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Banerjee S, Nahar U, Dahiya D, Gupta R, Mukherjee S, Sachdeva N, Sood A, Dey P, Radotra B, Bhansali A. IL-17 A correlates with disease progression in papillary thyroid carcinoma. Diagn Pathol 2023; 18:93. [PMID: 37563607 PMCID: PMC10413719 DOI: 10.1186/s13000-023-01362-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 06/05/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Cancer progression can be promoted by chronic inflammation. Local immune response may be associated with favourable or unfavourable prognosis of Papillary Thyroid Carcinoma (PTC). Regulatory T (Treg) cells and T helper 17 (Th17) cells exert opposing function and their balance may have a vital role in promotion of tumor growth. Treg cells in tumor microenvironment (TME) may promote tumor progression and reduced survival of patients. Whereas, Th17 cells can promote or inhibit tumor progression depending on phenotypic characteristics of tumor. In this study, we aimed to analyse the kind of immune response developed and its prognostic impact in future therapeutics. METHODS Cytometric Bead Array (CBA) analysis of pro and anti-inflammatory cytokines (IFN-gamma, IL-2, IL-6, IL-17 A, TNF-alpha and IL-4, IL-10) was done in 15 PTC irrespective of Lymphocytic Thyroiditis (LT) and 16 Hashimoto's Thyroiditis (HT) cases. Immunohistochemical expression of FoxP3 and IL-17 A was studied in 27 cases of PTC with LT. Whereas, quantitative gene expression of both was analysed in 10 cases. RESULTS All the pro-inflammatory cytokines showed mild elevation in PTC with LT. On IHC, IL-17 A expression was observed in 74% PTC with LT. Whereas, FoxP3 was present in only 40% cases. Also, IL-17 A expression was significantly associated with age group (> 45 years), tumor size ≤ 1 cm and disease progression. CONCLUSIONS Increased expression of cytokines suggested correlation between inflammatory factors and progression of thyroid tumors. Along with this, the balance between IL-17 A and FoxP3 may play an important role in PTC development, prognosis and future management.
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Affiliation(s)
- Sohini Banerjee
- Department of Histopathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Uma Nahar
- Department of Histopathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India.
| | - Divya Dahiya
- Department of General Surgery, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Rijuneeta Gupta
- Department of Otolaryngology (ENT), Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Soham Mukherjee
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Ashwani Sood
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Pranab Dey
- Department of Cytology and Gynaecological Pathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Bishan Radotra
- Department of Histopathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Anil Bhansali
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
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Diamantopoulos LN, Kalligeros M, Halfdanarson TR, Diamantis N, Toumpanakis C. Combination Systemic Therapies in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): A Comprehensive Review of Clinical Trials and Prospective Studies. BIOLOGY 2023; 12:1069. [PMID: 37626955 PMCID: PMC10452098 DOI: 10.3390/biology12081069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 08/27/2023]
Abstract
There is an evolving landscape of systemic combination regimens for patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this review, we provide a comprehensive outline of the existing clinical trials/prospective studies investigating these combinations. PubMed was searched using key relevant terms to identify articles referring to GEP-NETs and combination treatments. No systematic search of the literature or metanalysis of the data was performed, and we focused on the most recent literature results. Primarily, phase 1 and 2 clinical trials were available, with a smaller number of phase 3 trials, reporting results from combination treatments across a wide range of antiproliferative agents. We identified significant variability in the anti-tumor activity of the reported combinations, with occasional promising results, but only a very small number of practice-changing phase 3 clinical trials. Overall, the peptide receptor radionuclide therapy (PRRT)-based combinations (with chemotherapy, dual PPRT, and targeted agents) and anti-vascular endothelial growth factor (VEGF) agent combinations with standard chemotherapy were found to have favorable results and may be worth investigating in future, larger-scale trials. In contrast, the immune-checkpoint inhibitor-based combinations were found to have limited applicability in advanced, well-differentiated GEP-NETs.
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Affiliation(s)
- Leonidas N. Diamantopoulos
- Department of Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA;
| | - Markos Kalligeros
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | | | - Nikolaos Diamantis
- Department of Medical Oncology, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK;
| | - Christos Toumpanakis
- Neuroendocrine Tumor Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK
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3
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Dang Y, Ma C, Chen K, Chen Y, Jiang M, Hu K, Li L, Zeng Z, Zhang H. The Effects of a High-Fat Diet on Inflammatory Bowel Disease. Biomolecules 2023; 13:905. [PMID: 37371485 DOI: 10.3390/biom13060905] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
The interactions among diet, intestinal immunity, and microbiota are complex and play contradictory roles in inflammatory bowel disease (IBD). An increasing number of studies has shed light on this field. The intestinal immune balance is disrupted by a high-fat diet (HFD) in several ways, such as impairing the intestinal barrier, influencing immune cells, and altering the gut microbiota. In contrast, a rational diet is thought to maintain intestinal immunity by regulating gut microbiota. In this review, we emphasize the crucial contributions made by an HFD to the gut immune system and microbiota.
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Affiliation(s)
- Yuan Dang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chunxiang Ma
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kexin Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yiding Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kehan Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
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Koffas A, Giakoustidis A, Papaefthymiou A, Bangeas P, Giakoustidis D, Papadopoulos VN, Toumpanakis C. Diagnostic work-up and advancement in the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. Front Surg 2023; 10:1064145. [PMID: 36950054 PMCID: PMC10025557 DOI: 10.3389/fsurg.2023.1064145] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 02/07/2023] [Indexed: 03/08/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms ranging from well-differentiated, slowly growing tumors to poorly differentiated carcinomas. These tumors are generally characterized by indolent course and quite often absence of specific symptoms, thus eluding diagnosis until at an advanced stage. This underscores the importance of establishing a prompt and accurate diagnosis. The gold-standard remains histopathology. This should contain neuroendocrine-specific markers, such as chromogranin A; and also, an estimate of the proliferation by Ki-67 (or MIB-1), which is pivotal for treatment selection and prognostication. Initial work-up involves assessment of serum Chromogranin A and in selected patients gut peptide hormones. More recently, the measurement of multiple NEN-related transcripts, or the detection of circulating tumor cells enhanced our current diagnostic armamentarium and appears to supersede historical serum markers, such as Chromogranin A. Standard imaging procedures include cross-sectional imaging, either computed tomography or magnetic resonance, and are combined with somatostatin receptor scintigraphy. In particular, the advent of 111In-DTPA-octreotide and more recently PET/CT and 68Ga-DOTA-Octreotate scans revolutionized the diagnostic landscape of NENs. Likewise, FDG PET represents an invaluable asset in the management of high-grade neuroendocrine carcinomas. Lastly, endoscopy, either conventional, or more advanced modalities such as endoscopic ultrasound, capsule endoscopy and enteroscopy, are essential for the diagnosis and staging of gastroenteropancreatic neuroendocrine neoplasms and are routinely integrated in clinical practice. The complexity and variability of NENs necessitate the deep understanding of the current diagnostic strategies, which in turn assists in offering optimal patient-tailored treatment. The current review article presents the diagnostic work-up of GEP-NENs and all the recent advances in the field.
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Affiliation(s)
- Apostolos Koffas
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Correspondence: Apostolos Koffas
| | - Alexandros Giakoustidis
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Apostolis Papaefthymiou
- Pancreaticobiliary Medicine Unit, University College London Hospitals (UCLH), London, United Kingdom
| | - Petros Bangeas
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Giakoustidis
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Vasileios N Papadopoulos
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Christos Toumpanakis
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, United Kingdom
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Poradowski D, Chrószcz A. Equine Stomach Development in the Foetal Period of Prenatal Life-An Immunohistochemical Study. Animals (Basel) 2022; 13:ani13010161. [PMID: 36611768 PMCID: PMC9817933 DOI: 10.3390/ani13010161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/21/2022] [Accepted: 12/29/2022] [Indexed: 01/04/2023] Open
Abstract
The study consisted of the immunohistochemical analysis of fundic and pyloric mucosa in the equine stomach between the 4th and 11th month of gestation. The accessible material was classified into three age groups using the CRL method. The adult reference group was used to define potential differences between foetal and adult populations of gastric APUD cells. The samples were preserved, prepared, and stained according to the standard protocols. The immunohistochemical reaction was assessed using the semi-quantitative IRS method. The results were documented and statistically analysed. The most significant increase was seen in gastrin (G) cell activity. The activity of other endocrine cells (cholecystokinin (I) cells, somatostatin (D) cells, and somatotropin receptor (SR) cells) was less dynamic. This study proved that the development of APUD cells within the stomach mucosa undergoes quantitative and qualitative changes during stomach development. Our results correspond with the findings described in the accessible literature and prove a strong correlation between morphological changes in the stomach wall and the organ development, growth, and maturation.
