millar, Walter L. Miller, Madhusmita Misra, Mark E. Molitch, Molly B. Moravek, Damian G. Morris, Sapna Nagar, Jon Nakamoto, Maria I. New, Lynnette K. Nieman, John H. Nilson, Georgia Ntali, Moira O’Bryan, Stephen O’Rahilly, Kjell Öberg, Jerrold M. Olefsky, Matthew T. Olson, Karel Pacak, Furio Pacini, Shetal H. Padia, Ralf Paschke, Francisco J. Pasquel, Katherine Wesseling Perry, Luca Persani, Louis H. Philipson, Christian Pina, Frank B. Pomposelli, John T. Potts, Charmian A. Quigley, Marcus O. Quinkler, Christine Campion Quirk, Ewa Rajpert-De Meyts, Eric Ravussin, David W. Ray, Samuel Refetoff, Ravi Retnakaran, Rodolfo A. Rey, Christopher J. Rhodes, E. Chester Ridgway, Gail P. Risbridger, Robert A. Rizza, Bruce G. Robinson, Pierre P. Roger, Michael G. Rosenfeld, Robert L. Rosenfield, Peter Rossing, Robert T. Rubin, Ileana G.S. Rubio, Neil B. Ruderman, Jose Russo, Irma H. Russo, Isidro B. Salusky, Nanette Santoro, Kathleen M. Scully, Patrick M. Sexton, Gerald I. Shulman, Paolo S. Silva, Shonni J. Silverberg, Frederick R. Singer, Niels E. Skakkebaek, Malgorzata E. Skaznik-Wikiel, Dorota Skowronska-Krawczyk, Carolyn L. Smith, Philip W. Smith, Roger Smith, Steven R. Smith, Peter J. Snyder, Donald L. St. Germain, René St-Arnaud, Donald F. Steiner, Paul M. Stewart, Marek Strączkowski, Jerome F. Strauss, Dennis M. Styne, Karena L. Swan, Ronald S. Swerdloff, Lyndal J. Tacon, Javier A. Tello, Rajesh V. Thakker, Christopher J. Thompson, Henri J.L.M. Timmers, Jorma Toppari, Michael L. Traub, Michael A. Tsoukas, Robert Udelsman, Guillermo E. Umpierrez, Greet Van den Berghe, Gilbert Vassart, Ashley H. Vernon, Eric Vilain, Theo J. Visser, Paolo Vitti, Geoffrey A. Walford, Christina Wang, Anthony P. Weetman, Nancy L. Weigel, Gordon C. Weir, Roy E. Weiss, Anne White, Kenneth E. White, Morris F. White, Michael P. Whyte, Wilmar M. Wiersinga, Holger S. Willenberg, Joseph I. Wolfsdorf, Fredric E. Wondisford, Ka Kit Wong, John J. Wysolmerski, Mabel Yau, Morag J. Young, Lisa M. Younk, Run Yu, Tony Yuen, Martha A. Zeiger, Bernard Zinman, and R. Thomas Zoeller
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- 2016
59. HLA-A2 Phenotype may be Protective Against Graves’ Disease but not Against Hashimoto’s Thyroiditis in Caucasians
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Holger S. Willenberg, Werner A. Scherbaum, C. Bernecker, Matthias Schott, A. Thiel, Margret Ehlers, M. Ostapczuk, S. Vordenbäumen, and Sven Schinner
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Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Graves' disease ,Clinical Biochemistry ,Population ,Hashimoto Disease ,Human leukocyte antigen ,medicine.disease_cause ,Biochemistry ,White People ,Thyroiditis ,Autoimmunity ,Autoimmune thyroiditis ,Young Adult ,Endocrinology ,Risk Factors ,Internal medicine ,HLA-A2 Antigen ,Odds Ratio ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Biochemistry (medical) ,Thyroid ,General Medicine ,Middle Aged ,medicine.disease ,Graves Disease ,Phenotype ,medicine.anatomical_structure ,Case-Control Studies ,Immunology ,Female ,business - Abstract
Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are the most common autoimmune thyroid diseases (AITDs) affecting up to 5% of the general population. In Caucasians HT has a prevalence of up to 4.60% and GD a prevalence of 1–2%. The aim of this study was to investigate the association between HLA-A2 and the AITDs GD and HT among Caucasians. HLA alleles of 33 patients with GD and 75 patients with HT were determined by serological typing. The frequency of HLA A2 was significantly reduced in GD (p=0.033) but not in HT (p=n.s.) as compared to control samples. In individuals positive for HLA-A2 odds ratio for protection from GD was found to be 2.8 . This study supports the hypothesis that genetic predisposition to GD is not restricted to MHC class II molecules. The significant negative association between HLA A2 and GD supports the hypothesis that MHC class I genes may be relevant for the protection from GD. In contrast the nonsignificant results for HT indicate that this association may not apply to AITDs in general.
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- 2012
60. Immunoregulatory Natural Killer Cells Suppress Autoimmunity by Down-Regulating Antigen-Specific CD8+ T Cells in Mice
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Werner A. Scherbaum, Matthias Schott, Margret Ehlers, Klaus L. Meyer, Claudia Papewalis, Evelyn Ullrich, Wiebke Stenzel, Benedikt Jacobs, René Deenen, Laurence Zitvogel, Holger S. Willenberg, Annette Thiel, and Sven Schinner
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medicine.medical_specialty ,CD8 Antigens ,T-Lymphocytes ,Apoptosis ,Autoimmunity ,Biology ,Diabetes Mellitus, Experimental ,Mice ,Interleukin 21 ,Endocrinology ,NK-92 ,Mice, Inbred NOD ,Internal medicine ,medicine ,Animals ,Antigen-presenting cell ,Cells, Cultured ,Lymphokine-activated killer cell ,Reverse Transcriptase Polymerase Chain Reaction ,Janus kinase 3 ,Flow Cytometry ,Natural killer T cell ,Cell biology ,Killer Cells, Natural ,Mice, Inbred C57BL ,Microscopy, Fluorescence ,Myeloid-derived Suppressor Cell ,Interleukin 12 - Abstract
Natural killer (NK) cells belong to the innate immune system. Besides their role in antitumor immunity, NK cells also regulate the activity of other cells of the immune system, including dendritic cells, macrophages, and T cells, and may, therefore, be involved in autoimmune processes. The aim of the present study was to clarify the role of NK cells within this context. Using two mouse models for type 1 diabetes mellitus, a new subset of NK cells with regulatory function was identified. These cells were generated from conventional NK cells by incubation with IL-18 and are characterized by the expression of the surface markers CD117 (also known as c-Kit, stem cell factor receptor) and programmed death (PD)-ligand 1. In vitro analyses demonstrated a direct lysis activity of IL-18-stimulated NK cells against activated insulin-specific CD8+ T cells in a PD-1/PD-ligand 1-dependent manner. Flow cytometry analyses revealed a large increase of splenic and lymphatic NK1.1+/c-Kit+ NK cells in nonobese diabetic mice at 8 wk of age, the time point of acceleration of adaptive cytotoxic immunity. Adoptive transfer of unstimulated and IL-18-stimulated NK cells into streptozotocin-treated mice led to a delayed diabetes development and partial disease prevention in the group treated with IL-18-stimulated NK cells. Consistent with these data, mild diabetes was associated with increased numbers of NK1.1+/c-Kit+ NK cells within the islets. Our results demonstrate a direct link between innate and adaptive immunity in autoimmunity with newly identified immunoregulatory NK cells displaying a potential role as immunosuppressors.
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- 2012
61. Trends in adrenal surgery: institutional review of 528 consecutive adrenalectomies
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Andreas Raffel, Achim Wolf, Holger S. Willenberg, Matthias Schott, Anja Lachenmayer, Kenko Cupisti, Wolfram T. Knoefel, and Claus F. Eisenberger
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Diagnostic Imaging ,Male ,medicine.medical_specialty ,Adrenal surgery ,Adrenal Gland Neoplasms ,chemistry.chemical_compound ,Postoperative Complications ,Germany ,Adrenal Glands ,medicine ,Humans ,Single institution ,Adrenal tumors ,Retrospective Studies ,Chi-Square Distribution ,Aldosterone ,business.industry ,General surgery ,Adrenalectomy ,Retrospective cohort study ,Length of Stay ,Middle Aged ,Vascular surgery ,Surgery ,Treatment Outcome ,chemistry ,Cardiothoracic surgery ,Female ,Laparoscopy ,business ,Abdominal surgery - Abstract
The increasing detection of adrenal tumors and the availability of a more sophisticated biochemical work-up leading to rising numbers of sub-clinical Conn's and Cushing's syndromes coincide with a rising number of adrenalectomies worldwide. The aim of our study was to report a single institution's experience with adrenal surgery.We report data of 528 adrenalectomies, operated at our institution before and after the onset of minimally invasive endoscopic surgery (1986-1994, 1995-2008). Gender, age, indication, imaging, surgical approach, operating time, histology, tumor size, hospital stay, and complications were analyzed retrospectively.A total of 478 patients underwent adrenal surgery during the time observed. The average number of yearly adrenalectomies increased from 14 to 21 (p = 0.001) after the onset of laparoscopic surgery. Imaging techniques showed a significant shift towards magnetic resonance imaging (p 0.001) and preoperative assessment of tumor size was significantly correlated to malignancy: 10.8 % (11/102) and 42 % (21/50) of tumors measuring 4-6 cm and ≥6 cm, respectively, were malignant in the final histology report (p 0.001). Patients operated by minimally invasive endoscopy were significantly younger (mean 49.4 years, p = 0.046), had significantly shorter operating times (mean 118 min, p 0.001), had shorter hospital stays (mean 7.1 days, p 0.001), and had less complications (6.9 %, p = 0.004) compared to patients resected through open procedures.Although adrenalectomy rates increased and minimally invasive endoscopic surgery reduced hospital stay and complications at our institution, the yearly number of procedures was still low with often high surgical complexity. We therefore believe that adrenal surgery remains a highly specialized procedure that should preferably be performed at endocrine surgery centers.
