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K M Biernacka IGFs & Metabolic Endocrinology Group, School of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK

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R A Persad Department of Urology, Southmead Hospital, Bristol, UK

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A Bahl Department of Clinical Oncology, Bristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK

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D Gillatt Department of Urology, Southmead Hospital, Bristol, UK

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J M P Holly IGFs & Metabolic Endocrinology Group, School of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK

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C M Perks IGFs & Metabolic Endocrinology Group, School of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK

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( Murtola et al . 2008 , Wright & Stanford 2009 ) and improved survival in prostate cancer patients ( He et al . 2011 ). The anticancer effects of metformin could be mediated by a canonical pathway involving the activation of AMP-activated protein

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Roeliene C Kruizinga Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Wim J Sluiter Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Elisabeth G E de Vries Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Bernard A Zonnenberg Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Cornelis J Lips Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Anouk N A van der Horst-Schrivers Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Annemiek M E Walenkamp Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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Thera P Links Departments of Medical Oncology, Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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calculated age for starting surveillance was 6 years later for the retina ( Hes & van der Luijt 2000 , Poulsen et al . 2010 , Lammens et al . 2011 , VHL family Alliance 2012 ), but 5 years earlier for the adrenal gland. Moreover, the calculated

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John P Wiebe Department of Biology, Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, London, Ontario, Canada N6A 5B7

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this progestagen. By 1954, almost 100 naturally occurring steroids had been isolated from tissue and urinary sources ( Dorfman 1954 ). The urinary P derivatives were assumed to result from metabolism in the liver and included 5β-pregnanes such as

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C Festuccia
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P Muzi
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D Millimaggi
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L Biordi
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G L Gravina
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S Speca
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A Angelucci
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V Dolo
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C Vicentini
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M Bologna
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, Canada) on cell lysates after partial purification on a MonoQ exchange column (2 mg protein in 1 ml column) with 10 mM MOPS, pH 7.2, 25 mM β-glycerophosphate, 5 mM EGTA, 2 mM EDTA, 2 mM sodium orthovanadate and 2 mM dithiothreitol and eluted using 12 ml

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Tahmineh Tabrizian Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA

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Donghai Wang Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

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Fangxia Guan Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

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Zunju Hu Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

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Amanda P Beck Department of Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, New York, USA

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Fabien Delahaye Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA

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Derek M Huffman Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, USA
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

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Introduction Evidence suggests that intestinal stem cell (ISC) populations can serve as the origin of tumor development. Indeed, increased Wnt/β-catenin signaling in Lgr5+, Bmi1+ or Lrig1+ ISCs, as well as Ah -cre cells in the transit

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Yuet-Kin Leung Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Hung-Ming Lam Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Shulin Wu Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Dan Song Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Linda Levin Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Liang Cheng Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Chin-Lee Wu Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Shuk-Mei Ho Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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addition to the wild-type ERβ or ERβ1, four spliced variants designated as ERβ2–5 have been identified ( Moore et al . 1998 ). The ERβ2–5 isoforms share the first four functional domains with ERβ1, but each has a unique activation function 2 (AF2) domain

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Marek Dedecjus
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Jozef Tazbir
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Zbigniew Kaurzel
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Andrzej Lewinski
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Grzegorz Strozyk
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Jan Brzezinski
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portal for a 4 or 5 F-size angiographic catheter (Vertebral – Cordis, Europe NV, The Netherlands and Multipurpose, Balton, Poland). The catheter was advanced from the femoral artery via the abdominal aorta and, sequentially, to both the superior and one

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Ernst von Dobschuetz Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Helena Leijon Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Camilla Schalin-Jäntti Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Francesca Schiavi Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Michael Brauckhoff Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Mariola Peczkowska Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Giovanna Spiazzi Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Serena Demattè Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Maria Enrica Cecchini Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Paola Sartorato Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Jolanta Krajewska Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Kornelia Hasse-Lazar Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Katarzyna Roszkowska-Purska Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Elisa Taschin Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Angelica Malinoc Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Lars A Akslen Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Johanna Arola Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Dariusz Lange Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Ambrogio Fassina Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Gianmaria Pennelli Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Mattia Barbareschi Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Jutta Luettges Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Aleksander Prejbisz Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Andrzej Januszewicz Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Tim Strate Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Birke Bausch Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Frederic Castinetti Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Barbara Jarzab Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Giuseppe Opocher Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Charis Eng Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Hartmut P H Neumann Section of Endocrine Surgery, Department of Pathology, Division of Endocrinology, Familial Cancer Clinic and Onco‐Endocrinology, Department of Endocrine Surgery, Department of Hypertension, Endocrinology, Units of Internal Medicine, Department of Internal Medicine, Department of Nuclear Medicine and Endocrine Oncology, Department of Pathology and Laboratory Diagnostics, Section for Preventive Medicine, Section for Pathology, Department of Tumor Pathology, Surgical Pathology and Cytopathology Unit, Department of Pathology, Department of Pathology, Department of Gastroenterology, Department of Endocrinology, Genomic Medicine Institute, Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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. Negative staining is shown for CK-PAN, calcitonin, and TTF1. Figure 5 Immunohistochemistry of case 5: H&E, chromogranin, synaptophysin, S-100, CK-PAN, calcitonin, and TTF1. Note that there is positive staining of the tumor for chromogranin and synaptophysin

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Xiaqing Xu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Meimei Si Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Honggang Lou Department of Clinical Pharmacology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

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Youyou Yan Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Yunxi Liu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Hong Zhu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Xiaoe Lou Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Jian Ma Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Difeng Zhu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Honghai Wu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Haoshu Wu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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Qiaojun He Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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were purchased from the Cell Bank of the China Science Academy (Shanghai, China). Cells were maintained in RPMI-1640 or DMEM medium at 37°C in a humidified atmosphere with 5% CO 2 . All media were supplemented with 10% heat-inactivated fetal bovine

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Arivarasan Karunamurthy Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

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Federica Panebianco Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

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Susan J Hsiao Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

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Jennie Vorhauer Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

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Marina N Nikiforova Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

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Simion Chiosea Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

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Yuri E Nikiforov Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

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mutations in exons 2, 5, and 6 was performed using Sanger sequencing or next-generation sequencing panel (ThyroSeq v2) as previously described ( Nikiforov et al. 2014 ). In addition to EIF1AX , the panel included the analysis of point mutations in the

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