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6
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Gubbi S, Vijayvergia N, Yu JQ, Klubo-Gwiezdzinska J, Koch CA. Immune Checkpoint Inhibitor Therapy in Neuroendocrine Tumors. Horm Metab Res 2022; 54:795-812. [PMID: 35878617 PMCID: PMC9731788 DOI: 10.1055/a-1908-7790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Neuroendocrine tumors (NETs) occur in various regions of the body and present with complex clinical and biochemical phenotypes. The molecular underpinnings that give rise to such varied manifestations have not been completely deciphered. The management of neuroendocrine tumors (NETs) involves surgery, locoregional therapy, and/or systemic therapy. Several forms of systemic therapy, including platinum-based chemotherapy, temozolomide/capecitabine, tyrosine kinase inhibitors, mTOR inhibitors, and peptide receptor radionuclide therapy have been extensively studied and implemented in the treatment of NETs. However, the potential of immune checkpoint inhibitor (ICI) therapy as an option in the management of NETs has only recently garnered attention. Till date, it is not clear whether ICI therapy holds any distinctive advantage in terms of efficacy or safety when compared to other available systemic therapies for NETs. Identifying the characteristics of NETs that would make them (better) respond to ICIs has been challenging. This review provides a summary of the current evidence on the value of ICI therapy in the management of ICIs and discusses the potential areas for future research.
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Affiliation(s)
- Sriram Gubbi
- Endocrinology, National Institutes of Health Clinical Center, Bethesda,
United States
| | | | - Jian Q Yu
- Nuclear Medicine, Fox Chase Cancer Center, Philadelphia, United
States
| | - Joanna Klubo-Gwiezdzinska
- National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, United States
| | - Christian A. Koch
- Medicine/Endocrinology, The University of Tennessee Health
Science Center, Memphis, United States
- Medicine, Fox Chase Cancer Center, Philadelphia, United
States
- Correspondence Prof. Christian A. Koch, FACP,
MACE Fox Chase Cancer
CenterMedicine, 333 Cottman
AvePhiladelphia19111-2497United
States215 728 2713
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Modica R, Liccardi A, Minotta R, Cannavale G, Benevento E, Colao A. Therapeutic strategies for patients with neuroendocrine neoplasms: current perspectives. Expert Rev Endocrinol Metab 2022; 17:389-403. [PMID: 35822906 DOI: 10.1080/17446651.2022.2099840] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/06/2022] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies mainly arising in the gastroenteropancreatic (GEP) and bronchopulmonary systems, with steadily increasing incidence. The therapeutic landscape has widened and the therapeutic strategy should be based on new sequences and combinations, still debated. AREAS COVERED Herein, we provide an overview of current approved pharmacological treatments in patients with NENs, with the aim to summarize evidence of efficacy of the main different options in GEP and pulmonary NENs, principally focusing on somatostatin analogs (SSAs), targeted therapy with everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT) and chemotherapy. We discuss biological rationale and toxicities, including current indications according to differentiation and placement in the therapeutic algorithm, clinical trials, and combinations. Furthermore, we recommend areas for further research. EXPERT OPINION Therapeutic management of patients with NENs represents a challenge for clinicians and the identification of effective sequences and combinations is of utmost importance. Major efforts should be directed to early identify and overcome resistance and to limit toxicity. The progress in the therapeutic management of NENs grows faster and the choice of the best approach should be based on randomized clinical trials, as well as on long-term, real-world data.
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Affiliation(s)
- Roberta Modica
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Alessia Liccardi
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Roberto Minotta
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Giuseppe Cannavale
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Elio Benevento
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- UNESCO Chair, Education for Health and Sustainable Development, Federico II University, Naples, Italy
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Tian Y, Shu R, Lei Y, Xu Y, Zhang X, Luo H. Somatostatin attenuates intestinal epithelial barrier injury during acute intestinal ischemia-reperfusion through Tollip/Myeloiddifferentiationfactor 88/Nuclear factor kappa-B signaling. Bioengineered 2022; 13:5005-5020. [PMID: 35164650 PMCID: PMC8973595 DOI: 10.1080/21655979.2022.2038450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In the process of ischemia-reperfusion injury, intestinal ischemia and inflammation interweave, leading to tissue damage or necrosis. However, oxygen radicals and inflammatory mediators produced after reperfusion cause tissue damage again, resulting in severe intestinal epithelial barrier dysfunction. The aim of this study was to determine the protective effect of somatostatin on intestinal epithelial barrier function during intestinal ischemia-reperfusion injury and explore its mechanism. By establishing a rat intestinal ischemia-reperfusion model, pretreating the rats with somatostatin, and then detecting the histopathological changes, intestinal permeability and expression of tight junction proteins in intestinal tissues, the protective effect of somatostatin on the intestinal epithelial barrier was measured in vivo. The mechanism was determined in interferon γ (IFN-γ)-treated Caco-2 cells in vitro. The results showed that somatostatin could ameliorate ischemia-reperfusion-induced intestinal epithelial barrier dysfunction and protect Caco-2 cells against IFN-γ-induced decreases in tight junction protein expression and increases in monolayer cell permeability. The expression of Tollip was upregulated by somatostatin both in ischemia-reperfusion rats and IFN-γ-treated Caco-2 cells, while the activation of TLR2/MyD88/NF-κB signaling was inhibited by somatostatin. Tollip inhibition reversed the protective effect of somatostatin on the intestinal epithelial barrier. In conclusion, somatostatin could attenuate ischemia-reperfusion-induced intestinal epithelial barrier injury by inhibiting the activation of TLR2/MyD88/NF-κB signaling through upregulation of Tollip.
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Affiliation(s)
- Yan Tian
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ruo Shu
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yi Lei
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yu Xu
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xinfeng Zhang
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Huayou Luo
- Department of Gastrointestinal and Hernia Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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Arrivi G, Fazio N. Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs) : The Role of Checkpoint Inhibitors. Curr Cancer Drug Targets 2022; 22:629-638. [PMID: 35034595 DOI: 10.2174/1568009622666220114124335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/11/2021] [Accepted: 11/18/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The treatment options for GEP-NENs includes various drugs and is based on grading, morphology and location of the primary. <p> Objective: The aim of our work is to investigate the clinical impact of new immune checkpoint inhibitors in order to define a new possible strategy of use within GEP-NENs. <p> Method: A scientific literature search from 2015 to January 2020 was performed by using PubMed and Embase: reviews and prospective or retrospective studies with a minimum of twenty patients were selected; conference proceedings were included. <p> Results: several studies have been conducted to assess the role of immune checkpoint inhibitors in NENs, but nowadays the current knowledge in this field is mainly based on a phase I-II studies. Immunotherapy showed limited antitumor activity, but higher response rate was reported in poor-differentiated neuroendocrine tumors. No specific biomarkers were identified for patient selection and response assessment. <p> Conclusion: Immunotherapy appears as a powerful possibility to help our patients, but nowadays we see many gaps in this field. We must balance therapeutic possibility offered by precision oncology with the understanding the limitations of application of testing and treatment in clinical practice. Future efforts should focus on research of the best patients to candidate for immunotherapy in term of disease characteristics and previous treatments, and how to select them with accurate biomarkers.
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Affiliation(s)
- Giulia Arrivi
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant' Andrea University Hospital, Rome, Italy
| | - Nicola Fazio
- Gastrointestinal and Neuroendocrine Oncology Unit, European Institute of Oncology (IEO), IRCCS, Milan, Italy
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Fijalkowski R, Reher D, Rinke A, Gress TM, Schrader J, Baum RP, Kaemmerer D, Hörsch D. Clinical Features and Prognosis of Patients with Carcinoid Syndrome and Carcinoid Heart Disease: A Retrospective Multicentric Study of 276 Patients. Neuroendocrinology 2022; 112:547-554. [PMID: 34348326 DOI: 10.1159/000518651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/22/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. METHODS We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. RESULTS Carcinoid syndrome patients had a mean age of 57 years (range 21-84) and a normal BMI of 24.9 (SD 4.5; range 13.8-39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. DISCUSSION/CONCLUSION Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.