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- 2012
62. Evidence of a Combined Cytotoxic Thyroglobulin and Thyroperoxidase Epitope-Specific Cellular Immunity in Hashimoto's Thyroiditis
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Margret Ehlers, Werner A. Scherbaum, Annette Thiel, Hubertus Hautzel, Claudia Papewalis, Matthias Schott, Holger S. Willenberg, Sven Schinner, Dominika Porwol, and Christian Bernecker
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Adult ,Male ,endocrine system ,medicine.medical_specialty ,Cellular immunity ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Biopsy, Fine-Needle ,Clinical Biochemistry ,Thyroid Gland ,Hashimoto Disease ,CD8-Positive T-Lymphocytes ,Autoantigens ,Iodide Peroxidase ,Thyroglobulin ,Biochemistry ,Thyroiditis ,Epitope ,Epitopes ,Young Adult ,Endocrinology ,Antibody Specificity ,Thyroid peroxidase ,Iron-Binding Proteins ,Internal medicine ,HLA-A2 Antigen ,medicine ,Humans ,Cytotoxic T cell ,Aged ,Autoantibodies ,Immunity, Cellular ,biology ,Goiter ,business.industry ,Biochemistry (medical) ,Thyroid ,Antibody-Dependent Cell Cytotoxicity ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Immunology ,biology.protein ,Female ,business - Abstract
Hashimoto's thyroiditis (HT) is a common autoimmune disease leading to thyroid destruction due to lymphocytic infiltration. Only rare data are available regarding the recognition of specific cellular antigens, e.g. of thyroperoxidase (TPO) and thyroglobulin (Tg).The aim of this study was to quantify and characterize TPO- and Tg-epitope-specific CD8-positive T cells of HT patients.Six different human leukocyte antigen (HLA)-A2 restricted, TPO- or Tg-specific tetramers were synthesized and used for measuring CD8-positive T cells in HT patients and controls.The frequency of peripheral TPO- and Tg-specific CD8-positive T cells was significantly higher in HLA-A2-positive HT patients (2.8 ± 9.5%) compared with HLA-A2-negative HT patients (0.5 ± 0.7%), HLA-A2-positive nonautoimmune goiter patients (0.2 ± 0.4%), and HLA-A2-positive healthy controls (0.1 ± 0.2%). The frequency of Tg-specific T cells (3.0%) was very similar to those of TPO-specific CD8-positive T cells (2.9%). Subgroup analyses revealed a steady increase of the number of epitope-specific CD8-positive T cells from 0.6 ± 1.0% at initial diagnosis up to 9.4 ± 18.3% in patients with long-lasting disease. Analyses of the number of thyroid-infiltrating cells as well as the cytotoxic capacity revealed a similar picture for TPO- and Tg-specific T cells.We here report for the first time that both antigens, TPO and Tg, are recognized by CD8-positive T cells and are involved in the thyroid destruction process leading to clinical disease manifestation.
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- 2012
63. Endokrine Hypertonie - Neuigkeiten und jüngste Entwicklungen
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Stefan R. Bornstein, Graeme Eisenhofer, Matthias Gruber, and Holger S. Willenberg
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Pheochromocytoma ,chemistry.chemical_compound ,medicine.medical_specialty ,Aldosterone ,Endocrinology ,chemistry ,business.industry ,Internal medicine ,medicine ,General Medicine ,business ,medicine.disease ,Endocrine hypertension - Published
- 2012
64. Adipocyte-secreted factors increase osteoblast proliferation and the OPG/RANKL ratio to influence osteoclast formation
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Sven Schinner, Werner A. Scherbaum, Markus C. Kühn, Ulla Stumpf, Matthias Schott, Claudia Papewalis, Holger S. Willenberg, and Sascha Flohé
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musculoskeletal diseases ,medicine.medical_specialty ,Cell signaling ,Osteoclasts ,Enzyme-Linked Immunosorbent Assay ,Real-Time Polymerase Chain Reaction ,Biochemistry ,Mice ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Endocrinology ,Osteogenesis ,Osteoclast ,Internal medicine ,Adipocyte ,Adipocytes ,medicine ,Animals ,Humans ,Secretion ,RNA, Messenger ,Receptor, Fibroblast Growth Factor, Type 1 ,Protein Kinase Inhibitors ,Molecular Biology ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Phosphoinositide-3 Kinase Inhibitors ,Osteoblasts ,biology ,Chemistry ,RANK Ligand ,Osteoprotegerin ,Cell Differentiation ,Osteoblast ,medicine.anatomical_structure ,RANKL ,Culture Media, Conditioned ,biology.protein ,Platelet-derived growth factor receptor - Abstract
Several studies have reported a positive relationship of the body fat mass and bone density. However, it is not clear whether adipocyte-derived signaling molecules directly act on osteoblasts or osteoclasts. Therefore, we investigated the effect of fat cell-secreted factors on the proliferation and differentiation of preosteoblasts and the molecular mechanisms involved. This stimulation led to an increased proliferation of MC3T3-E1 and primary preosteoblastic cells (2.8-fold and 1.5-fold, respectively; p
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- 2012
65. Loss of PTEN Expression in Neuroendocrine Pancreatic Tumors
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M. Krausch, Holger S. Willenberg, Matthias Schott, Kenko Cupisti, Andreas Raffel, Nadja Lehwald, Wolfram T. Knoefel, D Hafner, Martin Anlauf, and Eisenberger Cf
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Tumor suppressor gene ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Neuroendocrine tumors ,World Health Organization ,Biochemistry ,Young Adult ,Endocrinology ,medicine ,Humans ,PTEN ,Tensin ,Survival analysis ,Aged ,Neoplasm Staging ,Aged, 80 and over ,biology ,Biochemistry (medical) ,PTEN Phosphohydrolase ,Cell migration ,General Medicine ,Middle Aged ,medicine.disease ,Survival Analysis ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,Tumor progression ,Lymphatic Metastasis ,biology.protein ,Cancer research ,Immunohistochemistry ,Female - Abstract
PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor.
- Published
- 2011
66. Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism
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Martin Späth, Martin Anlauf, Holger S. Willenberg, Christiane Antke, and Svetlana Korovkin
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medicine.medical_specialty ,Hydrocortisone ,Adenoma ,Endocrinology, Diabetes and Metabolism ,Adrenal Gland Neoplasms ,chemistry.chemical_compound ,Endocrinology ,Primary aldosteronism ,Internal medicine ,Hyperaldosteronism ,medicine ,Animals ,Humans ,Aldosterone ,Dexamethasone ,Subclinical infection ,business.industry ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,chemistry ,Zona glomerulosa ,business ,Glucocorticoid ,Hormone ,medicine.drug - Abstract
Current guidelines suggest proving angiotensin-independent aldosterone secretion in patients with primary aldosteronism (PA). It is further recommended to demonstrate unilateral disease because of its consequence for therapy. A general screening for excess secretion of other hormones is not recommended. However, clinically relevant autonomous aldosterone production rarely originates in adrenal tumors, compromised of zona glomerulosa cells only. This article reviews published data on aldosterone- and cortisol-co-secreting tumors and shows that pre-operative diagnosis of such a lesion is beneficial for patients. Overt or subclinical glucocorticoid hypersecretion may interfere with diagnostic studies, e.g. adrenal venous sampling, screening of familial forms of PA on the basis of serum 18-hydroxy-cortisol (18-OH-F) determination, and provoke glucocorticoid deficiency after surgical removal of the tumor. In addition, knowledge from histological and molecular studies in patients with aldosterone- and cortisol-co-secreting tumors challenges some concepts of the development of adrenal autonomy. The presence of an aldosterone- and cortisol-co-secreting adrenocortical tumor should be considered if a patient has i) PA and an adenoma that is larger than 2.5 cm, ii) cortisol that is non-suppressible with overnight low-dose dexamethasone, or iii) grossly elevated serum levels of hybrid steroids, such as 18-OH-F.
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- 2011
67. Chromogranin A as potential target for immunotherapy of malignant pheochromocytoma
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Claudia Papewalis, Andreas Raffel, Dominika Porwol, Benedikt Jacobs, Holger S. Willenberg, Hartmut P. H. Neumann, Stefan R. Bornstein, Margret Ehlers, Sven Schinner, Werner A. Scherbaum, Matthias Schott, Christiane Kouatchoua, Martin Anlauf, and Graeme Eisenhofer
- Subjects
endocrine system ,endocrine system diseases ,T-Lymphocytes ,medicine.medical_treatment ,Adrenal Gland Neoplasms ,Bone Marrow Cells ,Mice, Transgenic ,Pheochromocytoma ,Biology ,Cancer Vaccines ,Biochemistry ,Mice ,Endocrinology ,Immune system ,Cell Line, Tumor ,medicine ,Animals ,Cytotoxic T cell ,Amino Acid Sequence ,neoplasms ,Molecular Biology ,Liver Neoplasms ,Chromogranin A ,Dendritic Cells ,Dendritic cell ,Immunotherapy ,medicine.disease ,Xenograft Model Antitumor Assays ,Mice, Inbred C57BL ,CTL ,Immunology ,biology.protein ,Cancer research ,Lymph Nodes ,Peptides ,Spleen ,CD8 - Abstract
Currently, no effective treatment for malignant pheochromocytoma exists. The aim of our study was to investigate the role of chromogranin A (CgA) as a specific target molecule for immunotherapy in a murine model for pheochromocytoma. Six amino acid-modified and non-modified CgA peptides were used for dendritic cell vaccination. Altogether, 50 mice received two different CgA vaccination protocols; another 20 animals served as controls. In vitro tetramer analyses revealed large increases of CgA-specific cytotoxic T cells (CTL) in CgA-treated mice. Tumors of exogenous applied pheochromocytoma cells showed an extensive infiltration by CD8+ T cells. In vitro, CTL of CgA-treated mice exhibited strong MHC I restricted lysis capacities towards pheochromocytoma cells. Importantly, these mice showed strongly diminished outgrowth of liver tumors of applied pheochromocytoma cells. Our data clearly demonstrate that CgA peptide-based immunotherapy induces a cytotoxic immune response in experimental pheochromocytoma, indicating potential for therapeutic applications in patients with malignant pheochromocytoma.
