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Strategies to Increase ß-Cell Mass Expansion
This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Strategies to increase -cell mass expansion Drynda, Robert Lech Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Strategies to increase β-cell mass expansion A thesis submitted by Robert Drynda For the degree of Doctor of Philosophy from King’s College London Diabetes Research Group Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London 2017 Table of contents Table of contents ................................................................................................. -
Redirecting Intracellular Trafficking and the Secretion Pattern of FSH Dramatically Enhances Ovarian Function in Mice
Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice Huizhen Wanga, Melissa Larsona, Albina Jablonka-Shariffb, Christopher A. Pearlb, William L. Millerc, P. Michael Connd, Irving Boimeb, and T. Rajendra Kumara,e,1 Departments of aMolecular and Integrative Physiology and ePathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160; bDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110; cDepartment of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695; and dDepartments of Internal Medicine and Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430 Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved February 28, 2014 (received for review November 14, 2013) FSH and luteinizing hormone (LH) are secreted constitutively or in Results pulses, respectively, from pituitary gonadotropes in many vertebrates, Strategy to Redirect FSH from the Constitutive to Regulated Pathway. Our and regulate ovarian function. The molecular basis for this evolution- in vitro screens indicated that a carboxyterminal (C′)-heptapeptide arily conserved gonadotropin-specific secretion pattern is not un- in the human LHβ (LSGLLFL) (12) or a modified FSHβ con- derstood. Here, we show that the carboxyterminal heptapeptide in taining this peptide (13) favors secretion of corresponding dimers LH is a gonadotropin-sorting determinant in vivo that directs pulsatile via the regulated pathway in heterologous somatotrope cells. secretion. FSH containing this heptapeptide enters the regulated Based on these initial data, we engineered human transgenes en- pathway in gonadotropes of transgenic mice, and is released in β ′ response to gonadotropin-releasing hormone, similar to LH. -
Dynamic Gnrh and Hcg Testing: Establishment of New Diagnostic Reference Levels
176:4 PROOF ONLY A K Bang and others Reference levels on GnRH and 176:4 379–391 Clinical Study hCG tests Dynamic GnRH and hCG testing: establishment of new diagnostic reference levels A Kirstine Bang1,2, Loa Nordkap1,2, Kristian Almstrup1,2, Lærke Priskorn1,2, Jørgen Holm Petersen1,2,3, Ewa Rajpert-De Meyts1,2, Anna-Maria Andersson1,2, Anders Juul1,2 and Niels Jørgensen1,2 1Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Correspondence Denmark, 2International Center for Research and Research Training in Endocrine Disruption of Male should be addressed Reproduction and Child Health (EDMaRC), Rigshospitalet, Denmark, and 3Department of Biostatistics, to N Jørgensen University of Copenhagen, Copenhagen, Denmark Email [email protected] Abstract Objective: Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) stimulation tests may be used to evaluate the pituitary and testicular capacity. Our aim was to evaluate changes in follicular-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone after GnRH and hCG stimulation in healthy men and assess the impact of six single nucleotide polymorphisms on the responses. Design: GnRH and hCG stimulation tests were performed on 77 healthy men, 18–40 years (reference group) at a specialized andrology referral center at a university hospital. The potential influence of the tests was illustrated by results from 45 patients suspected of disordered hypothalamic–pituitary–gonadal axis. Methods: Baseline, stimulated, relative and absolute changes in serum FSH and LH were determined by ultrasensitive TRIFMA, and testosterone was determined by LC–MS/MS. Results: For the reference group, LH and FSH increased almost 400% and 40% during GnRH testing, stimulated levels varied from 4.4 to 58.8 U/L and 0.2 to 11.8 U/L and FSH decreased in nine men. -
Maternal Adiponectin Prevents Visceral Adiposity and Adipocyte Hypertrophy in Prenatal Androgenized Female Mice