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Affiliation(s)
- Robert Fijalkowski
- ENETS Center of Excellence Bad Berka, Internal Medicine/Gastroenterology and Endocrinology, Bad Berka, Germany
| | - Dominik Reher
- I. Department of Medicine, ENETS Center of Excellence, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anja Rinke
- ENETS Center of Excellence, Internal Medicine, Philipps-University Marburg, Marburg, Germany
| | - Thomas M Gress
- ENETS Center of Excellence, Internal Medicine, Philipps-University Marburg, Marburg, Germany
| | - Jörg Schrader
- I. Department of Medicine, ENETS Center of Excellence, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard P Baum
- ENETS Center of Excellence Bad Berka, Molecular Radiotherapy, Bad Berka, Germany
- CURANOSTICUM Wiesbaden-Frankfurt, DKD Helios Clinic, Wiesbaden, Germany
| | - Daniel Kaemmerer
- ENETS Center of Excellence Bad Berka, General and Visceral Surgery, Bad Berka, Germany
| | - Dieter Hörsch
- ENETS Center of Excellence Bad Berka, Internal Medicine/Gastroenterology and Endocrinology, Bad Berka, Germany
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11
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Gubbi S, Koch CA, Klubo-Gwiezdzinska J. Peptide Receptor Radionuclide Therapy in Thyroid Cancer. Front Endocrinol (Lausanne) 2022; 13:896287. [PMID: 35712243 PMCID: PMC9197113 DOI: 10.3389/fendo.2022.896287] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/19/2022] [Indexed: 01/03/2023] Open
Abstract
The treatment options that are currently available for management of metastatic, progressive radioactive iodine (RAI)-refractory differentiated thyroid cancers (DTCs), and medullary thyroid cancers (MTCs) are limited. While there are several systemic targeted therapies, such as tyrosine kinase inhibitors, that are being evaluated and implemented in the treatment of these cancers, such therapies are associated with serious, sometimes life-threatening, adverse events. Peptide receptor radionuclide therapy (PRRT) has the potential to be an effective and safe modality for treating patients with somatostatin receptor (SSTR)+ RAI-refractory DTCs and MTCs. MTCs and certain sub-types of RAI-refractory DTCs, such as Hürthle cell cancers which are less responsive to conventional modalities of treatment, have demonstrated a favorable response to treatment with PRRT. While the current literature offers hope for utilization of PRRT in thyroid cancer, several areas of this field remain to be investigated further, especially head-to-head comparisons with other systemic targeted therapies. In this review, we provide a comprehensive outlook on the current translational and clinical data on the use of various PRRTs, including diagnostic utility of somatostatin analogs, theranostic properties of PRRT, and the potential areas for future research.
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Affiliation(s)
- Sriram Gubbi
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christian A. Koch
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA, United States
- Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Joanna Klubo-Gwiezdzinska
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Joanna Klubo-Gwiezdzinska,
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12
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Kalligeros M, Diamantopoulos L, Toumpanakis C. Biomarkers in Small Intestine NETs and Carcinoid Heart Disease: A Comprehensive Review. BIOLOGY 2021; 10:biology10100950. [PMID: 34681049 PMCID: PMC8533230 DOI: 10.3390/biology10100950] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/19/2021] [Accepted: 09/13/2021] [Indexed: 02/06/2023]
Abstract
Simple Summary Neuroendocrine tumors (NET), a heterogeneous group of tumors arising from neuroendocrine cells, often pose a diagnostic and therapeutic challenge for the clinician. Biomarkers can serve as a useful diagnostic, prognostic, and predictive tool in the management of these rare tumors. For years the field of NET biomarkers was mainly based on products se-creted by neuroendocrine tumor cells, however, during the last decade the development of nov-el multianalyte biomarkers has rapidly evolved the field. The aim of this review is to summa-rize the literature on the use and limitations of available NET biomarkers for the diagnosis and management of small intestine neuroendocrine tumors (SI-NETs) and carcinoid heart disease. Abstract Biomarkers remain a valuable tool for the diagnosis and management of Neuroendocrine tumors (NETs). Traditional monoanalyte biomarkers such as Chromogranin A (CgA) and 5-Hydrocyondoleacetic acid (5-HIAA) have been widely used for many years as diagnostic, predictive and prognostic biomarkers in the field of NETs. However, the clinical utility of these molecules often has limitations, mainly inherent to the heterogeneity of NETs and the fact that these tumors can often be non-secretory. The development of new molecular multianalyte biomarkers, especially the mRNA transcript based “NETest”, has rapidly evolve the field and gives the ability for a “liquid biopsy” which can reliably assess disease status in real time. In this review we discuss the use of established and novel biomarkers in the diagnosis and management of small intestine NETs and carcinoid heart disease.
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Affiliation(s)
- Markos Kalligeros
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | | | - Christos Toumpanakis
- Neuroendocrine Tumor Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free Hospital NHS Foundation Trust, London NW3 2QG, UK
- Correspondence:
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13
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Diamantopoulos LN, Laskaratos FM, Kalligeros M, Shah R, Navalkissoor S, Gnanasegaran G, Banks J, Smith J, Jacobs B, Galanopoulos M, Mandair D, Caplin M, Toumpanakis C. Antiproliferative Effect of Above-Label Doses of Somatostatin Analogs for the Management of Gastroenteropancreatic Neuroendocrine Tumors. Neuroendocrinology 2021; 111:650-659. [PMID: 32541155 DOI: 10.1159/000509420] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 06/15/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. OBJECTIVE To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. METHODS Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. RESULTS The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9-33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, p = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. CONCLUSIONS Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach.
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Affiliation(s)
| | - Faidon-Marios Laskaratos
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Markos Kalligeros
- Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Ruchir Shah
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Shaunak Navalkissoor
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Gopinath Gnanasegaran
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Jamie Banks
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Jack Smith
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Benjamin Jacobs
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | | | - Dalvinder Mandair
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom
| | - Christos Toumpanakis
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London, United Kingdom,
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14
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Koffas A, Toumpanakis C. Comparative safety review of the current therapies for gastroenteropancreatic neuroendocrine tumors. Expert Opin Drug Saf 2020; 20:321-334. [PMID: 33338383 DOI: 10.1080/14740338.2021.1867097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of neoplasms, whose management requires complex and individualized clinical decisions. Over the last decades the advent of novel medications and advanced diagnostic and therapeutic modalities, alongside our deeper understanding of the disease, revolutionized the landscape of their management, significantly improving both prognosis and quality of life of patients.Area covered: Treatment-related adverse events and safety concerns as demonstrated in clinical trials, as well as in real-world clinical practice.Expert opinion: The only true curative option for NENs remains surgery, whereas high-grade advanced neuroendocrine carcinomas should be primarily managed with platinum-based chemotherapy. For the remaining cases, that comprise the vast majority, the current armamentarium includes somatostatin analogs, interferon, telotristat ethyl, molecular targeted therapies, chemotherapy, peptide receptor radionuclide therapy, and locoregional treatment. The use of the aforementioned therapeutic options is associated with several and not uncommonly severe treatment-related adverse events. However, the benefits offered inclusive of improved prognosis, amelioration of symptoms, and better quality of life amidst others, by far outweighs any adverse event.
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Affiliation(s)
- Apostolos Koffas
- Department of Gastroenterology, General University Hospital of Larisa, Mezourlo Larisa, Greece
| | - Christos Toumpanakis
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
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15
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Gong Y, Fan Z, Luo G, Huang Q, Qian Y, Cheng H, Jin K, Ni Q, Yu X, Liu C. Absolute Counts of Peripheral Lymphocyte Subsets Correlate with the Progression-Free Survival and Metastatic Status of Pancreatic Neuroendocrine Tumour Patients. Cancer Manag Res 2020; 12:6727-6737. [PMID: 32848455 PMCID: PMC7425098 DOI: 10.2147/cmar.s257492] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/21/2020] [Indexed: 11/23/2022] Open
Abstract
Purpose Pancreatic neuroendocrine tumours (panNETs) are rare tumours of pancreas. Lymphocyte subsets in the peripheral blood are reported to reflect tumour prognosis and progression. The objective of the study is to investigate the hypotheses that the levels of peripheral lymphocytes may reflect tumour progression and may predict the prognosis of pancreatic neuroendocrine tumours (panNETs). Patients and Methods A retrospective cohort study consisting of 73 patients diagnosed with panNETs was conducted. Kaplan-Meier methods and Log rank tests were used to compare the survival rates, and a Cox regression model was used to perform multivariate analyses. Results panNET patients with distant metastasis were associated with lower peripheral total T cell (p = 0.039) and CD4+ T cell (p = 0.006) counts. Lower peripheral B cells (p = 0.007) and higher peripheral NK cell (p = 0.001) counts indicated worse progression-free survival (PFS) in Log rank tests. In multivariate analyses, low B cell count (hazard ratio (HR): 6.769, 95% confidence interval (CI): 2.158 to 21.228, p = 0.001) and high NK cell count (HR: 3.715, 95% CI: 1.164 to 11.855, p = 0.027) were independent risk factors for progression. NK cells and B cells were also significantly associated with PFS following radical surgical resection. Conclusion Peripheral total T cell and CD4+ T cell counts may reflect the distant metastasis status in panNET patients. The absolute count of peripheral B cells and NK cells may independently predict the progression of panNET patients, making them promising prognostic indicators and potential targets for treatment of panNETs.