- Published
- 2011
68. Many Channels Lead to Aldosterone
- Author
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Holger S. Willenberg
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Calcium Channels, L-Type ,lcsh:Medicine ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Calcium Channels, T-Type ,Internal medicine ,Hyperaldosteronism ,CACNA1H ,medicine ,Animals ,Humans ,Adrenal ,Lead (electronics) ,Aldosterone ,lcsh:R5-920 ,Tumor ,biology ,business.industry ,lcsh:R ,General Medicine ,medicine.disease ,030104 developmental biology ,Endocrinology ,chemistry ,G Protein-Coupled Inwardly-Rectifying Potassium Channels ,Mutation (genetic algorithm) ,Mutation ,Hypertension ,biology.protein ,Commentary ,business ,lcsh:Medicine (General) - Published
- 2016
69. Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome
- Author
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Silviu Sbiera, Stefanie Hahner, Sebastian Schmull, Patrick Adam, Martin Fassnacht, Holger S. Willenberg, Martina Hartmann, Marcus Quinkler, Wolfgang Saeger, Hans-Ullrich Voelker, Barbara Heinrich, Bruno Allolio, and Philipp Ströbel
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Gene Expression ,Polymerase Chain Reaction ,Pathology and Forensic Medicine ,Adrenocortical adenoma ,Surgical pathology ,Gene expression ,Biomarkers, Tumor ,medicine ,Humans ,Adrenocortical carcinoma ,Epidermal growth factor receptor ,Aged ,Aged, 80 and over ,biology ,Gene Expression Profiling ,Middle Aged ,Prognosis ,medicine.disease ,Immunohistochemistry ,Adrenal Cortex Neoplasms ,ErbB Receptors ,Gene expression profiling ,Tissue Array Analysis ,Adrenocortical Adenoma ,biology.protein ,Female ,Hematopathology - Abstract
Adrenocortical carcinoma is a rare but highly malignant neoplasm with still limited treatment options. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in many solid tumors, but its expression in adrenocortical carcinoma has been studied only in a limited number of cases. Therefore, we analyzed the expression of EGFR in 169 adrenocortical carcinoma samples and compared it with 31 adrenocortical adenomas. Additionally, in 30 cases of adrenocortical carcinoma, exons 18-21 of the EGFR gene were cloned and sequenced. EGFR expression was found in 128 of 169 adrenocortical carcinoma samples (76%), and in 60 of these samples (=36%) strong membrane staining was detected. However, there was no significant correlation with clinical outcome. In addition, all 30 sequenced cases revealed unmutated EGFR genes. In contrast, only 1 out of 31 adrenocortical adenomas weakly expressed the EGFR (3%). In summary, EGFR was overexpressed in more than three-quarters of adrenocortical carcinoma cases of this series. However, no mutations of the EGFR gene were found and EGFR expression was not of prognostic relevance. As EGFR is hardly expressed in adrenocortical adenomas, our results suggest that its expression in adrenocortical tumors indicates a malignant phenotype, which may be used in the differential diagnosis between adrenocortical adenomas and carcinomas.
- Published
- 2010
70. A new mutation in the menin gene causes the multiple endocrine neoplasia type 1 syndrome with adrenocortical carcinoma
- Author
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Elke Kaminsky, Matthias Schott, Holger S. Willenberg, Matthias Haase, Sven Schinner, Martin Anlauf, and Werner A. Scherbaum
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,endocrine system diseases ,Tumor suppressor gene ,Endocrinology, Diabetes and Metabolism ,Neuroendocrine tumors ,Biology ,Fatal Outcome ,Endocrinology ,Proto-Oncogene Proteins ,Adrenocortical Carcinoma ,Multiple Endocrine Neoplasia Type 1 ,medicine ,Humans ,Point Mutation ,Adrenocortical carcinoma ,Endocrine system ,Neoplasm Invasiveness ,MEN1 ,Multiple endocrine neoplasia ,Family Health ,Adrenal cortex ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,medicine.anatomical_structure ,Cancer research ,Female ,Pancreas - Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome that may be caused by mutations in the MEN1 gene on 11q13. Loss of function of the tumor suppressor gene MEN1 leads to synchronous or metachronous appearance of neuroendocrine tumors arising from neuroendocrine cells of the parathyroid and pituitary glands, the duodenum and pancreatic islets, and other endocrine organs such as the adrenal cortex. We here present a patient with MEN1 who developed hyperparathyroidism, multiple well differentiated functionally inactive neuroendocrine tumors of the pancreas and an adrenal carcinoma. We describe a new mutation at codon 443 in the coding region of exon 9 in the MEN1 gene, where a cytosine residue was exchanged for adenosine (TCCTAC) and, consequently, serine for tyrosine (p.Ser443Tyr; c.1328CA). [corrected] Also, we provide clinical data that may add to the genotype-phenotype discussion. We conclude that the novel mutation in the MEN1 gene described herein was clinically relevant.
- Published
- 2010
71. High Diagnostic and Prognostic Value of Steroidogenic Factor-1 Expression in Adrenal Tumors
- Author
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Holger S. Willenberg, Silviu Sbiera, Melanie Beyer, Stefanie Hahner, Felix Beuschlein, Luitgard Kraus, Martin Fassnacht, Guillaume Assié, Sebastian Schmull, Bruno Ragazzon, Bruno Allolio, Hans-Ullrich Voelker, Jérôme Bertherat, and Wolfgang Saeger
- Subjects
Adult ,Male ,Steroidogenic factor 1 ,medicine.medical_specialty ,Pathology ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Adrenal Gland Neoplasm ,Context (language use) ,Ovary ,Biology ,Steroidogenic Factor 1 ,Sensitivity and Specificity ,Biochemistry ,Cohort Studies ,Diagnosis, Differential ,Translational Highlights from Jcem ,Endocrinology ,Predictive Value of Tests ,Internal medicine ,Adrenocortical Carcinoma ,Biomarkers, Tumor ,medicine ,Humans ,Adrenocortical carcinoma ,Neoplasm Metastasis ,Molecular Biology ,Neoplasm Staging ,Biochemistry (medical) ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Adrenal Cortex Neoplasm ,Immunohistochemistry ,Adrenal Cortex Neoplasms ,Gene Expression Regulation, Neoplastic ,stomatognathic diseases ,medicine.anatomical_structure ,Adrenocortical Adenoma ,Female ,Differential diagnosis - Abstract
No immunohistochemical marker has been established to reliably differentiate adrenocortical tumors from other adrenal masses. A panel of markers like melan-A and inhibin-α is currently used for this purpose but suffers from limited diagnostic accuracy. We hypothesized that expression of steroidogenic factor-1 (SF-1), a transcription factor involved in adrenal development, is of value for the differential diagnosis of adrenal masses and predicts prognosis in adrenocortical carcinoma (ACC).SF-1 protein expression was assessed by immunohistochemistry on tissue samples from 167 ACC, 52 adrenocortical adenomas (ACA), six normal adrenal glands, six normal ovaries and 73 neoplastic nonsteroidogenic tissues. In an independent cohort of 33 ACC and 58 ACA, SF-1 mRNA expression was analyzed. SF-1 expression was correlated with clinical outcome in patients with ACC.SF-1 protein staining was detectable in 158 of 161 (98%) evaluable ACC samples including 49 (30%) with strong SF-1 staining and in all normal and benign steroidogenic tissues. In addition, SF-1 mRNA expression was present in all 91 analyzed adrenocortical tumors. In contrast, SF-1 expression was absent in all nonsteroidogenic tumors. Strong SF-1 protein expression significantly correlated with poor clinical outcome: tumor stage-adjusted hazard ratio for death 2.46 [95% confidence interval (CI) = 1.30-4.64] and for recurrence 3.91 (95% CI = 1.71-8.94). Similar results were obtained in the independent cohort using RNA analysis [tumor stage-adjusted hazard ratio for death 4.69 (95% CI = 1.44-15.30)].SF-1 is a highly valuable immunohistochemical marker to determine the adrenocortical origin of an adrenal mass with high sensitivity and specificity. In addition, SF-1 expression is of stage-independent prognostic value in patients with ACC.
- Published
- 2010
72. The CB-1 Receptor Antagonist Rimonabant Modulates the Interaction Between Adipocytes and Pancreatic Beta-Cells in Vitro
- Author
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Matthias Schott, Holger S. Willenberg, F Ülgen, Werner A. Scherbaum, Kenko Cupisti, Sven Schinner, C. Herder, and M. C. Kühn
- Subjects
medicine.medical_specialty ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,Biology ,Statistics, Nonparametric ,chemistry.chemical_compound ,Endocrinology ,Piperidines ,Rimonabant ,Insulin-Secreting Cells ,Adipocyte ,Internal medicine ,Insulin Secretion ,Adipocytes ,Internal Medicine ,medicine ,Humans ,Insulin ,Receptor ,Cannabinoid Receptor Antagonists ,Cells, Cultured ,Cell Proliferation ,Adiponectin ,Wnt signaling pathway ,General Medicine ,Receptor antagonist ,chemistry ,Pyrazoles ,Cannabinoid receptor antagonist ,medicine.drug - Abstract
Background Adipocytes produce signalling molecules which can act on target cells including pancreatic beta-cells. In previous studies we found adipocytes to directly stimulate insulin secretion and the proliferation of pancreatic beta-cells in vitro. Rimonabant acts as an antagonist at the cannabinoid-1 (CB-1) receptor which is expressed on adipocytes. Rimonabant decreases insulin levels in vivo. This effect can either be explained by improving insulin sensitivity or by effects on beta-cells including the modulation of adipocyte - beta-cell interactions. Objectives To test how pre-treatment of primary human adipocytes with rimonabant affects the cross-talk between adipocytes and pancreatic beta-cells in vitro. Results Rimonabant had no direct effect on insulin secretion or beta-cell proliferation at a concentration range from 1 nM to 1 μM. This is in line with previous findings showing that in the murine pancreas CB-1 receptors are preferentially expressed on non-beta-cells, while rimonabant is a selective blocker of CB-1 receptors. We found fat-cell conditioned-medium without (FCCM) and after pre-treatment for 24 h with 100 nM rimonabant (FCCM-RB) to induce insulin secretion from primary murine beta-cells to a similar extent. Proliferation of a pancreatic beta-cell line was enhanced by FCCM to 219%, while FCCM-RB inhibited proliferation to 53%. As we previously found Wnt-signalling to mediate effects of adipocytes on beta-cell proliferation we tested the ability of FCCM and FCCM-RB to activate canonical Wnt-signalling in target cells. However, there was no significant difference between the groups: FCCM and FCCM-RB stimulated Wnt reporter gene activity to 181% and 179%, respectively. In addition, there was no significant difference in adiponectin levels between FCCM and FCCM-RB (56.8 vs. 58.1 ng/ml), showing that adiponectin does not mediate the differential effects on beta-cell proliferation by FCCM and FCCM-RB. Conclusion Our data show that rimonabant modulates the adipocyte - beta-cell interaction with respect to beta-cell proliferation and indicate that signalling molecules other than adiponectin and components of the Wnt pathway mediate this cross-talk.