Received: 25 September 2020 | Revised: 26 November 2020 | Accepted: 7 December 2020 DOI: 10.1096/fj.202002212R RESEARCH ARTICLE Maternal adiponectin prevents visceral adiposity and adipocyte hypertrophy in prenatal androgenized female mice Yanling Wu1 | Belén Chanclón1 | Peter Micallef1 | qElisabet Stener-Victorin2 | Ingrid Wernstedt Asterholm1 | Anna Benrick1,3 1Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Abstract Academy, University of Gothenburg, Hyperandrogenism is the main characteristic of polycystic ovary syndrome, which Gothenburg, Sweden affects placental function and fetal growth, and leads to reproductive and metabolic 2 Department of Physiology and dysfunction in female offspring. Adiponectin acts on the placenta and may exert Pharmacology, Karolinska Institute, Stockholm, Sweden endocrine effects on the developing fetus. This study aims to investigate if mater- 3School of Health Sciences, University of nal and/or fetal adiponectin can prevent metabolic and reproductive dysfunction in Skövde, Skövde, Sweden prenatal androgenized (PNA) female offspring. Adiponectin transgenic (APNtg) and wild-type dams received dihydrotestosterone/vehicle injections between gesta- Correspondence Anna Benrick, Department of Physiology, tional days 16.5-18.5 to induce PNA offspring, which were followed for 4 months. University of Gothenburg, Institute of Offspring from APNtg dams were smaller than offspring from wild-type dams, in- Neuroscience and Physiology, Box 423, 405 30 Gothenburg, Sweden. dependent of genotype. Insulin sensitivity was higher in wild-type mice from APNtg Email: [email protected] dams compared to wild-types from wild-type dams, and insulin sensitivity correlated with fat mass and adipocyte size. PNA increased visceral fat% and adipocyte size in Funding information Novo Nordisk Fonden (NNF), Grant/ wild-type offspring from wild-type dams, while wild-type and APNtg offspring from Award Number: NNF19OC0056601; APNtg dams were protected against this effect. -
Primary Hepatic Neuroendocrine Carcinoma: Report of Two Cases and Literature Review
The Jackson Laboratory The Mouseion at the JAXlibrary Faculty Research 2018 Faculty Research 3-1-2018 Primary hepatic neuroendocrine carcinoma: report of two cases and literature review. Zi-Ming Zhao The Jackson Laboratory, [email protected] Jin Wang Ugochukwu C Ugwuowo Liming Wang Jeffrey P Townsend Follow this and additional works at: https://mouseion.jax.org/stfb2018 Part of the Life Sciences Commons, and the Medicine and Health Sciences Commons Recommended Citation Zhao, Zi-Ming; Wang, Jin; Ugwuowo, Ugochukwu C; Wang, Liming; and Townsend, Jeffrey P, "Primary hepatic neuroendocrine carcinoma: report of two cases and literature review." (2018). Faculty Research 2018. 71. https://mouseion.jax.org/stfb2018/71 This Article is brought to you for free and open access by the Faculty Research at The ousM eion at the JAXlibrary. It has been accepted for inclusion in Faculty Research 2018 by an authorized administrator of The ousM eion at the JAXlibrary. For more information, please contact [email protected]. Zhao et al. BMC Clinical Pathology (2018) 18:3 https://doi.org/10.1186/s12907-018-0070-7 CASE REPORT Open Access Primary hepatic neuroendocrine carcinoma: report of two cases and literature review Zi-Ming Zhao1,2*† , Jin Wang3,4,5†, Ugochukwu C. Ugwuowo6, Liming Wang4,8* and Jeffrey P. Townsend2,7* Abstract Background: Primary hepatic neuroendocrine carcinoma (PHNEC) is extremely rare. The diagnosis of PHNEC remains challenging—partly due to its rarity, and partly due to its lack of unique clinical features. Available treatment options for PHNEC include surgical resection of the liver tumor(s), radiotherapy, liver transplant, transcatheter arterial chemoembolization (TACE), and administration of somatostatin analogues. -
What Is a Gastrointestinal Carcinoid Tumor?
cancer.org | 1.800.227.2345 About Gastrointestinal Carcinoid Tumors Overview and Types If you have been diagnosed with a gastrointestinal carcinoid tumor or are worried about it, you likely have a lot of questions. Learning some basics is a good place to start. ● What Is a Gastrointestinal Carcinoid Tumor? Research and Statistics See the latest estimates for new cases of gastrointestinal carcinoid tumor in the US and what research is currently being done. ● Key Statistics About Gastrointestinal Carcinoid Tumors ● What’s New in Gastrointestinal Carcinoid Tumor Research? What Is a Gastrointestinal Carcinoid Tumor? Gastrointestinal carcinoid tumors are a type of cancer that forms in the lining of the gastrointestinal (GI) tract. Cancer starts when cells begin to grow out of control. To learn more about what cancer is and how it can grow and spread, see What Is Cancer?1 1 ____________________________________________________________________________________American Cancer Society cancer.org | 1.800.227.2345 To understand gastrointestinal carcinoid tumors, it helps to know about the gastrointestinal system, as well as the neuroendocrine system. The gastrointestinal system The gastrointestinal (GI) system, also known as the digestive system, processes food for energy and rids the body of solid waste. After food is chewed and swallowed, it enters the esophagus. This tube carries food through the neck and chest to the stomach. The esophagus joins the stomachjust beneath the diaphragm (the breathing muscle under the lungs). The stomach is a sac that holds food and begins the digestive process by secreting gastric juice. The food and gastric juices are mixed into a thick fluid, which then empties into the small intestine. -
Follicle-Stimulating Hormone Regulates Expression and Activity of Epidermal Growth Factor Receptor in the Murine Ovarian Follicle