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Affiliation(s)
- Yitao Gong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Zhiyao Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Qiuyi Huang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Yunzhen Qian
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, People's Republic of China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People's Republic of China
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von Arx C, Rea G, Napolitano M, Ottaiano A, Tatangelo F, Izzo F, Petrillo A, Clemente O, Di Sarno A, Botti G, Scala S, Tafuto S. Effect of Octreotide Long-Acting Release on Tregs and MDSC Cells in Neuroendocrine Tumour Patients: A Pivotal Prospective Study. Cancers (Basel) 2020; 12:E2422. [PMID: 32859050 PMCID: PMC7563951 DOI: 10.3390/cancers12092422] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 02/08/2023] Open
Abstract
Octreotide long-acting repeatable (LAR) is largely used to treat functional and/or metastatic neuroendocrine neoplasms (NENs). Its effect in controlling carcinoid syndrome and partially reduce tumour burden is attributable to the ability of octreotide to bind somatostatin receptors (SSTRs) on the tumour and metastasis, regulating growth hormone secretion and cell growth. Notably, SSTRs are also expressed, at different levels, on Tregs. Tregs, together with myeloid-derived suppressor cells (MDSCs), are key components in the anti-tumour immunoregulation. This is the first prospective study aimed to explore the impact of Octreotide (OCT) LAR on the immune system, with a particular focus on Tregs and MDSC cells. Here, we show that circulating Tregs are elevated in NENs patients compared to healthy donors and that treatment with OCT LAR significantly decrease the level of total Tregs and of the three functional Tregs populations: nTregs, eTregs and non-Tregs. Furthermore, OCT LAR treatment induces a functional impairment of the remaining circulating Tregs, significantly decreasing the expression of PD1, CTLA4 and ENTPD1. A trend in circulating MDSC cells is reported in patients treated with OCT LAR. The results reported here suggest that the effect of OCT LAR on Tregs could tip the balance of the patients' immune-system towards a durable anti-tumour immunosurveillance with consequent long-term control of the NENs disease.
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Affiliation(s)
- Claudia von Arx
- Department of Clinical and Experimental Thoracic oncology Istituto Nazionale Tumori, IRCCS Fondazione G.Pascale, 80131 Naples, Italy;
| | - Giuseppina Rea
- UOC Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (G.R.); (M.N.); (S.S.)
| | - Maria Napolitano
- UOC Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (G.R.); (M.N.); (S.S.)
| | - Alessandro Ottaiano
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (F.I.); (O.C.)
| | - Fabiana Tatangelo
- Department of Pathology, Istituto Nazionale Tumori, IRCCS-Fondazione G. Pascale, 80131 Naples, Italy;
| | - Francesco Izzo
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (F.I.); (O.C.)
| | - Antonella Petrillo
- Department of Diagnostic Imaging, Radiant and Metabolic Therapy, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy;
| | - Ottavia Clemente
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.O.); (F.I.); (O.C.)
| | - Antonella Di Sarno
- Department of Internal Medicine, AORN dei Colli, Ospedale “A. Monaldi”, 80131 Naples, Italy;
| | - Gerardo Botti
- Scientific Directorate, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy;
| | - Stefania Scala
- UOC Bersagli Molecolari del Microambiente, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (G.R.); (M.N.); (S.S.)
| | - Salvatore Tafuto
- Sarcomas and Rare Tumours Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy
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17
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Ramírez-Rentería C, Ferreira-Hermosillo A, Marrero-Rodríguez D, Taniguchi-Ponciano K, Melgar-Manzanilla V, Mercado M. An Update on Gastroenteropancreatic Neuroendocrine Neoplasms: From Mysteries to Paradigm Shifts. Arch Med Res 2020; 51:765-776. [PMID: 32654882 DOI: 10.1016/j.arcmed.2020.06.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 06/23/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023]
Abstract
Although neuroendocrine neoplasms (NEN) were once thought to be rare and mostly "benign" diseases, they are now being redefined in light of recently discovered molecular information. NENs constitute a spectrum of variably differentiated neoplasms, ranging from well-differentiated tumors with a protracted course over many years to very aggressive neuroendocrine carcinomas. Although the majority of NEN are non-functional lesions, some of these tumors, do produce a hormonal hypersecretion syndrome. Their reappraisal has led scientist to unveil previously unknown oncogenic pathways and connections that resulted in a new category in the International Classification of Diseases (ICD-11) and a revised version of the World Health Organization Classification (WHO 2018). Complex diseases like NEN require a multidisciplinary approach that includes the perspectives of endocrinologists, medical and surgical oncologists, radiation oncologists, imaging specialists and pathologists. There are currently virtually thousands of ongoing trials evaluating the efficacy and safety of several molecular targeted therapies. The purpose of this review was to critically evaluate recent information regarding the pathogenesis, diagnosis and treatment of NEN.
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Affiliation(s)
- Claudia Ramírez-Rentería
- Unidad de Investigación Médica en Enfermedades Endocrinas. Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Aldo Ferreira-Hermosillo
- Unidad de Investigación Médica en Enfermedades Endocrinas. Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Daniel Marrero-Rodríguez
- Unidad de Investigación Médica en Enfermedades Endocrinas. Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Keiko Taniguchi-Ponciano
- Unidad de Investigación Médica en Enfermedades Endocrinas. Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Virgilio Melgar-Manzanilla
- Unidad de Investigación Médica en Enfermedades Endocrinas. Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Moisés Mercado
- Unidad de Investigación Médica en Enfermedades Endocrinas. Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
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18
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Xi C, Zhang GQ, Sun ZK, Song HJ, Shen CT, Chen XY, Sun JW, Qiu ZL, Luo QY. Interleukins in Thyroid Cancer: From Basic Researches to Applications in Clinical Practice. Front Immunol 2020; 11:1124. [PMID: 32655554 PMCID: PMC7325887 DOI: 10.3389/fimmu.2020.01124] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 05/07/2020] [Indexed: 12/16/2022] Open
Abstract
Inflammation is crucial to tumorigenesis and progression of many cancers. Inflammatory molecules in tumor microenvironment exert pro- or anti-tumor effects. Among them, interleukin, mainly produced by CD3+ and CD4+ T lymphocytes, is a class of small molecule proteins which play an important role in intercellular communication. Numerous studies have confirmed that interleukins are closely related to thyroid cancer. Interleukins regulate the proliferation and migration of thyroid cancer cells and they have prospects in discriminating benign and malignant thyroid diseases, predicting the risk of tumorigenesis, evaluating the prognosis and monitoring the recurrence of thyroid cancer. Besides, the effective application of interleukins in treatment of thyroid cancer has been confirmed by some cell and animal researches. The present review will introduce the potential mechanisms of interleukins in thyroid cancer and focus on the applications of interleukins in clinical practice of thyroid cancer, which will help update understanding of the progress of interleukins researches in thyroid cancer.
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Affiliation(s)
- Chuang Xi
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Guo-Qiang Zhang
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhen-Kui Sun
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hong-Jun Song
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chen-Tian Shen
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiao-Yue Chen
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jian-Wen Sun
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhong-Ling Qiu
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Quan-Yong Luo
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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19
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Yu Y, Yang W, Li Y, Cong Y. Enteroendocrine Cells: Sensing Gut Microbiota and Regulating Inflammatory Bowel Diseases. Inflamm Bowel Dis 2020; 26:11-20. [PMID: 31560044 PMCID: PMC7539793 DOI: 10.1093/ibd/izz217] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Indexed: 12/12/2022]
Abstract
Host sensing in the gut microbiota has been crucial in the regulation of intestinal homeostasis. Although inflammatory bowel diseases (IBDs), multifactorial chronic inflammatory conditions of the gastrointestinal tract, have been associated with intestinal dysbiosis, the detailed interactions between host and gut microbiota are still not completely understood. Enteroendocrine cells (EECs) represent 1% of the intestinal epithelium. Accumulating evidence indicates that EECs are key sensors of gut microbiota and/or microbial metabolites. They can secrete cytokines and peptide hormones in response to microbiota, either in traditional endocrine regulation or by paracrine impact on proximal tissues and/or cells or via afferent nerve fibers. Enteroendocrine cells also play crucial roles in mucosal immunity, gut barrier function, visceral hyperalgesia, and gastrointestinal (GI) motility, thereby regulating several GI diseases, including IBD. In this review, we will focus on EECs in sensing microbiota, correlating enteroendocrine perturbations with IBD, and the underlying mechanisms.
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Affiliation(s)
- Yanbo Yu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, P.R. China,Department of Microbiology and Immunology and Branch, Galveston, Texas, USA
| | - Wenjing Yang
- Department of Microbiology and Immunology and Branch, Galveston, Texas, USA
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, P.R. China
| | - Yingzi Cong
- Department of Microbiology and Immunology and Branch, Galveston, Texas, USA,Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA,Address correspondence to: Yingzi Cong, PhD, Department of Microbiology and Immunology, University of Texas Medical Branch, 4.142C Medical Research Building, 301 University Blvd, Galveston, TX 77555-1019 ()
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20
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Abstract
Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.
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Gonkowski S, Rytel L. Somatostatin as an Active Substance in the Mammalian Enteric Nervous System. Int J Mol Sci 2019; 20:ijms20184461. [PMID: 31510021 PMCID: PMC6769505 DOI: 10.3390/ijms20184461] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/22/2019] [Accepted: 09/08/2019] [Indexed: 12/12/2022] Open
Abstract
Somatostatin (SOM) is an active substance which most commonly occurs in endocrine cells, as well as in the central and peripheral nervous system. One of the parts of the nervous system where the presence of SOM has been confirmed is the enteric nervous system (ENS), located in the wall of the gastrointestinal (GI) tract. It regulates most of the functions of the stomach and intestine and it is characterized by complex organization and a high degree of independence from the central nervous system. SOM has been described in the ENS of numerous mammal species and its main functions in the GI tract are connected with the inhibition of the intestinal motility and secretory activity. Moreover, SOM participates in sensory and pain stimuli conduction, modulation of the release of other neuronal factors, and regulation of blood flow in the intestinal vessels. This peptide is also involved in the pathological processes in the GI tract and is known as an anti-inflammatory agent. This paper, which focuses primarily on the distribution of SOM in the ENS and extrinsic intestinal innervation in various mammalian species, is a review of studies concerning this issue published from 1973 to the present.