- Published
- 2010
73. Gastroenteropankreatische neuroendokrine Tumoren: Molekulargenetische Charakteristika
- Author
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M. Krausch, Andreas Raffel, Paul Komminoth, Kenko Cupisti, Holger S. Willenberg, Günter Klöppel, Wolfram T. Knoefel, Anja Schmitt, Sebastian Heikaus, Nikolas H. Stoecklein, Aurel Perren, Martin Anlauf, Matthias Schott, and Juliane Bauersfeld
- Subjects
Gastrointestinal ,Pankreas ,Neuroendokriner Tumor ,Expressions-Array ,Komparative genomische Hybridisierung ,LOH ,Verlust der Heterozygosität ,Mutationsanalyse ,Gastroenterology ,Surgery ,ddc - Abstract
Neuroendokrine Tumoren des gastroenteropankreatischen Systems (GEP-NET) sind charakterisiert durch die Expression neuroendokriner Marker sowie die Synthese, Speicherung und Sekretion von Peptidhormonen und/ oder biogenen Aminen. Es handelt sich um mehr als 50 unterschiedliche Tumorentitäten mit klinisch sehr unterschiedlichem Verlauf. Sie können sporadisch oder familiär auftreten. Die hohe biologische und klinische Vielfalt äußert sich in unterschiedlichen genetischen Profilen auf DNA- und mRNA-Ebene, welche wie folgt zusammengefasst werden können: 1. NET unterscheiden sich genetisch von den häufigen nichtneuroendokrinen Karzinomen des Verdauungstraktes. 2. Die klinisch-pathologische Heterogenität der GEP-NET spiegelt sich auch auf genetischer Ebene wider. 3. Bei pankreatischen NET finden sich deutliche genetische Unterschiede zwischen Insulinomen und anderen Entitäten. 4. Die Tumorprogression geht bei pankreatischen NET mit einer Zunahme von genetischen Veränderungen einher. 5. Pankreatische NET unterscheiden sich genetisch von gastrointestinalen NET. 6. Sporadische GEP-NET unterscheiden sich genetisch von hereditären (familiären) GEP-NET.
- Published
- 2010
74. Inhalt Band 26, 2010 / Contents Vol. 26, 2010
- Author
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Nour Eldin A. Nour-Eldin, Thomas M. Gress, Martin Anlauf, Andrea Frilling, Bertram Wiedenmann, Juliane Bauersfeld, Georgios C. Sotiropoulos, Andreas Raffel, Marianne Pavel, Dirk L. Stippel, Matthias Schott, Nikolaus Lubomierski, Thomas J. Vogl, Frank Grünwald, Günter Klöppel, Jörg Bojunga, Michele Tedeschi, Paul Komminoth, Stefan Zangos, Tatjana Gruber-Rouh, Anja Rinke, Anja Schmitt, Jun Li, Oskar Kornasiewicz, Nikolas H. Stoecklein, Aurel Perren, Jörg Trojan, Holger S. Willenberg, Sebastian Heikaus, M. Krausch, Kenko Cupisti, Ursula Plöckinger, and Wolfram T. Knoefel
- Subjects
Gastroenterology ,Surgery - Published
- 2010
75. Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: Antiproliferative effects of peptide analogues
- Author
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Andrew V. Schally, Stefan R. Bornstein, Andrea Treszl, A Erler, Louise Young, Graeme Eisenhofer, Linda Gebauer, S Petersenn, Monika Ehrhart-Bornstein, Christian G. Ziegler, L M Fishman, J B Engel, Jacqueline T. Brown, and Holger S. Willenberg
- Subjects
Receptors, Neuropeptide ,endocrine system ,medicine.medical_specialty ,Receptor expression ,Cell ,Adrenal Gland Neoplasms ,Gene Expression ,Neuropeptide ,Biology ,PC12 Cells ,Cell Line, Tumor ,Internal medicine ,Adrenal Glands ,medicine ,Animals ,Humans ,Pyrroles ,Elméleti orvostudományok ,RNA, Messenger ,Receptors, Somatostatin ,Receptor ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,2-Hydroxyphenethylamine ,Aniline Compounds ,Multidisciplinary ,Cell growth ,Neuropeptides ,Orvostudományok ,Biological Sciences ,Cytostatic Agents ,Rats ,Somatostatin ,Endocrinology ,medicine.anatomical_structure ,Doxorubicin ,Hormone receptor ,Receptors, LHRH ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Peptide analogues targeting various neuropeptide receptors have been used effectively in cancer therapy. A hallmark of adrenocortical tumor formation is the aberrant expression of peptide receptors relating to uncontrolled cell proliferation and hormone overproduction. Our microarray results have also demonstrated a differential expression of neuropeptide hormone receptors in tumor subtypes of human pheochromocytoma. In light of these findings, we performed a comprehensive analysis of relevant receptors in both human adrenomedullary and adrenocortical tumors and tested the antiproliferative effects of peptide analogues targeting these receptors. Specifically, we examined the receptor expression of somatostatin-type-2 receptor, growth hormone-releasing hormone (GHRH) receptor or GHRH receptor splice variant-1 (SV-1) and luteinizing hormone-releasing hormone (LHRH) receptor at the mRNA and protein levels in normal human adrenal tissues, adrenocortical and adrenomedullary tumors, and cell lines. Cytotoxic derivatives of somatostatin AN-238 and, to a lesser extent, AN-162, reduced cell numbers of uninduced and NGF-induced adrenomedullary pheochromocytoma cells and adrenocortical cancer cells. Both the splice variant of GHRH receptor SV-1 and the LHRH receptor were also expressed in adrenocortical cancer cell lines but not in the pheochromocytoma cell line. The GHRH receptor antagonist MZ-4–71 and LHRH antagonist Cetrorelix both significantly reduced cell growth in the adrenocortical cancer cell line. In conclusion, the expression of receptors for somatostatin, GHRH, and LHRH in the normal human adrenal and in adrenal tumors, combined with the growth-inhibitory effects of the antitumor peptide analogues, may make possible improved treatment approaches to adrenal tumors.
- Published
- 2009
76. Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy
- Author
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Sarah Johanssen, Luitgard Kraus, Sebastian Wortmann, Cristina L. Ronchi, Silviu Sbiera, Bruno Allolio, Martin Fassnacht, Patrick Adam, Stefanie Hahner, and Holger S. Willenberg
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Platinum Compounds ,Gastroenterology ,Cohort Studies ,Endocrinology ,ERCC1 Protein Expression ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Adrenocortical Carcinoma ,Biomarkers, Tumor ,medicine ,Humans ,Adrenocortical carcinoma ,Excision repair cross-complementing ,Retrospective Studies ,Chemotherapy ,business.industry ,Hazard ratio ,Cancer ,Middle Aged ,Endonucleases ,Prognosis ,medicine.disease ,Adrenal Cortex Neoplasms ,DNA-Binding Proteins ,Oncology ,Immunohistochemistry ,Female ,ERCC1 ,business ,Follow-Up Studies - Abstract
Therapeutic progress in adrenocortical carcinoma (ACC) is severely hampered by its low incidence. Platinum-based chemotherapies are the most effective cytotoxic treatment regimens in ACC but response rates remain n=45), objective response to platinum compounds was observed in 3/21 patients (14.3%) with high ERCC1 expression and in 7/24 patients (29.2%) with low ERCC1 expression (P=0.23). ERCC1 expression was strongly correlated with overall survival after platinum treatment (median: eight months in patients with high ERCC1 versus 24 months in low ERCC1 expression, hazard ratio (HR) 2.95 (95% confidence interval (CI) 1.4–6.2), P=0.004). Multivariate analysis confirmed that high ERCC1 expression was a predictive factor for poor prognosis in platinum treated patients (HR 2.2, 95% CI 1.0–4.5, P=0.038). Our findings suggest that ERCC1 expression is the first factor for predicting survival in ACC patients treated with platinum-based chemotherapy.
- Published
- 2009
77. Stathmin as a Marker for Malignancy in Pheochromocytomas
- Author
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Kenko Cupisti, Anders Isaksson, Holger S. Willenberg, Gunnar Westin, Mårten Fryknäs, Göran Åkerström, Peyman Björklund, and Per Hellman
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Microarray ,Endocrinology, Diabetes and Metabolism ,Blotting, Western ,Adrenal Gland Neoplasms ,Stathmin ,Pheochromocytoma ,Malignancy ,Metastasis ,Diagnosis, Differential ,Young Adult ,Endocrinology ,Biomarkers, Tumor ,Internal Medicine ,medicine ,Humans ,RNA, Messenger ,Aged ,Oligonucleotide Array Sequence Analysis ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Gene Expression Profiling ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Adrenal Medulla ,biology.protein ,Female ,Differential diagnosis ,business - Abstract
Pheochromocytomas of the adrenal medulla may be life-threatening catecholamine-producing tumors which are malignant in about 10% of cases. Differential diagnosis between malignant and benign tumors is dependent on the development of metastasis or extensive local invasion. A number of genetic aberrations have been described in pheochromocytomas, but no marker associated to malignancy has been reported. We applied an expression microarray containing 7770 cDNA clones and analysed the expression profiles in eleven tumors compared to normal adrenal medulla. Stathmin (STMN1, Op18) was most conspiciously overexpressed among the differentially expressed genes. RT-PCR analysis further confirmed mRNA overexpression, 6 to 8-fold for benign and malignant tumors, and 16-fold for metastases. Stathmin protein overexpression was observed by immunohistochemistry, and distinct differential protein expression between benign and malignant/metastasis specimens was confirmed by Western blot analysis. The results introduce stathmin as a possible diagnostic marker for malignant pheochromocytomas, and further evaluations are warranted.
- Published
- 2009
78. The serum sodium to urinary sodium to (serum potassium)2to urinary potassium (SUSPPUP) ratio in patients with primary aldosteronism
- Author
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Holger S. Willenberg, Marcus Quinkler, W. A. Scherbaum, M. Krausch, Kenko Cupisti, C. Kolentini, and Matthias Schott
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,Potassium ,Statistics as Topic ,Clinical Biochemistry ,Urology ,chemistry.chemical_element ,Urine ,Essential hypertension ,Biochemistry ,Primary Adrenal Insufficiency ,chemistry.chemical_compound ,Primary aldosteronism ,Mineralocorticoids ,Internal medicine ,Hyperaldosteronism ,Renin ,medicine ,Humans ,Aldosterone ,business.industry ,Sodium ,General Medicine ,medicine.disease ,Endocrinology ,chemistry ,Mineralocorticoid ,Female ,business - Abstract
Background The aldosterone-to-renin ratio (ARR) is an established diagnostic tool in the screening for primary aldosteronism (PA). However, hormonal determinations are time consuming and expensive. Therefore, we studied the effectiveness of the serum sodium to urinary sodium to (serum potassium)2 to urinary potassium (SUSPPUP) ratio in the diagnosis of PA. Design This study included 35 patients with PA, 71 patients with essential hypertension to whom this diagnosis could be excluded, 23 normal subjects without hypertension, and 22 patients with primary adrenal insufficiency. We compared the SUSPPUP ratios with the ARR in these patient groups. Results We show that the ARR distinguished PA from essential hypertension with a sensitivity of 94·2% and a specificity of 92·1% at a cutoff of 33 (ng L−1: ng L−1). It correlated well with the SUSPPUP ratio. The sensitivity and specificity of SUSPPUP was 88·6% and 85·9% at a cutoff of 5.3 (mmol L−1)−1, respectively, and thus not as good as the ARR. Conclusions The ARR is a good parameter in the screening for PA. The SUSPPUP ratio is a cheap and rapid tool to assess the extent of mineralocorticoid excess and, therefore, can be offered to more patients. In addition, the application of the SUSPPUP ratio can be extended to patients who suffer from other forms of mineralocorticoid hypertension (e.g. with low aldosterone levels).
