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Paul Benjamin Loughrey Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Brian Herron Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK

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Stephen Cooke Department of Neurosurgery, Belfast Health and Social Care Trust, Belfast, UK

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Philip Weir Department of Neurosurgery, Belfast Health and Social Care Trust, Belfast, UK

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Jayna Elizabeth Smyth Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Karen R Mullan Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Estelle G Healy Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK

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Jane Evanson Department of Radiology, Barts Health NHS Trust, London, UK

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Stephanie G Craig Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK

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Jacqueline A James Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, UK
Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
Northern Ireland Biobank, Belfast Health and Social Care Trust, Belfast, UK

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Márta Korbonits Department of Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Steven J Hunter Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK

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Cushing’s disease is a rare condition that occurs due to an adrenocorticotrophin-producing corticotrophinoma arising from the pituitary gland. The consequent hypercortisolaemia results in multisystem morbidity and mortality. This study aims to report incidence, clinicopathological characteristics, remission outcomes and mortality in a regional pituitary neurosurgical cohort of patients diagnosed with Cushing’s disease in Northern Ireland (NI) from 2000 to 2019. Clinical, biochemical and radiological data from a cohort of patients operated for Cushing’s disease were retrospectively collected and analysed. Fifty-three patients were identified, resulting in an estimated annual incidence of Cushing’s disease of 1.39–1.57 per million population per year. Females accounted for 72% (38/53) of the cohort. The majority (74%, 39/53) of corticotrophinomas were microadenomas and in 44% (17/39) of these no tumour was identified on preoperative magnetic resonance imaging. Histopathological characterisation was similarly difficult, with no tumour being identified in the histopathological specimen in 40% (21/53) of cases. Immediate postoperative remission rates were 53% and 66% when considering serum morning cortisol cut-offs of ≤ 50 nmol/L (1.8 µg/dL) and ≤ 138 nmol/L (5 µg/dL), respectively, in the week following pituitary surgery. Approximately 70% (37/53) of patients achieved longer-term remission with a single pituitary surgery. Three patients had recurrent disease. Patients with Cushing’s disease had a significantly higher mortality rate compared to the NI general population (standardised mortality ratio 8.10, 95% CI 3.3–16.7, P < 0.001). Annual incidence of Cushing’s disease in NI is consistent with other Northern European cohorts. Functioning corticotrophinomas are a clinically, radiologically and histopathologically elusive disease with increased mortality compared to the general population.

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André Wendindondé Nana PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan

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Yu-Tang Chin PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Chi-Yu Lin Center for Teeth Bank and Dental Stem Cell Technology and School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan

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Yih Ho School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

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James A Bennett Center for Immunology and Microbial Diseases, Albany Medical College, Albany, New York, USA

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Ya-Jung Shih Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Yi-Ru Chen Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Chun A Changou PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
Integrated Laboratory, Center of Translational Medicine, Core Facility, Taipei Medical University, Taipei, Taiwan

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Jens Z Pedersen Department of Biology, University Tor Vergata, Rome, Italy

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Sandra Incerpi Department of Sciences, University Roma Tre, Rome, Italy

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Leroy F Liu Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Jacqueline Whang-Peng Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

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Earl Fu Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan

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Wen-Shan Li Laboratory of Chemical Biology and Medicinal Chemistry, Institute of Chemistry, Academia Sinica, Taipei, Taiwan
Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Taipei, Taiwan

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Shaker A Mousa Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA

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Hung-Yun Lin PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

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Paul J Davis Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
Department of Medicine, Albany Medical College, Albany, New York, USA

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The molecular pathogenesis of colorectal cancer encompasses the activation of several oncogenic signaling pathways that include the Wnt/β-catenin pathway and the overexpression of high mobility group protein A2 (HMGA2). Resveratrol – the polyphenolic phytoalexin – binds to integrin αvβ3 to induce apoptosis in cancer cells via cyclooxygenase 2 (COX-2) nuclear accumulation and p53-dependent apoptosis. Tetraiodothyroacetic acid (tetrac) is a de-aminated derivative of l-thyroxine (T4), which – in contrast to the parental hormone – impairs cancer cell proliferation. In the current study, we found that tetrac promoted resveratrol-induced anti-proliferation in colon cancer cell lines, in primary cultures of colon cancer cells, and in vivo. The mechanisms implicated in this action involved the downregulation of nuclear β-catenin and HMGA2, which are capable of compromising resveratrol-induced COX-2 nuclear translocation. Silencing of either β-catenin or HMGA2 promoted resveratrol-induced anti-proliferation and COX-2 nuclear accumulation which is essential for integrin αvβ3-mediated-resveratrol-induced apoptosis in cancer cells. Concurrently, tetrac enhanced nuclear abundance of chibby family member 1, the nuclear β-catenin antagonist, which may further compromise the nuclear β-catenin-dependent gene expression and proliferation. Taken together, these results suggest that tetrac targets β-catenin and HMGA2 to promote resveratrol-induced-anti-proliferation in colon cancers, highlighting its potential in anti-cancer combination therapy.

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