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Affiliation(s)
- Slawomir Gonkowski
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowski Str. 13, 10-718 Olsztyn, Poland.
| | - Liliana Rytel
- Department and Clinic of Internal Diseases, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowski Str. 14, 10-718 Olsztyn, Poland.
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22
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Pastrián LG, Ruz-Caracuel I, Gonzalez RS. Giant Primary Neuroendocrine Neoplasms of the Liver: Report of 2 Cases With Molecular Characterization. Int J Surg Pathol 2019; 27:893-899. [DOI: 10.1177/1066896919855764] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary neuroendocrine neoplasms of the liver have occasionally been reported in the liver, though many reports do not convincingly exclude metastases. In this article, we report 2 “giant” hepatic neuroendocrine lesions without evidence of a primary elsewhere after clinical workup. One occurred in a 21-year-old male; the lesion was a large cell neuroendocrine carcinoma measuring 24 cm. The patient died of disease in 10 months. The other occurred in a 25-year-old patient, was 18 cm wide, and was diagnosed as a well-differentiated neuroendocrine tumor, World Health Organization grade 3. The patient died of disease after 30 months. Molecular testing demonstrated only the presence of TP53 mutations in common. These cases expand our knowledge of seemingly primary neuroendocrine neoplasms of the liver, in particular, giant cases measuring more than 8 cm. Guidelines for clinical workup and therapy for these lesions remain unclear, but future thorough workup of such cases is necessary for specific characterization.
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23
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Pardini B, Calin GA. MicroRNAs and Long Non-Coding RNAs and Their Hormone-Like Activities in Cancer. Cancers (Basel) 2019; 11:cancers11030378. [PMID: 30884898 PMCID: PMC6468345 DOI: 10.3390/cancers11030378] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/02/2019] [Accepted: 03/11/2019] [Indexed: 12/12/2022] Open
Abstract
Hormones are messengers circulating in the body that interact with specific receptors on the cell membrane or inside the cells and regulate, at a distal site, the activities of specific target organs. The definition of hormone has evolved in the last years. Hormones are considered in the context of cell–cell communication and mechanisms of cellular signaling. The best-known mechanisms of this kind are chemical receptor-mediated events, the cell–cell direct interactions through synapses, and, more recently, the extracellular vesicle (EV) transfer between cells. Recently, it has been extensively demonstrated that EVs are used as a way of communication between cells and that they are transporters of specific messenger signals including non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Circulating ncRNAs in body fluids and extracellular fluid compartments may have endocrine hormone-like effects because they can act at a distance from secreting cells with widespread consequences within the recipient cells. Here, we discuss and report examples of the potential role of miRNAs and lncRNAs as mediator for intercellular communication with a hormone-like mechanism in cancer.
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Affiliation(s)
- Barbara Pardini
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA.
- Department of Medical Sciences, University of Turin, Turin 10126, Italy.
- Italian Institute for Genomic Medicine (IIGM), Turin 10126, Italy.
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA.
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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24
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Koch CA, Krabbe S, Hehmke B. Statins, metformin, proprotein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors and sex hormones: Immunomodulatory properties? Rev Endocr Metab Disord 2018; 19:363-395. [PMID: 30673921 DOI: 10.1007/s11154-018-9478-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The immune system is closely intertwined with the endocrine system. Many effects of medications used for various clinical endocrine conditions such as the metabolic syndrome, hypercholesterolemia, diabetes mellitus, hypertension, Graves' disease and others also have an impact on the immune system. Some drugs including statins, metformin, angiotensin converting enzyme and proprotein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors and sex hormones are known to have immunomodulatory properties. We here review the literature on this topic and provide some clinical examples including the use of statins in Graves' orbitopathy, rheumatoid arthritis, multiple sclerosis, and adult-onset Still's disease. In that context, we introduce a special immunodiagnostics method developed at the Institute of Diabetes "Gerhardt Katsch" in Karlsburg, Germany, to not only measure but also monitor immune disease activity.
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Affiliation(s)
- Christian A Koch
- Medicover GmbH Berlin, Berlin, Germany.
- Carl von Ossietzky University, Oldenburg, Germany.
- Technical University of Dresden, Dresden, Germany.
- University of Louisville, Louisville, KY, USA.
- University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Siegfried Krabbe
- Medicover GmbH Berlin, Berlin, Germany
- Carl von Ossietzky University, Oldenburg, Germany
- University of Greifswald, Greifswald, Germany
| | - Bernd Hehmke
- Institute of Diabetes ''Gerhardt Katsch'', Karlsburg, Germany.
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25
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Dong H, Wei Y, Xie C, Zhu X, Sun C, Fu Q, Pan L, Wu M, Guo Y, Sun J, Shen H, Ye J. Structural and functional analysis of two novel somatostatin receptors identified from topmouth culter (Erythroculter ilishaeformis). Comp Biochem Physiol C Toxicol Pharmacol 2018; 210:18-29. [PMID: 29698686 DOI: 10.1016/j.cbpc.2018.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 04/18/2018] [Accepted: 04/20/2018] [Indexed: 12/14/2022]
Abstract
In the present study, we cloned and characterized two somatostatin (SS) receptors (SSTRs) from topmouth culter (Erythroculter ilishaeformis) designated as EISSTR6 and EISSTR7. Analysis of EISSTR6 and EISSTR7 signature motifs, 3D structures, and homology with the known members of the SSTR family indicated that the novel receptors had high similarity to the SSTRs of other vertebrates. EISSTR6 and EISSTR7 mRNA expression was detected in 17 topmouth culter tissues, and the highest level was observed in the pituitary. Luciferase reporter assay revealed that SS14 significantly inhibited forskolin-stimulated pCRE-luc promoter activity in HEK293 cells transiently expressing EISSTR6 and EISSTR7, indicating that the receptors can be activated by SS14. We also identified phosphorylation sites important for the functional activity of EISSTR6 and EISSTR7 by mutating Ser23, 43, 107, 196, 311 and Ser7, 29, 61, 222, 225 residues, respectively, to Ala, which significantly reduced the inhibitory effects of SS14 on the CRE promoter mediated by EISSTR6 and EISSTR7. Furthermore, treatment of juvenile topmouth culters with microcystin-LR or 17β-estradiol significantly affected EISSTR6 and EISSTR7 transcription in the brain, liver and spleen, suggesting that these receptors may be involved in the pathogenic mechanisms induced by endocrine disruptors. Our findings should contribute to the understanding of the structure-function relationship and evolution of the SSTR family.
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Affiliation(s)
- Haiyan Dong
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China; National-local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Zhejiang Provincial Key Laboratory of Aquatic Resources Conservation and Development, Key Laboratory of Aquatic Animal Genetic Breeding and Nutrition of Chinese Academy of Fishery Sciences, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China.
| | - Yunhai Wei
- Department of Gastrointestinal Surgery, the Central Hospital of Huzhou, 198 Hongqi Road, Huzhou, Zhejiang 313000, PR China
| | - Chao Xie
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Xiaoxuan Zhu
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Chao Sun
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Qianwen Fu
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Lei Pan
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Mengting Wu
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Yinghan Guo
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Jianwei Sun
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Hong Shen
- Department of Basic Medical Science, Huzhou University, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China
| | - Jinyun Ye
- National-local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Zhejiang Provincial Key Laboratory of Aquatic Resources Conservation and Development, Key Laboratory of Aquatic Animal Genetic Breeding and Nutrition of Chinese Academy of Fishery Sciences, 759 Erhuan East Road, Huzhou, Zhejiang 313000, PR China.
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26
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Bhanat E, Koch CA, Parmar R, Garla V, Vijayakumar V. Somatostatin receptor expression in non-classical locations - clinical relevance? Rev Endocr Metab Disord 2018; 19:123-132. [PMID: 30324319 DOI: 10.1007/s11154-018-9470-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In-111 pentetreotide (Octreoscan) is a radiolabeled somatostatin analog with high binding affinity to somatostatin receptors (SSTR) used in somatostatin receptor scintigraphy (SRS). Pentetreotide labelled with In-111 is widely used due to its high affinity to SSTR 2 and 5. SSTR are expressed on neuroendocrine cells as well as several non-neural and non-endocrine cells with varying levels of density. We retrospectively reviewed articles and publications related to octreoscan accumulation in sites that classically do not have high concentrations of SSTR as well as in organs and tissues from diseases which are not usually diagnosed by octreoscan. The significance of a positive uptake as assessed by octreoscan in non-somatostatin receptor related diseases is not fully understood yet. Localization of octreotide in non-oncological disease states such as inflammation is due to presence of SSTR in activated immunological cells, over-expression by activated cells in the respective tissue and SSTR expression by blood vessels. In granulomatous diseases, over-expression of SSTR2 preferential binding sites were detected in epitheloid and giant cells. The purpose of the current study is to identify octreoscan localization in non-somatostatin receptor related disease sites to better understand the mechanism of this nonspecific accumulation which may help expand the clinical utilization of functional imaging utilizing somatostatin receptor scintigraphy in diagnosis and perhaps therapy.