- Published
- 2009
79. Association of Impaired Glucose Metabolism in Morbid Obesity with Hypoadiponectinaemia
- Author
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Werner A. Scherbaum, Kerstin Kempf, Holger S. Willenberg, H. Overmann, C. Herder, Sven Schinner, B. Rose, and Matthias Schott
- Subjects
Adult ,Male ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Inflammation ,Proinflammatory cytokine ,Cohort Studies ,Impaired glucose tolerance ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Glucose Intolerance ,Internal Medicine ,medicine ,Humans ,RNA, Messenger ,Chemokine CCL2 ,Adiponectin ,Interleukin-6 ,business.industry ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,General Medicine ,Middle Aged ,medicine.disease ,Obesity ,Obesity, Morbid ,Glucose ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Cytokines ,Female ,medicine.symptom ,business ,Body mass index ,hormones, hormone substitutes, and hormone antagonists - Abstract
Background: Increased circulating levels of cytokines and chemokines and decreased adiponectin levels are associated with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). As obesity is the major risk factor for T2DM it is not clear why many patients with morbid obesity remain normoglycaemic and if this protection can be attributed to a lower grade of inflammation or higher adiponectin levels. Materials and methods: Glucose tolerance of morbidly obese patients (n=2754, body mass index ≥40kg/m 2 ) was assessed by oral glucose tolerance tests. In a case-control design we compared levels of eight immune mediators and adiponectin from patients with IGT/T2DM (n=52) and normal glucose tolerance (NGT; n=59). Gene expression in peripheral blood was determined by quantitative RT-PCR, and serum concentrations of immune mediators and adiponectin were measured by ELISA and bead-based multiplex technology. Results: About 54% of the patients in our morbidly obese cohort were normoglycaemic, while 14% were diagnosed with IGT and 32% with T2DM. There was no statistically significant difference in mRNA expression or serum levels of proinflammatory markers. Interestingly, we could demonstrate an association of NGT with higher adiponectin levels (p=0.039). Adiponectin levels were negatively correlated with interleukin (IL)-6 and macrophage chemoattractant protein (MCP)-1, but independent the other immune mediators. Conclusions: We found an association of lower adiponectin levels with IGT/T2DM, but no further increase in inflammatory markers in morbid obesity. This suggests that in addition to chronic, low-grade inflammation, adiponectin is an important factor in the development of, or protection against, T2DM in obesity.
- Published
- 2008
80. The Endothelium Secretes Interleukin-6 (IL-6) and Induces IL-6 and Aldosterone Generation by Adrenocortical Cells
- Author
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I. Ansurudeen, A Raffel, Matthias Schott, Sven Schinner, B Wess, Werner A. Scherbaum, K Schebesta, Matthias Haase, and Holger S. Willenberg
- Subjects
Cortisol secretion ,medicine.medical_specialty ,Endothelium ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Biology ,Transfection ,chemistry.chemical_compound ,Endocrinology ,Genes, Reporter ,Internal medicine ,Paracrine Communication ,Internal Medicine ,medicine ,Humans ,Aldosterone ,Cells, Cultured ,Interleukin-6 ,Adrenal cortex ,Adrenal gland ,General Medicine ,Angiotensin II ,Coculture Techniques ,medicine.anatomical_structure ,Cytokine ,chemistry ,Mineralocorticoid ,Culture Media, Conditioned ,Adrenal Cortex ,Endothelium, Vascular - Abstract
Endothelial cells have been shown to induce adrenal steroidogenesis and to enhance aldosterone secretion via angiotensin II and endothelin 1-independent mechanisms. It has been demonstrated that endothelial cells and adrenocortical cells are capable of producing interleukin-6 (IL-6) and IL-6 is a factor known to stimulate adrenal cortisol secretion. We therefore asked whether endothelial cells have an effect on adrenal IL-6 generation and whether IL-6 mediates biosynthesis of aldosterone as is observed after exposure of adrenocortical cells to endothelial cell-conditioned medium (ECCM). Cells from the adrenocortical cancer cell line NCI-H295R were incubated with ECCM produced from human umbilical vein endothelial cells at increasing concentrations. As detected by an enzyme-linked immunosorbent assay, pure ECCM significantly increased IL-6 protein secretion by cultured adrenocortical cells in a dose-dependent fashion, to a 18.0+/-2.0 pg/mL (mean+/-SEM). This was paralleled by an enhanced IL-6 promoter activity as determined with the transfection of an IL-6-promoter-luciferase reporter gene construct. Pure ECCM also induced aldosterone secretion by adrenocortical cells more than three times that of controls with serum-free medium. ECCM PER SE contains significant amounts of IL-6 protein. However, blockade of IL-6 signal transduction did not interfere with aldosterone synthesis. These data suggest that endothelial cells secrete IL-6 and that endothelial cell-derived factors regulate adrenal IL-6 synthesis which does not alter adrenal aldosterone secretion. Our findings support the hypothesis that the endothelium and the adrenal gland may play a role in the development of some forms of hypertension and - more speculative - inflammation.
- Published
- 2008
81. Grundlagen und Management der glukokortikoidinduzierten Osteoporose
- Author
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Hendrik Lehnert and Holger S. Willenberg
- Subjects
Gynecology ,Fracture risk ,medicine.medical_specialty ,business.industry ,Internal Medicine ,medicine ,Bone mass density ,business - Abstract
Glukokortikoide beeintrachtigen den Knochenstoffwechsel auf verschiedenen Ebenen. Entsprechend ist die glukokortikoidinduzierte Osteoporose (GIO) die haufigste Form der sekundaren Osteoporose, und bis zu 50% der Patienten mit chronischer Glukokortikoidtherapie erleiden Frakturen. Das liegt u. a. auch daran, dass diese Osteoporoseform immer noch zu wenig diagnostiziert und behandelt wird. Auserdem ist das Frakturrisiko bei vergleichbarer Knochendichte gegenuber dem der primaren Ostepoporose erhoht. Das Frakturrisiko wird wesentlich durch die Hohe der Glukokortikoiddosis und die Dauer der Behandlung bestimmt, wenngleich der Knochenmasseverlust innerhalb der ersten 3–12 Monate nach Beginn der Glukokortikoidtherapie am grosten ist. Daneben haben auch weitere Faktoren – wie insbesondere die Grunderkrankung – wesentlichen Einfluss auf das Frakturrisiko. Ein diagnostisches Basisprogramm ist deshalb in allen Fallen notwendig und beinhaltet neben einer spezifischen Anamnese die korperliche Untersuchung, Laborbestimmungen, Knochendichtemessung und bildgebende Untersuchungen. Die Aufklarung und die medikamentose Pravention haben einen hohen Stellenwert, antiresorptive Therapeutika werden fruher eingesetzt als bei primarer Osteoporose, und auch die osteoanabole Therapie ist effektiv. Die evidenzbasierten Leitlinien des Dachverbands Osteologie stellen eine sehr wertvolle Hilfe bei der Betreuung betroffener Patienten dar.
- Published
- 2008
82. Amino Acid-Modified Calcitonin Immunization Induces Tumor Epitope-Specific Immunity in a Transgenic Mouse Model for Medullary Thyroid Carcinoma
- Author
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Claudia Papewalis, Benedikt Jacobs, Holger S. Willenberg, Werner A. Scherbaum, Caroline Kessler, Sven Schinner, Thomas Baehring, Margret Wuttke, Christine Kouatchoua, Matthias Schott, and Yvonne Meyer
- Subjects
Calcitonin ,Genetically modified mouse ,medicine.medical_specialty ,Epitopes, T-Lymphocyte ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Epitope ,Mice ,Endocrinology ,Immune system ,Antibody Specificity ,Antigens, Neoplasm ,Internal medicine ,medicine ,Animals ,Cytotoxic T cell ,Thyroid Neoplasms ,Amino Acids ,business.industry ,Immunotherapy, Active ,medicine.disease ,Tumor antigen ,Tumor Burden ,Mice, Inbred C57BL ,Disease Models, Animal ,Neutrophil Infiltration ,Medullary carcinoma ,Carcinoma, Medullary ,Immunization ,business ,CD8 - Abstract
Up to now, no relevant tumor antigen has been identified in medullary thyroid carcinoma (MTC). The aim of the present study was to prove the concept of an immunization with an amino acid-modified calcitonin (CT) for the treatment of MTC in a transgenic mouse model. Amino acid-modified (human) CT has been chosen for vaccination because of its higher binding affinity to the murine H2-Kb-MHC molecule. Mice were immunized over 6 months with monthly injections of amino acid-modified CT-pulsed dendritic cells. For enumeration of tumor epitope-specific CD8+ cytotoxic T cells, tetramer analyses were performed. CT peptide-treated mice revealed a mean 0.73 ± 0.45 and 0.91 ± 0.59% positive cells, depending on the two tetramers tested, whereas no increase was seen in control protein-immunized mice (0.08–0.12% tetramer-positive cells). Importantly, the subset of CT-specific CD8+ T cells also showed a high expression of interferon-γ. In line with these results, CT-immunized mice also showed an intratumor infiltration with CD8+ T lymphocytes. Importantly, we also found a diminished tumor outgrowth of −57% and a decrease of the serum CT levels (2.0 ± 0.1 pg/ml) compared with control protein-immunized Ret/Cal mice (3.0 ± 0.4 pg/ml). In summary, we show that amino acid-modified CT is recognized from the immune system leading to a specific antitumor immune response and a diminished tumor outgrowth in transgenic MTC mice. The results are of potential importance because they might be applicable to patients with metastatic spread of a MTC.
- Published
- 2008
83. New Mechanisms to Control Aldosterone Synthesis
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I. Ansurudeen, Sven Schinner, and Holger S. Willenberg
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Biogenic Amines ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Adrenal Gland Diseases ,Receptors, Cytoplasmic and Nuclear ,Secondary hypertension ,Adrenocorticotropic hormone ,Models, Biological ,Biochemistry ,chemistry.chemical_compound ,Catecholamines ,Endocrinology ,Primary aldosteronism ,Adipokines ,Adrenocorticotropic Hormone ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,Humans ,Aldosterone ,Angiotensin II receptor type 1 ,business.industry ,Neuropeptides ,Biochemistry (medical) ,General Medicine ,medicine.disease ,Conn's syndrome ,chemistry ,Pathophysiology of hypertension ,Cytokines ,Endothelium, Vascular ,business ,Metabolic Networks and Pathways - Abstract
Arterial hypertension is a frequent and leading cardiovascular risk factor, and primary aldosteronism is a well-recognized cause of secondary hypertension. Aldosterone is the basic regulator of extracellular fluid volume and electrolyte balance. Alterations in plasma aldosterone levels significantly contribute to the development and the severity of hypertension. Adrenal steroidogenesis is controlled by two major feedback loops: the hypothalamic-pituitary-adrenal axis, which regulates cortisol synthesis, and the renin-angiotensin-aldosterone system, which directs aldosterone production. In addition to angiotensin, potassium, and corticotropin-which belong to the classic stimulators of aldosterone-neuropeptides, catecholamines, and prostaglandins are also known to stimulate aldosterone synthesis. Recently, several new mechanisms have been characterized that control the release of aldosterone by adrenocortical cells, among them endothelial cell-derived factors and adipokines. Further identification and characterization of these factors may help in the development of novel therapies for the treatment of arterial hypertension, various metabolic diseases, and other disorders.