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Affiliation(s)
- Eldrin Bhanat
- Department of Radiation Oncology, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Christian A Koch
- Medicover GmbH and Technical University of Dresden, Dresden, Germany
- Department of Medicine/Endocrinology, University of Louisville, Louisville, KY, 40292, USA
| | - Rinkuben Parmar
- Department of Microbiology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Vishnu Garla
- Department of Medicine/Endocrinology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Vani Vijayakumar
- Division of Nuclear Medicine and Department of Radiology, University of Mississippi Medical Center, Jackson, MS, USA.
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27
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El-Salhy M, Patcharatrakul T, Hatlebakk JG, Hausken T, Gilja OH, Gonlachanvit S. Chromogranin A cell density in the large intestine of Asian and European patients with irritable bowel syndrome. Scand J Gastroenterol 2017; 52:691-697. [PMID: 28346031 DOI: 10.1080/00365521.2017.1305123] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Patients with irritable bowel syndrome (IBS) in Asia show distinctive differences from those in the western world. The gastrointestinal endocrine cells appear to play an important role in the pathophysiology of IBS. The present study aimed at studying the density of chromogranin A (CgA) cells in the large intestine of Thai and Norwegian IBS patients. METHODS Thirty Thai IBS patients and 20 control subjects, and 47 Norwegian IBS patients and 20 control subjects were included. A standard colonoscopy was performed in both the patients and controls, and biopsy samples were taken from the colon and the rectum. The biopsy samples were stained with hematoxylin-eosin and immunostained for CgA. The density of CgA cells was determined by computerized image analysis. RESULTS In the colon and rectum, the CgA cell densities were far higher in both IBS and healthy Thai subjects than in Norwegians. The colonic CgA cell density was lower in Norwegian IBS patients than in controls, but did not differ between Thai IBS patients and controls. In the rectum, the CgA cell densities in both Thai and Norwegian patients did not differ from those of controls. CONCLUSIONS The higher densities of CgA cells in Thai subjects than Norwegians may be explained by a higher exposure to infections at childhood and the development of a broad immune tolerance, by differences in the intestinal microbiota, and/or differing diet habits. The normal CgA cell density in Thai IBS patients in contrast to that of Norwegians may be due to differences in pathophysiology.
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Affiliation(s)
- Magdy El-Salhy
- a Department of Medicine, Section for Gastroenterology , Stord Helse-Fonna Hospital , Stord , Norway.,b Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c Department of Medicine , National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital , Bergen , Norway
| | - Tanisa Patcharatrakul
- d Division of Gastroenterology, Department of Medicine Faculty of Medicine , GI Motility Research Unit, Chulalongkorn University , Bangkok , Thailand.,e Thai Red Cross Society , King Chulalongkorn Memorial Hospital , Bangkok , Thailand
| | - Jan Gunnar Hatlebakk
- b Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c Department of Medicine , National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital , Bergen , Norway
| | - Trygve Hausken
- b Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c Department of Medicine , National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital , Bergen , Norway.,e Thai Red Cross Society , King Chulalongkorn Memorial Hospital , Bangkok , Thailand
| | - Odd Helge Gilja
- b Department of Clinical Medicine , University of Bergen , Bergen , Norway.,c Department of Medicine , National Centre for Functional Gastrointestinal Disorders, Haukeland University Hospital , Bergen , Norway.,f Department of Medicine , National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital , Bergen , Norway
| | - Sutep Gonlachanvit
- d Division of Gastroenterology, Department of Medicine Faculty of Medicine , GI Motility Research Unit, Chulalongkorn University , Bangkok , Thailand.,e Thai Red Cross Society , King Chulalongkorn Memorial Hospital , Bangkok , Thailand
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28
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El-Salhy M, Solomon T, Hausken T, Gilja OH, Hatlebakk JG. Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease. World J Gastroenterol 2017; 23:5068-5085. [PMID: 28811704 PMCID: PMC5537176 DOI: 10.3748/wjg.v23.i28.5068] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/15/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn’s disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients’ quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease.
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29
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Pavel ME, Sers C. WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine. Endocr Relat Cancer 2016; 23:T135-T154. [PMID: 27649723 DOI: 10.1530/erc-16-0370] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 09/20/2016] [Indexed: 12/19/2022]
Abstract
Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms. Evidence-based treatment options for antiproliferative therapy include somatostatin analogues, the mTOR inhibitor everolimus, the multiple tyrosine kinase inhibitor sunitinib and peptide receptor radionuclide therapy with 177-Lu-octreotate. In the absence of definite predictive markers, therapeutic decision making follows clinical and pathological criteria. As objective response rates with targeted drugs are rather low, and response duration is limited in most patients, numerous combination therapies targeting multiple pathways have been explored in the field. Upfront combination of drugs, however, is associated with increasing toxicity and has shown little benefit. Major advancements in the molecular understanding of NET based on genomic, epigenomic and transcriptomic analysis have been achieved with prognostic and therapeutic impact. New insight into molecular alterations has paved the way to biomarker-driven clinical trials and may facilitate treatment stratification toward personalized medicine in the near future. However, an improved understanding of the complexity of pathway interactions is required for successful treatment. A systems biology approach is one of the tools that may help to achieve this endeavor.
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Affiliation(s)
- Marianne E Pavel
- Medical DepartmentDivision of Hepatology and Gastroenterology including Metabolic Diseases, Campus Virchow Klinikum, Charité University Medicine, Berlin, Germany
| | - Christine Sers
- Institute of PathologyCharité University Medicine, Berlin, Germany
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30
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El-Salhy M, Hatlebakk JG. Changes in enteroendocrine and immune cells following colitis induction by TNBS in rats. Mol Med Rep 2016; 14:4967-4974. [PMID: 27840918 PMCID: PMC5355731 DOI: 10.3892/mmr.2016.5902] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 08/04/2016] [Indexed: 12/11/2022] Open
Abstract
Approximately 3.6 million individuals suffer from inflammatory bowel disease (IBD) in the western world, with an annual global incidence rate of 3–20 cases/100,000 individuals. The etiology of IBD is unknown, and the currently available treatment options are not satifactory for long-term treatment. Patients with inflammatory bowel disease present with abnormalities in multiple intestinal endocrine cell types, and a number of studies have suggested that interactions between gut hormones and immune cells may serve a pivotal role in the pathophysiology of IBD. The aim of the present study was to investigate alterations in colonic endocrine cells in a rat model of IBD. A total of 30 male Wistar rats were divided into control and trinitrobenzene sulfonic acid (TNBS)-induced colitis groups. Colonoscopies were performed in the control and TNBS groups at day 3 following the induction of colitis, and colonic tissues were collected from all animals. Colonic endocrine and immune cells in the obtained tissue samples were immunostained and their densities were quantified. The densities of chromogranin A, peptide YY, and pancreatic polypeptide-producing cells were significantly lower in the TNBS group compared with the control group, whereas the densities of serotonin, oxyntomodulin, and somatostatin-producing cells were significantly higher in the TNBS group. The densities of mucosal leukocytes, B/T-lymphocytes, T-lymphocytes, B-lymphocytes, macrophages/monocytes and mast cells were significantly higher in the TNBS group compared with the controls, and these differences were strongly correlated with alterations in all endocrine cell types. In conclusion, the results suggest the presence of interactions between intestinal hormones and immune cells.