- Published
- 2008
84. Carcinogenic Hypergastrinemia: Signet-Ring Cell Carcinoma in a Patient with Multiple Endocrine Neoplasia Type 1 with Zollinger-Ellison’s Syndrome
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Kai Zacharowski, Andrea Varro, Sven Schinner, Holger S. Willenberg, Aurel Perren, Claus F. Eisenberger, Werner A. Scherbaum, Matthias Schott, Andreas Raffel, Cornelia Sagert, and Uwe Ramp
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Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Neuroendocrine tumors ,Models, Biological ,Biochemistry ,Zollinger-Ellison Syndrome ,Endocrinology ,Stomach Neoplasms ,Internal medicine ,Signet ring cell carcinoma ,Gastrins ,Multiple Endocrine Neoplasia Type 1 ,Carcinoma ,medicine ,Humans ,Enterochromaffin-like cell ,Multiple endocrine neoplasia ,Ultrasonography ,Gastrin ,Gastrinoma ,business.industry ,Biochemistry (medical) ,Middle Aged ,Cadherins ,medicine.disease ,digestive system diseases ,Zollinger-Ellison syndrome ,business ,Carcinoma, Signet Ring Cell - Abstract
Context: Gastric neuroendocrine tumors are rare neoplasms that originate from gastric enterochromaffin-like (ECL) cells in the oxyntic mucosa. Gastrin and its derivates have been reported to regulate epithelial cell proliferation, migration, and differentiation. Mutations in the epithelial cadherin (E-cadherin) gene have been shown to be associated with the occurrence of diffuse gastric carcinomas in affected families. Objective: In this study we investigated the histopathological and molecular findings in the gastrointestinal wall of a patient with multiple endocrine neoplasia type 1 with malignant duodenal gastrinoma and multiple gastric ECL cell tumors, who additionally developed a signet-ring cell carcinoma of the stomach. Design and Patient: Biopsies from the gastrointestinal tract of a patient with multiple endocrine neoplasia type 1 were immunostained for vesicular monoamine transporter-2 and E-cadherin. Nonamidated gastrin products were measured in the serum of the patient using antibodies that react with progastrin, Gly-extended, and amidated gastrins. Genetic analyses were performed to exclude germ-line mutations within the E-cadherin gene. Results: Immunohistochemical studies of gastric ECL cell tumors showed a largely diminished E-cadherin expression in comparison to gastric surface mucosa cells and a loss of E-cadherin expression in the cells of the signet-ring carcinoma. Detailed biochemical measurements revealed progastrin concentrations that were approximately 20%, and Gly-gastrin concentrations that were approximately 10% the amidated gastrin concentrations in plasma. Molecular analyses revealed no E-cadherin germ-line mutation. Conclusion: Our immunohistochemical studies might suggest that the gastrinoma-associated excessive progastrin tissue concentrations led to diminished expression of E-cadherin within the gastric mucosa and promoted tumor development of a signet-ring cell carcinoma.
- Published
- 2007
85. Serum Selenium Levels in Patients with Remission and Relapse of Graves Disease
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Cornelia Sagert, Joachim Feldkamp, Tina Wertenbruch, Holger S. Willenberg, Thi-Bang-Tam Nguyen, Matthias Schott, Claus Groeger, Maryam Bahlo, Werner A. Scherbaum, and Derik Hermsen
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Adult ,Male ,medicine.medical_specialty ,Graves' disease ,Trab ,Autoimmune thyroiditis ,Selenium ,Recurrence ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Outpatient clinic ,Euthyroid ,Aged ,Autoantibodies ,Retrospective Studies ,chemistry.chemical_classification ,business.industry ,Glutathione peroxidase ,Remission Induction ,Autoantibody ,Receptors, Thyrotropin ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Graves Disease ,Selenocysteine ,Treatment Outcome ,Endocrinology ,chemistry ,Female ,business - Abstract
Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyze the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and a thyroidal autoimmune process. The aim of this study was to investigate whether serum Se levels may influence the outcome of Graves' disease (GD).83 patients (77 women, 6 men) with active GD were retrospectively analyzed (mean age 40,0 years). Twenty-four GD patients went into remission and were euthyroid during follow-up (median follow-up: 20.1 months), whereas 59 patients did not go into remission or developed relapse over the following 24 months. TSH receptor autoantibodies (TRAb) were measured using the second generation assay on the basis of human TSH receptor. Se levels were determined at the first visit in our outpatient clinic and were correlated with TRAb levels and clinical outcome of these patients.Median TRAb levels in the group of remission were significantly (p0.0001) lower than TRAb values in the relapse group (2.1 as compared to 8.6 IU/l). By comparing mean serum Se levels in the remission and relapse group no significant differences were seen (73.0 vs. 71.7 microg/l). Detailed analyses of both groups of patients, however, revealed that highest serum Se levels (120 microg/l) were seen in the remission group, indicating a positive effect of Se levels on the outcome of GD. In addition, we also compared these results with TRAb levels of these patients. We could show that TRAb levels and serum Se values were positively correlated in the relapse group, whereas a negative correlation of both parameters were seen in the remission group, supporting the idea of a positive effect of Se on thyroidal autoimmune process.Our data indicate that high serum Se levels (120 microg/l) may influence the outcome of GD. This is important, as Se administration trials in GD, which are under discussion need to be performed with Se supplementation at higher dosages than used in autoimmune thyroiditis.
- Published
- 2007
86. Identification of occult metastases of medullary thyroid carcinoma by pentagastrin-stimulated intravenous calcitonin sampling followed by targeted surgery
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Wolfram T. Knoefel, Sven Schinner, Werner A. Scherbaum, Holger S. Willenberg, Thi-Bang-Tam Nguyen, Mathias Cohnen, Kenko Cupisti, Claus F. Eisenberger, Cornelia Sagert, and Matthias Schott
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Adult ,Calcitonin ,Male ,medicine.medical_specialty ,Luminescence ,Neoplasm, Residual ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Multiple Endocrine Neoplasia Type 2a ,Thyroid carcinoma ,Endocrinology ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Thyroid Neoplasms ,Thyroid cancer ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Thyroidectomy ,Magnetic resonance imaging ,Neck dissection ,Middle Aged ,medicine.disease ,Surgery ,Pentagastrin ,Medullary carcinoma ,Carcinoma, Medullary ,Lymphatic Metastasis ,Original Article ,Female ,business ,medicine.drug - Abstract
Summary Background High calcitonin (CT) serum levels suggest metastatic spread in medullary thyroid carcinoma (MTC) after thyroidectomy. In limited disease stages, however, morphological investigations including ultrasound, magnetic resonance imaging (MRI) and 18FFDG positron emission tomography ([18F]FDG-PET) may often fail to identify exact tumour sites. Objective The aim of the present study was to establish an improved strategy to identify small cervical tumours by combining pentagastrin stimulation with bilateral cervical intravenous CT sampling followed by high-resolution ultrasound. Design and patients Six MTC patients were examined, of whom five patients already had bilateral neck dissection. Five patients had sporadic MTC, and one patient suffered from MEN2a. Results Retrospective analysis of all patients revealed a highly sensitive positive correlation between an early calcitonin peak (20 ‐ 40 s after pentagastrin injection) and site of cervical tumour affection. Postinterventional ultrasound examination of the affected regions of the neck revealed suspicious presence; in some cases small lymph nodes of less than 1 cm in size were then surgically excised. On histology, small tumours could be identified in four patients. Postsurgical examination revealed a clear decline of basal serum calcitonin levels in four patients (between − 41% and − 100%). In two patients CT normalized to baseline levels (< 10 pg /ml) and in another two patients CT rendered to near normal (14 and 17 pg/ml). Conclusion Pentagastrin stimulation-based intravenous catheter sampling may be beneficial in the diagnostic work-up of MTC after thyroidectomy. Our data show that an early calcitonin peak (20 ‐ 40 s after administration of pentagastrin) helps to identify tumour-affected regions.
- Published
- 2007
87. Improved Prediction of Relapse of Graves' Thyrotoxicosis by Combined Determination of TSH Receptor and Thyroperoxidase Antibodies
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Holger S. Willenberg, Werner A. Scherbaum, Matthias Schott, Anja Eckstein, T. Nguyen, and N. G. Morgenthaler
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Graves' disease ,Clinical Biochemistry ,Trab ,Thyroperoxidase Antibody ,Iodide Peroxidase ,Biochemistry ,Endocrinology ,Recurrence ,Thyroid peroxidase ,Internal medicine ,medicine ,Humans ,In patient ,Receptor ,Aged ,Autoantibodies ,biology ,business.industry ,Biochemistry (medical) ,Receptors, Thyrotropin ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Predictive value ,Graves Disease ,Thyrotoxicosis ,biology.protein ,Female ,Antibody ,business - Abstract
Background: Recently, we and others have demonstrated that high levels of auto-antibodies to the human TSH-receptor (TRAb) predict relapse of hyperthyroidism in Graves' disease (GD). Our objective was to extend the outcome of the prediction by combining TRAb with thyroperoxidase antibody (TPO-Ab) measurement. Patients and Methods: One hundred and thirty-one GD patients (118 females, 13 males) were analysed, of whom 94 patients (71.8%) had relapse, whereas 37 (28.2%) went into remission. Second generation TRAb and TPO-Ab assays were performed in GD patients with relapse and remission in mean 4.3 months after initial diagnosis. Results: The mean anti-TPO-Ab levels were similar in all patients with relapse and remission. However, there was a steady decline from 4047U/ml to 530U/ml in the remission group that correlated positively with TRAb values (>2 to >10 IU/l). The relapse group remained at consistently high levels. The positive predictive value (PPV) for relapse in patients with TRAbs >6 IU/l and anti-TPO-Abs >5000U/ml was 100, whereas TRAbs >6 IU/l and anti-TPO-Abs >500 U/ml were associated with a PPV of 93.7 up to 96 (p=0.008). These Ab constellations accounted for about one third of all CD patients. For patients with TRAbs between >2 and
- Published
- 2007
88. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas
- Author
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Hendrik Lehnert, Gunnar Westin, Martin Bäckdahl, Kenko Cupisti, Samuel Backman, Ana Moser, Holger S. Willenberg, Julian C. Y. Ip, Peyman Björklund, Rajani Maharjan, Johan Botling, Henning Dralle, K. Alexander Iwen, Bruce G. Robinson, Stan B. Sidhu, Tobias Åkerström, Cristina D Volpe, Jan Zedenius, Per Hellman, Peter Stålberg, and Martin K. Walz
- Subjects
Adult ,Male ,Cancer Research ,Microarray ,Calcium Channels, L-Type ,Somatic cell ,Endocrinology, Diabetes and Metabolism ,Polymerase Chain Reaction ,Transcriptome ,Immunoenzyme Techniques ,Plasma Membrane Calcium-Transporting ATPases ,Endocrinology ,KCNJ5 ,Hyperaldosteronism ,Biomarkers, Tumor ,Missense mutation ,Humans ,Gene ,Aldosterone ,Aged ,Neoplasm Staging ,Genetics ,Aged, 80 and over ,biology ,Gene Expression Profiling ,Middle Aged ,Prognosis ,Phenotype ,Adrenal Cortex Neoplasms ,Gene expression profiling ,Oncology ,Adrenocortical Adenoma ,Mutation ,Cancer research ,biology.protein ,Female ,Sodium-Potassium-Exchanging ATPase ,Follow-Up Studies - Abstract
Aldosterone-producing adenomas (APAs) are found in 1.5–3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca2+ regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca2+ levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.