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Affiliation(s)
- Magdy El-Salhy
- Division of Gastroenterology, Department of Medicine, Stord Hospital, 5416 Stord, Norway
| | - Jan Gunnar Hatlebakk
- Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway
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31
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El-Salhy M, Mazzawi T, Umezawa K, Gilja OH. Enteroendocrine cells, stem cells and differentiation progenitors in rats with TNBS-induced colitis. Int J Mol Med 2016; 38:1743-1751. [PMID: 27779708 PMCID: PMC5117771 DOI: 10.3892/ijmm.2016.2787] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 09/14/2016] [Indexed: 12/15/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD), as well as animal models of human IBD have abnormal enteroendocrine cells. The present study aimed to identify the possible mechanisms underlying these abnormalities. For this purpose, 40 male Wistar rats were divided into 4 groups as follows: the control group, the group with trinitrobenzene sulfonic acid (TNBS)-induced colitis with no treatment (TNBS group), the group with TNBS-induced colitis treated with 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G; an activator protein-1 inhibitor) (DTCM-G group), and the group with TNBS-induced colitis treated with dehydroxymethylepoxyquinomicin (DHMEQ; a nuclear factor-κB inhibitor) treatment (DHMEQ group). Three days following the administration of TNBS, the rats were treated as follows: those in the control and TNBS groups received 0.5 ml of the vehicle [0.5% carboxymethyl cellulose (CMC)], those in the DTCM-G group received DTCM-G at 20 mg/kg body weight in 0.5% CMC, and those in the DHMEQ group received DHMEQ at 15 mg/kg body weight in 0.5% CMC. All injections were administered intraperitoneally twice daily for 5 days. The rats were then sacrificed, and tissue samples were taken from the colon. The tissue sections were stained with hemotoxylin-eosin and immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP), somatostatin, Musashi1 (Msi1), Math1, Neurogenin3 (Neurog3) and NeuroD1. The staining was quantified using image analysis software. The densities of CgA-, PYY-, PP-, Msi1-, Neurog3- and NeuroD1-positive cells were significantly lower in the TNBS group than those in the control group, while those of serotonin-, oxyntomodulin- and somatostatin-positive cells were significantly higher in the TNBS group than those in the control group. Treatment with either DTCM-G or DHMEQ restored the densities of enteroendocrine cells, stem cells and their progenitors to normal levels. It was thus concluded that the abnormalities in enteroendocrine cells and stem cells and their differentiation progenitors may be caused by certain signaling substances produced under inflammatory processes, resulting in changes in hormone expression in enteroendocrine cells. These substances may also interfere with the colonogenic activity and the differentiation of the stem-cell secretory lineage into mature enteroendocrine cells.
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Affiliation(s)
- Magdy El-Salhy
- Division of Gastroenterology, Department of Medicine, Stord Helse-Fonna Hospital, 5416 Stord, Norway
| | - Tarek Mazzawi
- Division of Gastroenterology, Institute of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
| | - Kazuo Umezawa
- Department of Molecular Target Medicine, School of Aichi Medical University, School of Medicine, Nagakute, 480-1195 Aichi, Japan
| | - Odd Helge Gilja
- Division of Gastroenterology, Institute of Clinical Medicine, University of Bergen, 5020 Bergen, Norway
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El-Salhy M, Umezawa K. Effects of AP‑1 and NF‑κB inhibitors on colonic endocrine cells in rats with TNBS‑induced colitis. Mol Med Rep 2016; 14:1515-22. [PMID: 27357734 PMCID: PMC4940105 DOI: 10.3892/mmr.2016.5444] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 05/31/2016] [Indexed: 02/07/2023] Open
Abstract
Interactions between intestinal neuroendocrine peptides/amines and the immune system appear to have an important role in the pathophysiology of inflammatory bowel disease (IBD). The present study investigated the effects of activator protein (AP)‑1 and nuclear factor (NF)‑κB inhibitors on inflammation‑induced alterations in enteroendocrine cells. A total of 48 male Wistar rats were divided into the following four groups (n=12 rats/group): Control, trinitrobenzene sulfonic acid (TNBS)‑induced colitis only (TNBS group), TNBS‑induced colitis with 3‑[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM‑G) treatment (DTCM‑G group), and TNBS‑induced colitis with dehydroxymethylepoxyquinomicin (DHMEQ) treatment (DHMEQ group). A total of 3 days following administration of TNBS, the rats were treated as follows: The control and TNBS groups received 0.5 ml vehicle (0.5% carboxymethyl cellulose; CMC), respectively; the DTCM‑G group received DTCM‑G (20 mg/kg body weight) in 0.5% CMC; and the DHMEQ group received DHMEQ (15 mg/kg body weight) in 0.5% CMC. All injections were performed intraperitoneally twice daily for 5 days. The rats were sacrificed, and tissue samples obtained from the colon were examined histopathologically and immunohistochemically. Inflammation was evaluated using a scoring system. In addition, the sections were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP) and somatostatin, and immunostaining was quantified using image‑analysis software. The density of cells expressing CgA, PYY and PP was significantly lower in the TNBS group compared with in the control group, whereas the density of cells expressing serotonin, oxyntomodulin and somatostatin was significantly higher in the TNBS group compared with in the control group. None of the endocrine cell types differed significantly between the control group and either the DTCM‑G or DHMEQ groups. All of the colonic endocrine cell types were affected in rats with TNBS‑induced colitis. The expression density of these endocrine cell types was restored to control levels following treatment with AP‑1 or NF‑κB inhibitors. These results indicated that the immune system and enteroendocrine cells interact in IBD.
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Affiliation(s)
- Magdy El-Salhy
- Division of Gastroenterology, Department of Medicine, Stord Helse‑Fonna Hospital, 5416 Stord, Norway
| | - Kazuo Umezawa
- Department of Molecular Target Medicine, School of Aichi Medical University, School of Medicine, Nagakute, Aichi 480‑1195, Japan
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El-Salhy M, Hausken T. The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD). Neuropeptides 2016; 55:137-44. [PMID: 26431932 DOI: 10.1016/j.npep.2015.09.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/11/2015] [Accepted: 09/15/2015] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) includes three main disorders: ulcerative colitis, Crohn's disease, and microscopic colitis. The etiology of IBD is unknown and the current treatments are not completely satisfactory. Interactions between the gut neurohormones and the immune system are thought to play a pivot role in inflammation, especially in IBD. These neurohormones are believed to include members of the neuropeptide YY (NPY) family, which comprises NPY, peptide YY (PYY), and pancreatic polypeptide (PP). Understanding the role of these peptides may shed light on the pathophysiology of IBD and potentially yield an effective treatment tool. Intestinal NPY, PYY, and PP are abnormal in both patients with IBD and animal models of human IBD. The abnormality in NPY appears to be primarily caused by an interaction between immune cells and the NPY neurons in the enteric nervous system; the abnormalities in PYY and PP appear to be secondary to the changes caused by the abnormalities in other gut neurohormonal peptides/amines that occur during inflammation. NPY is the member of the NPY family that can be targeted in order to decrease the inflammation present in IBD.
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Affiliation(s)
- Magdy El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Hospital, Stord, Norway; Section for Neuroendocrine Gastroenterology, Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen, Norway.
| | - Trygve Hausken
- Section for Neuroendocrine Gastroenterology, Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen, Norway.
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Yang X, Yang Y, Li Z, Cheng C, Yang T, Wang C, Liu L, Liu S. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLoS One 2015; 10:e0124884. [PMID: 25894842 PMCID: PMC4403810 DOI: 10.1371/journal.pone.0124884] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/18/2015] [Indexed: 02/07/2023] Open
Abstract
Background In previous decades, chromogranin A (CgA) has been demonstrated to be the most promising biomarker for the diagnosis of neuroendocrine tumors (NETs), but its diagnostic value is still controversial. This meta-analysis aimed to estimate the potential diagnostic value of circulating CgA for NETs. Methods We collected relevant studies from several electronic databases as well as from reference lists. Diagnostic indices of CgA were pooled with random effects models. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and summary receiver operating characteristic (SROC) curves for the diagnosis of NETs were used to estimate the overall diagnostic efficiency. Results Through a search strategy, 13 studies met the inclusion criteria and were included. These studies contained 1260 patients with NETs and 967 healthy controls in the total sample. As a result, the overall sensitivity, specificity and diagnostic odds ratio (DOR) were 0.73 (95% CI: 0.71 to 0.76), 0.95 (95% CI: 0.93 to 0.96) and 56.29 (95% CI: 25.27 to 125.38), respectively, while the summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 14.56 (95% CI: 6.62 to 32.02) and 0.26 (95% CI: 0.18 to 0.38), respectively. In addition, the area under the curve (AUC) of the circulating CgA in the diagnosis of NETs was 0.8962. Conclusions These data demonstrate that circulating CgA is an efficient biomarker for the diagnosis of NETs with high sensitivity and specificity, which indicates that it may be helpful for the clinical management of NETs. However, further studies are needed to clarify this issue.
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Affiliation(s)
- Xin Yang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan Yang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhilu Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chen Cheng
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ting Yang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Cheng Wang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shengchun Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- * E-mail:
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Laroia ST, Sasturkar S, Rastogi A, Pamecha V. Solitary hypervascular liver metastasis from neuroendocrine tumor mimicking hepatocellular cancer: All that glitters is not gold. Indian J Nucl Med 2015; 30:42-6. [PMID: 25589805 PMCID: PMC4290065 DOI: 10.4103/0972-3919.147535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Neuroendocrine tumor metastases to the liver can mimic primary hepatocellular carcinoma (HCC) on imaging, cytology, and core biopsy. We present a case study along with the literature review of a patient who presented as a solitary liver mass mimicking HCC and subsequently underwent a partial hepatectomy. The histopathology and immunohistochemisrty of the resected specimen revealed metastatic neuroendocrine carcinoma. Positron emission tomography (PET) scan with 68Ga-DOTA-NaI-octreotide (68Ga-DOTANOC) localized the primary tumor in the ileum. A curative follow-up surgery for resection of the small bowel containing the primary tumor was carried out. This case illustrates the shortcomings of routine imaging methods, utility of immunocytochemistry and the importance of 68Ga-DOTANOC PET in determining the metastatic spread as well as the origin of neuroendocrine tumors (NETs). This case report attempts to highlight the current imaging paradigms and management strategy of midgut and other NET's at the point of detection, staging and follow-up.