- Published
- 2015
89. Prevalence of neoplasms in patients with primary aldosteronism
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Anna Dietz, Oliver Vonend, Henri Wallaschofski, Katrin Weber, Martin Reincke, Stefanie Hahner, Holger S. Willenberg, Katharina Lang, Bruno Allolio, Marcus Quinkler, and Anke Hannemann
- Subjects
Pediatrics ,medicine.medical_specialty ,Primary aldosteronism ,business.industry ,medicine ,In patient ,medicine.disease ,business - Published
- 2015
90. General morbidity and working capacity in patients with chronic adrenal insufficiency – A prospective study
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B Allolio, Stephanie Hahner, C Spinnler, F Beuschlein, D Milovanovic, Marcus Quinkler, Katharina Lang, Stephanie Burger-Stritt, and Holger S. Willenberg
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medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Working capacity ,General Medicine ,medicine.disease ,Endocrinology ,Internal Medicine ,Adrenal insufficiency ,Medicine ,In patient ,business ,Intensive care medicine ,Prospective cohort study - Published
- 2015
91. Detection of Adrenaline Based on Substrate Recycling Amplification
- Author
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Holger S. Willenberg, Petra Siegert, Michael J. Schöning, Michael Keusgen, Denise Molinnus, Matthias Bäcker, Arshak Poghossian, and A. Bartz
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chemistry.chemical_classification ,Laccase ,Chromatography ,technology, industry, and agriculture ,Substrate (chemistry) ,General Medicine ,macromolecular substances ,biosensor ,Amperometry ,laccase ,law.invention ,Adrenaline ,chemistry.chemical_compound ,substrate recycling ,Enzyme ,chemistry ,law ,ddc:670 ,Ph range ,Glutaraldehyde ,Biosensor ,Clark electrode ,Engineering(all) - Abstract
An amperometric enzyme biosensor has been applied for the detection of adrenaline. The adrenaline biosensor has been prepared by modification of an oxygen electrode with the enzyme laccase that operates at a broad pH range between pH 3.5 to pH 8. The enzyme molecules were immobilized via cross-linking with glutaraldehyde. The sensitivity of the developed adrenaline biosensor in different pH buffer solutions has been studied.
- Published
- 2015
92. An LC-MS/MS method for steroid profiling during adrenal venous sampling for investigation of primary aldosteronism
- Author
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Mirko Peitzsch, Jacques W.M. Lenders, Gabriele Siegert, Holger S. Willenberg, Gerald Antoch, Fred C.G.J. Sweep, Tanja Dekkers, Graeme Eisenhofer, Ivo Quack, Jaap Deinum, and Matthias Haase
- Subjects
Adult ,Male ,medicine.medical_specialty ,Hydrocortisone ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Dehydroepiandrosterone ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Primary aldosteronism ,Corticosterone ,Tandem Mass Spectrometry ,Cosyntropin ,Internal medicine ,Adrenal Glands ,Hyperaldosteronism ,medicine ,Humans ,Molecular Biology ,Aged ,Immunoassay ,Aldosterone ,Chemistry ,Reproducibility of Results ,Cell Biology ,Middle Aged ,medicine.disease ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,Molecular Medicine ,Female ,Steroids ,Cortisone ,medicine.drug ,Chromatography, Liquid - Abstract
Item does not contain fulltext BACKGROUND: Steroid profiling for diagnosis of endocrine disorders featuring disordered production of steroid hormones is now possible from advances in liquid chromatography with tandem mass spectrometry (LC-MS/MS). Adrenal venous (AV) measurements of aldosterone and cortisol are a standard practice in the clinical work-up of primary aldosteronism, but do not yet take advantage of steroid profiling. METHODS: A novel LC-MS/MS based method was developed for simultaneous measurement of 15 adrenal steroids: aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, pregnenolone, cortisone, cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, 21-deoxycortisol, 18-oxocortisol and 18-hydroxycortisol. These were compared in peripheral venous (pV) and AV plasma from 70 patients undergoing AV sampling with and without cosyntropin stimulation. Aldosterone and cortisol levels measured by LC-MS/MS were compared with those measured by immunoassay. RESULTS: Reproducibility of measurements with coefficients of variation
- Published
- 2015
93. PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia : A single-center study of 60 cases
- Author
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Holger S. Willenberg, Matthias Schott, Gerald Goh, Ute I. Scholl, Matthias Haase, Anna-Carinna Reis, and Anne Thiel
- Subjects
Cortisol secretion ,Adult ,Male ,medicine.medical_specialty ,Hydrocortisone ,Endocrinology, Diabetes and Metabolism ,Medizin ,medicine.disease_cause ,chemistry.chemical_compound ,Endocrinology ,Germline mutation ,Internal medicine ,KCNJ5 ,medicine ,GNAS complex locus ,Humans ,Aldosterone ,Cushing Syndrome ,beta Catenin ,Aged ,Mutation ,Cyclic AMP-Dependent Protein Kinase Catalytic Subunits ,biology ,Adrenal Hyperplasia, Congenital ,business.industry ,Age Factors ,Adrenalectomy ,General Medicine ,Hyperplasia ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,PRKACA ,Phenotype ,chemistry ,Adrenocortical Adenoma ,biology.protein ,Female ,business - Abstract
ObjectiveCortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACAL206R mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.Design, patients, and methodsIn this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.ResultsAmong cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACAL206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions.ConclusionsPRKACAL206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.
- Published
- 2015
94. Conn-Syndrom
- Author
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Holger S. Willenberg
- Published
- 2015
95. Dendritic cells as potential adjuvant for immunotherapy in adrenocortical carcinoma
- Author
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Sven Schinner, Claudia Papewalis, Julia Domberg, Werner A. Scherbaum, Holger S. Willenberg, Ulrich-Peter Rohr, Stefan R. Bornstein, Matthias Schott, Martin Fassnacht, and Roland Fenk
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Antineoplastic Agents ,Cancer Vaccines ,Injections ,Fatal Outcome ,Endocrinology ,Adjuvants, Immunologic ,Antigen ,Antigens, Neoplasm ,Internal medicine ,Adrenocortical Carcinoma ,medicine ,Humans ,Cytotoxic T cell ,Hypersensitivity, Delayed ,Treatment Failure ,Antigen-presenting cell ,Hybridomas ,business.industry ,Dendritic Cells ,Dendritic cell ,Immunotherapy ,Middle Aged ,Flow Cytometry ,Adrenal Cortex Neoplasms ,Granzyme B ,Microscopy, Electron ,Immunology ,Cytokine secretion ,Mitotane ,business ,CD8 - Abstract
Summary Objective Adrenocortical carcinoma (ACC) is a rare malignancy associated with a dismal prognosis. Dendritic cells (DCs) are professional antigen-presenting cells leading to an antitumour immune response. The aim of this study was to elaborate two methods of antigen delivery to DCs and to evaluate an immunotherapy protocol in ACC patients. Design/patients Autologous DCs were pulsed with autologous tumour lysate (TL). Fusion of DCs with tumour cells was based on a polyethylene glycol method. Two patients with metastasized hypersecretory ACC were vaccinated twice. Measurements In vitro data were quantified by measurement of PBMC (peripheral blood mononuclear cell) responses and cytokine secretion and by flow cytometry analyses. Clinical response was monitored by CT scan of tumour mass and measurement of angiogenic factors. Results The maximum loading of TL was obtained at 24 h as 48·2% ( ± 26·8%) of DCs were TL-positive. The DC/tumour cell fusion efficacy was ∼ 45% as shown by double positive staining for ACTH receptor and DC-specific CD83. In vivo DC vaccination resulted in positive delayed-type hypersensitivity skin reactions reflecting specific memory T-lymphocyte reaction. In vitro analyses revealed specific T-cell proliferation in patient 1 (stimulation index: 5·7 compared to pretreatment) and induction of cytotoxic granzyme B secreting T cells in patient 2 (0·41% CD8 + cells vs. 0·06% pretreatment) as indicators of specific cytotoxic T cells. Although angiogenic serum markers could be stabilized, no impact on tumour growth could be observed. Conclusion Our data demonstrate that autologous dendritic cells induce antigen-specific Th1 immunity in adrenocortical carcinoma. The clinical outcome, however, was not improved in the patients studied here.
- Published
- 2006
96. A Case of Catecholamine and Glucocorticoid Excess Syndrome Due to a Corticotropin-Secreting Paraganglioma
- Author
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Holger S. Willenberg, Werner A. Scherbaum, Matthias Schott, Joachim Feldkamp, Peter E. Goretzki, and R. Lehmann
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Hypopituitarism ,General Biochemistry, Genetics and Molecular Biology ,Paraganglioma ,Pheochromocytoma ,Catecholamines ,Adrenocorticotropic Hormone ,History and Philosophy of Science ,Internal medicine ,medicine ,Humans ,Endocrine system ,Glucocorticoids ,Left kidney ,Ultrasonography ,business.industry ,General Neuroscience ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Endocrinology ,Catecholamine ,Female ,Tomography, X-Ray Computed ,business ,hormones, hormone substitutes, and hormone antagonists ,Glucocorticoid ,medicine.drug ,Hormone - Abstract
We present a case of a 61-year-old female patient with ectopic corticotropin (ACTH) syndrome, hypopituitarism, and catecholamine excess due to a paraganglioma at the inferior pole of the left kidney. In this article we discuss the hormonal findings in the patient and its consequences, the pitfalls of the endocrine workup, and the results of our immunohistological and molecular studies in more detail.