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Affiliation(s)
- Shalini Thapar Laroia
- Department of Radiology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Shridhar Sasturkar
- Department of Hepato-Pancreatico-Biliary and Liver Transplantation Surgery, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Viniyendra Pamecha
- Department of Hepato-Pancreatico-Biliary and Liver Transplantation Surgery, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
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Abstract
Sepsis is defined as severe systemic inflammation in response to invading pathogens, or an uncontrolled hyperinflammatory response, as mediated by the release of various proinflammatory mediators. Although some patients may die rapidly from septic shock accompanied by an overwhelming systemic inflammatory response syndrome (SIRS) triggered by a highly virulent pathogen, most patients survive the initial phase of sepsis, showing multiple organ damage days or weeks later. These patients often demonstrate signs of immune suppression accompanied by enhanced inflammation. Sepsis is a result of a complex process; there is interaction of various pathways, such as inflammation, immunity, coagulation, as well as the neuroendocrine system. This treatise is an attempt to provide a summary of several key regulatory mechanisms and to present the currently recognized molecular pathways that are involved in the pathogenesis of sepsis.
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Affiliation(s)
- Yong-Ming Yao
- Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, 51 Fu-cheng Road, Haidian District, Beijing, 100048, People's Republic of China
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Fazio N, Abdel-Rahman O, Spada F, Galdy S, De Dosso S, Capdevila J, Scarpa A. RAF signaling in neuroendocrine neoplasms: from bench to bedside. Cancer Treat Rev 2014; 40:974-9. [PMID: 24998490 DOI: 10.1016/j.ctrv.2014.06.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 06/16/2014] [Accepted: 06/17/2014] [Indexed: 12/23/2022]
Abstract
Neuroendocrine neoplasms are a low-incidence and heterogeneous group of malignancies. In the advanced stage, several therapeutic options can be discussed, including molecular-targeted agents, but biological predicting factors are lacking. A number of molecular targets have been studied over the last decade leading to several phase II studies; however, very few agents progressed to phase III clinical trials. The RAF family of proteins belongs to the mitogen-activated protein kinase (MAPK) pathway, that has a role in several types of cancers, particularly related to BRAF mutations. Indeed BRAF inhibitors have been reported as being effective, mainly in melanoma. However, in neuroendocrine neoplasms BRAF mutations are extremely rare and RAF-1 activation has been reported to inhibit tumor growth in a pre-clinical setting. Therefore, in this field, RAF-1 activators rather than BRAF inhibitors should be clinically investigated. This article reviews the basic science as well as clinical data of RAF signaling in advanced neuroendocrine neoplasms with special emphasis on the potential role of both RAF activators and inhibitors.
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Affiliation(s)
- Nicola Fazio
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.
| | - Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Francesca Spada
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy
| | - Salvatore Galdy
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy
| | - Sara De Dosso
- Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Jaume Capdevila
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Aldo Scarpa
- Department of Pathology and Diagnostics, ARC-NET Research Center, University of Verona, Italy
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Interleukins as markers of inflammation in malignant and benign thyroid disease. Inflamm Res 2014; 63:667-74. [DOI: 10.1007/s00011-014-0739-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 04/11/2014] [Accepted: 04/15/2014] [Indexed: 02/07/2023] Open
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Barbieri F, Albertelli M, Grillo F, Mohamed A, Saveanu A, Barlier A, Ferone D, Florio T. Neuroendocrine tumors: insights into innovative therapeutic options and rational development of targeted therapies. Drug Discov Today 2014; 19:458-68. [DOI: 10.1016/j.drudis.2013.10.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 09/02/2013] [Accepted: 10/21/2013] [Indexed: 02/07/2023]
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Woodbridge LR, Murtagh BM, Yu DFQC, Planche KL. Midgut Neuroendocrine Tumors: Imaging Assessment for Surgical Resection. Radiographics 2014; 34:413-26. [DOI: 10.1148/rg.342135504] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Walenkamp A, Crespo G, Fierro Maya F, Fossmark R, Igaz P, Rinke A, Tamagno G, Vitale G, Öberg K, Meyer T. Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. Endocr Relat Cancer 2014; 21:R445-60. [PMID: 25296914 DOI: 10.1530/erc-14-0106] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research.
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Affiliation(s)
- Annemiek Walenkamp
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Guillermo Crespo
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Felipe Fierro Maya
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Reidar Fossmark
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Peter Igaz
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Anja Rinke
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Gianluca Tamagno
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Giovanni Vitale
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Au
| | - Kjell Öberg
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Tim Meyer
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
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Yang H, Jin Y, Wang C, Tang C. Role of mesenteric lymph pathway in the effects of exogenous somatostatin against early intestinal injury after ischemia-reperfusion in rats. Neuropeptides 2013; 47:237-43. [PMID: 23706875 DOI: 10.1016/j.npep.2013.04.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Revised: 04/19/2013] [Accepted: 04/22/2013] [Indexed: 12/22/2022]
Abstract
Intestinal ischemia-reperfusion (I/R)-induced gut injury remains a challenge for critically ill patients. This study aims to test whether mesenteric lymph pathway is involved in intestinal I/R injury and whether somatostatin (SST) affects mesenteric lymph pathway after mesenteric reperfusion. Intestinal I/R rats were treated with SST-14 by intravenous injection combined with intraperitoneal injection before occlusion of the SMA until the end of the experiment. When intestinal I/R injury treated with SST, the volumes of mesenteric lymph flow at the 6th h after reperfusion following intestinal ischemia were increased ([0.55±0.24] ml/h vs [0.25±0.09] ml/h, p<0.05) and the number of intestinal lymphocytes per milliliter ([2.30±0.72]×10⁷/ml vs [1.16±0.63]×10⁷/ml, p<0.05) was also increased, which caused the number of intestinal lymphocytes output at the same period of time was significantly increased compared with intestinal I/R group ([1.33±0.88]×10⁷/h vs [0.28±0.15]×10⁷/h, p<0.05). Meanwhile, the number of ⁵¹Cr-lymphocytes migration from systemic circulation to the effector sites in GALT was significantly increased ([1.93±0.23]×10⁵/h vs [0.90±0.25]×10⁵/h, p<0.05), although the percentage of ⁵¹Cr-lymphocytes in the effector sites ([1.45±0.26]% vs [3.23±1.69]%, p<0.05) was sharply decreased compared with intestinal I/R group. The accompanying decreases of the endotoxin concentration ([0.038±0.017] EU/mL vs [0.110±0.028] EU/mL, compared with intestinal I/R group p<0.05) and the TNF-α levels ([37.50±10.45] ρg/ml) vs ([74.93±14.77] ρg/ml), compared with intestinal I/R group p<0.05) in mesenteric lymph and the improvement of vital organ dysfunction happened during the early intestinal I/R injury. Suppression of gut-derived toxic mediators reaching systemic circulation and increases of the number of lymphocytes homing to the effector sites in GALT to strengthen the effective immune responses in intestinal mucosa account for the protective effects of exogenous SST against early intestinal I/R injury.
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Affiliation(s)
- Hui Yang
- Department of Gastroenterology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
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Levels of dipeptidyl peptidase IV/CD26 substrates neuropeptide Y and vasoactive intestinal peptide in rheumatoid arthritis patients. Rheumatol Int 2013; 33:2867-74. [DOI: 10.1007/s00296-013-2823-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 07/05/2013] [Indexed: 01/28/2023]
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Peptide receptor targeting in cancer: the somatostatin paradigm. INTERNATIONAL JOURNAL OF PEPTIDES 2013; 2013:926295. [PMID: 23476673 PMCID: PMC3582104 DOI: 10.1155/2013/926295] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Revised: 12/10/2012] [Accepted: 12/28/2012] [Indexed: 02/06/2023]
Abstract
Peptide receptors involved in pathophysiological processes represent promising therapeutic targets. Neuropeptide somatostatin (SST) is produced by specialized cells in a large number of human organs and tissues. SST primarily acts as inhibitor of endocrine and exocrine secretion via the activation of five G-protein-coupled receptors, named sst1–5, while in central nervous system, SST acts as a neurotransmitter/neuromodulator, regulating locomotory and cognitive functions. Critical points of SST/SST receptor biology, such as signaling pathways of individual receptor subtypes, homo- and heterodimerization, trafficking, and cross-talk with growth factor receptors, have been extensively studied, although functions associated with several pathological conditions, including cancer, are still not completely unraveled. Importantly, SST exerts antiproliferative and antiangiogenic effects on cancer cells in vitro, and on experimental tumors in vivo. Moreover, SST agonists are clinically effective as antitumor agents for pituitary adenomas and gastro-pancreatic neuroendocrine tumors. However, SST receptors being expressed by tumor cells of various tumor histotypes, their pharmacological use is potentially extendible to other cancer types, although to date no significant results have been obtained. In this paper the most recent findings on the expression and functional roles of SST and SST receptors in tumor cells are discussed.
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