- Published
- 2006
97. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study
- Author
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Stefanie Hahner, Katharina Lang, Danijela Milovanovic, Felix Beuschlein, Bruno Allolio, Stephanie Burger-Stritt, Marcus Quinkler, Holger S. Willenberg, Christina Spinnler, and Martin Fassnacht
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biochemistry ,Young Adult ,Endocrinology ,Internal medicine ,Surveys and Questionnaires ,medicine ,Adrenal insufficiency ,Humans ,Prospective Studies ,Young adult ,Prospective cohort study ,Glucocorticoids ,Aged ,Aged, 80 and over ,business.industry ,Incidence (epidemiology) ,Incidence ,Biochemistry (medical) ,Adrenal crisis ,Middle Aged ,medicine.disease ,Addison's disease ,Female ,medicine.symptom ,business ,Complication ,Glucocorticoid ,medicine.drug ,Adrenal Insufficiency - Abstract
Adrenal crisis (AC) is a life-threatening complication of adrenal insufficiency (AI), which according to retrospective data represents a significant clinical complication. Here we aimed to prospectively assess incidence of AC and mortality associated with AC in patients with chronic AI.A total of 423 patients with AI (primary AI, n = 221; secondary AI, n = 202) were prospectively followed up for 2 years. Baseline assessment included a general questionnaire and detailed written instructions on glucocorticoid dose adaptation during stress. Patients received follow-up questionnaires every 6 months and were contacted by phone in case of reported adrenal crisis.A total of 423 data sets were available for baseline analysis, and 364 patients (86%) completed the whole study. Sixy-four AC in 767.5 patient-years were documented (8.3 crises per 100 patient-years). Precipitating causes were mainly gastrointestinal infection, fever, and emotional stress (20%, respectively) but also other stressful events (eg, major pain, surgery, strenuous physical activity, heat, pregnancy) or unexplained sudden onset of AC (7%) were documented. Patients with a previous AC were at higher risk of crisis (odds ratio 2.85, 95% confidence interval 1.5-5.5, P.01). However, no further risk factors could be identified. Ten patients died during follow-up; in four cases death was associated with AC (0.5 AC related deaths per 100 patient-years).Even in educated patients with chronic adrenal insufficiency, AC occurs in a substantial proportion of cases. Furthermore, we identified AC-associated mortality in approximately 6% of AC. Our findings further emphasize the need for improved management of AC in patients with chronic AI.
- Published
- 2014
98. Relevance of TSH Receptor Stimulating and Blocking Autoantibody Measurement for the Prediction of Relapse in Graves’ Disease
- Author
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A. Bergmann, Joachim Feldkamp, Waldemar B. Minich, N. G. Morgenthaler, Matthias Schott, Holger S. Willenberg, Werner A. Scherbaum, C. Papewalis, and J. Seissler
- Subjects
Adult ,Male ,endocrine system ,medicine.medical_specialty ,Adolescent ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Graves' disease ,Clinical Biochemistry ,Context (language use) ,Biochemistry ,Statistics, Nonparametric ,Endocrinology ,Predictive Value of Tests ,Recurrence ,Internal medicine ,medicine ,Humans ,Outpatient clinic ,Autoantibodies ,Retrospective Studies ,Pregnancy ,Chi-Square Distribution ,business.industry ,Biochemistry (medical) ,Autoantibody ,Receptors, Thyrotropin ,Retrospective cohort study ,General Medicine ,Middle Aged ,medicine.disease ,Graves Disease ,Predictive value of tests ,Biological Assay ,Female ,business ,Chi-squared distribution ,Follow-Up Studies ,Immunoglobulins, Thyroid-Stimulating - Abstract
Recently, we demonstrated that higher levels of autoantibodies to the human TSH receptor (TBII) predict relapse of hyperthyroidism in Graves' disease (GD). The aim of this study was to extend this outcome prediction by dividing TBII into stimulating (TSAb) and blocking (TBAb) TSH receptor autoantibodies. Altogether, ninety patients (81 female, 9 male) were retrospectively analyzed; sixty-four patients (71 %) did not go into remission or relapsed, whereas twenty-six patients (29 %) went into remission (median follow-up: 17.5 months). TSAb and TBAb measurement was performed in a CHO cell bioassay with cAMP readout at the time of their first visit in our outpatient clinic (single point measurement in median 6.5 months after initial diagnosis). In the remission group, eighteen of twenty-six patients (69 %) were TSAb-positive, whereas fifty-three of sixty-four patients (83 %) were TSAb-positive in the relapse group (p = ns). The mean stimulation indices (SI) were 4.1 in the remission group and 12.9 in the relapse group, respectively (p = 0.015). By using a threshold of 10 SI, the specificity for relapse was 96.0 %, as only one in twenty patients with an SI above 10 went into remission during follow-up (PPV 95 %). Most TSAb-positive patients also had high levels of TBII. Neither group showed any difference with respect to blocking type autoantibodies, which were mostly negative in both groups. In summary, high TSAb levels are similar but not superior to TBII for predicting relapse in GD patients. In contrast, TBAb measurement does not add any valuable information in this context. In the clinical routine, TSAb/TBAb measurement may not play an important role for diagnosis or outcome prediction of GD, since sensitive 2 (nd) generation TBII assays are easier to perform and offer similar information to the clinician. Bioassays should be reserved for special clinical questions such as Graves' disease in pregnancy.
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- 2005
99. Adrenal Pheochromocytoma with Contralateral Cortisol-producing Adrenal Adenoma: Diagnostic and Therapeutic Management
- Author
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Werner A. Scherbaum, Andreas Raffel, Stefan R. Bornstein, H. Geddert, Holger S. Willenberg, Wolfram T. Knoefel, A. Wolf, Kenko Cupisti, and Matthias Schott
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endocrine system ,Pathology ,medicine.medical_specialty ,Hydrocortisone ,endocrine system diseases ,Adenoma ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Pheochromocytoma ,Biochemistry ,Endocrinology ,Internal medicine ,medicine ,Humans ,Adrenal adenoma ,Multiple endocrine neoplasia ,biology ,Adrenal gland ,business.industry ,Incidentaloma ,Biochemistry (medical) ,Chromogranin A ,Adrenalectomy ,General Medicine ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,medicine.anatomical_structure ,Adrenocortical Adenoma ,biology.protein ,Catecholamine ,Female ,Laparoscopy ,Tomography, X-Ray Computed ,business ,medicine.drug - Abstract
There is evidence for a close interrelation between the adreno-medullary and adrenocortical tissues, and there are well-characterized models of their paracrine interaction. To contribute to the studies of systemic interactions between these tissues, we studied a 52-year-old female patient with a pheochromocytoma and a contralateral cortisol-producing adenoma. Due to a misunderstanding, she presented to her family doctor to have an inherited kidney disease ruled out. An adrenal mass was discovered incidentally by ultrasound. A computerized tomography of the abdomen revealed bilateral adrenal masses. Due to excess catecholamine secretion, bilateral pheochromocytomas based on multiple endocrine neoplasia syndrome were suspected. Laboratory work-up, selective adrenal venous sampling and magnetic resonance imaging studies established the diagnosis of a pheochromocytoma in the right-hand adrenal gland and a cortisol-producing adenoma on the left. Simultaneous bilateral laparoscopic subtotal adrenalectomy was performed. Immunohistochemistry showed positive staining against chromogranin A in a histological specimen obtained from the right-hand adrenal gland, while the left was negative; the left-hand adrenal gland stained positive against the ACTH receptor (MC2R) while the right was negative. Genetically, the patient was negative for MEN2, von Hippel-Lindau disease, and mutations in subunits B, C, and D of the succinate dehydrogenase gene. Although presence of bilateral adrenal adenomas or bilateral adrenal pheochromocytomas in certain inherited disorders are possible, this rare case of an adrenal pheochromocytoma combined with a contralateral cortisol-producing adrenal adenoma may further underline the wide range of complex interactions between the two endocrine systems.
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- 2005
100. Corticotropin-Releasing Hormone Receptor Expression on Normal and Tumorous Human Adrenocortical Cells
- Author
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Werner A. Scherbaum, Claudia Papewalis, Holger S. Willenberg, Matthias Haase, Matthias Schott, and Stefan R. Bornstein
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endocrine system ,medicine.medical_specialty ,Corticotropin-Releasing Hormone ,Endocrinology, Diabetes and Metabolism ,Corticotropin-releasing hormone receptor ,Stimulation ,Pheochromocytoma ,In situ hybridization ,Biology ,Receptors, Corticotropin-Releasing Hormone ,Cellular and Molecular Neuroscience ,Endocrinology ,Internal medicine ,Adrenocortical Carcinoma ,polycyclic compounds ,medicine ,Humans ,RNA, Messenger ,Receptor ,In Situ Hybridization ,Reverse Transcriptase Polymerase Chain Reaction ,Endocrine and Autonomic Systems ,Adrenal gland ,Cushing's disease ,medicine.disease ,Immunohistochemistry ,Adrenal Cortex Neoplasms ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Gene Expression Regulation ,Adrenocortical Adenoma ,Adrenal Cortex ,Microdissection ,hormones, hormone substitutes, and hormone antagonists ,Zona reticularis ,Hormone - Abstract
Corticotropin-releasing hormone (CRH) is not only the principal regulator of the central hypothalamic-pituitary-adrenal (HPA) axis but also exerts direct actions on peripheral tissues. We analyzed the expression of CRH receptors in microdissected preparations of normal human adrenal glands and in adrenocortical and adrenomedullary tumors, employing immunohistochemistry, quantitative RT-PCR of microdissected adrenal tissues, and in situ hybridization. The effect of CRH on adrenal steroidogenesis was tested in adrenal cells. Immunoreactive CRH1R was found primarily within the zona reticularis. In addition, we found a higher expression of CRH type-1 and 2 receptors mRNAs in preparations of adrenal cortices as compared to pheochromocytomas, a 6-fold increase in preparations of clinically unapparent adrenocortical adenomas, and a 10- to 60-fold increase in cortisol-producing adrenal adenomas. Stimulation of the adrenal tumor cell line NCI-H295R with CRH elicited a 1.4-fold increase in DHEA secretion. This result could be reproduced in a culture of primary human adrenocortical cells. We conclude that adrenocortical cells exhibit a higher expression of functional CRH receptors than chromaffin cells and that CRH acts on adrenal DHEA production. The data support the assertion of a direct action of CRH on human adrenocortical cells in addition to an intra-adrenal CRH receptor/adrenocorticotropin system. Enhanced CRH1R expression may be involved in adrenocortical tumorigenesis.
- Published
- 2005
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