Follicle-stimulating hormone regulates expression and activity of epidermal growth factor receptor in the murine ovarian follicle Stephany El-Hayeka,b,c, Isabelle Demeesterea,c,d, and Hugh J. Clarkea,b,c,e,1 Departments of aObstetrics and Gynecology, bBiology, and eMedicine, McGill University, Montreal, QC, Canada H3A 1A1; cResearch Institute–McGill University Health Centre; Montreal, QC, Canada H3A 1A1; and dResearch Laboratory on Human Reproduction Fertility Clinic, Université Libre de Bruxelles Erasme, 1070 Brussels, Belgium Edited by John J. Eppig, The Jackson Laboratory, Bar Harbor, ME, and approved October 21, 2014 (received for review August 4, 2014) Fertility depends on the precise coordination of multiple events view that the EGFR signaling mediates many or most ovulatory within the ovarian follicle to ensure ovulation of a fertilizable egg. events. First, the release of the EGFR ligands follows the LH surge FSH promotes late follicular development, including expression of but precedes the LH-dependent responses (9–11). Second, EGF luteinizing hormone (LH) receptor by the granulosa cells. Expres- and the EGFR ligands can induce cumulus expansion and oocyte sion of its receptor permits the subsequent LH surge to trigger the maturation in vitro, independently of LH (9, 10, 20, 29). Third, release of ligands that activate EGF receptors (EGFR) on the gran- these events are impaired in mice bearing a hypomorphic Egfr allele ulosa, thereby initiating the ovulatory events. Here we identify a previously unknown role for FSH in this signaling cascade. We that reduces EGFR activity by about one-half and in mice in which show that follicles of Fshb−/− mice, which cannot produce FSH, Egfr has been selectively inactivated in GCs through a targeted have a severely impaired ability to support two essential EGFR- mutation (22, 23). -
NCCN Guidelines for Neuroendocrine and Adrenal Tumors V.1.2020 – Annual 11/18/19
NCCN Guidelines for Neuroendocrine and Adrenal Tumors V.1.2020 – Annual 11/18/19 Guideline Page Institution Vote Panel Discussion/References and Request YES NO ABSTAIN ABSENT General Based on a review of data and discussion, the panel 0 24 0 4 External request: consensus did not support the inclusion of entrectinib and appropriate NTRK gene fusion testing for the treatment of Submission from Genentech to consider including NTRK gene fusion-positive neuroendocrine cancer, based entrectinib and appropriate NTRK gene fusion on limited available data. testing for the treatment of NTRK gene fusion- positive neuroendocrine cancers. NET-1 The panel consensus was to defer the submission until 0 24 0 4 External request: FDA approval. Submission from Curium to include copper Cu 64 dotatate as an option where somatostatin receptor- based imaging is recommended throughout the guideline. NET-7 Based on the discussion, the panel consensus was to 0 15 7 6 Internal request: remove chemoradiation as an adjuvant therapy option for intermediate grade (atypical) bronchopulmonary NET due Comment to reassess inclusion of chemoradiation to limited available data. as an adjuvant therapy option for intermediate grade (atypical) bronchopulmonary NET. NET-8 Based on the discussion, the panel consensus was to 0 24 0 4 Internal request: remove cisplatin/etoposide and carboplatin/etoposide from the primary therapy option for low grade (typical), Comment to reassess the inclusion of locoregional unresectable bronchopulmonary/thymus NET. platinum/etoposide as a primary therapy option for low grade (typical), locoregional unresectable bronchopulmonary/thymus NET. NET-8 Based on the discussion, the panel consensus was to 24 0 0 4 Internal request: include everolimus as a primary therapy option for intermediate grade (atypical), locoregional unresectable Comment to consider the inclusion of the following bronchopulmonary/thymus NET. -
Rising Incidence of Neuroendocrine Tumors
Rising Incidence of Neuroendocrine Tumors Dasari V, Yao J, et al. JAMA Oncology 2017 S L I D E 1 Overview Pancreatic Neuroendocrine Tumors • Tumors which arise from endocrine cells of the pancreas • 5.6 cases per million – 3% of pancreatic tumors • Median age at diagnosis 60 years • More indolent course compared to adenocarcinoma – 10-year overall survival 40% • Usually sporadic but can be associated with hereditary syndromes – Core genetic pathways altered in sporadic cases • DNA damage repair (MUTYH) Chromatin remodeling (MEN1) • Telomere maintenance (MEN1, DAXX, ATRX) mTOR signaling – Hereditary: 17% of patients with germline mutation Li X, Wang C, et al. Cancer Med 2018 Scarpa A, Grimond S, et al. NatureS L I2017 D E 2 Pathology Classification European American Joint World Health Organization Neuroendocrine Committee on Cancer (WHO) Tumor Society (AJCC) (ENETS) Grade Ki-67 Mitotic rt TNM TNM T1: limit to pancreas, <2 cm T1: limit to pancreas, ≦2 cm T2: limit to pancreas, 2-4 cm T2: >limit to pancreas, 2 cm T3: limit to pancreas, >4 cm, T3: beyond pancreas, no celiac or Low ≤2% <2 invades duodenum, bile duct SMA T4: beyond pancreas, invasion involvement adjacent organs or vessels T4: involves celiac or SMA N0: node negative No: node negative Intermed 3-20% 2-20 N1: node positive N1: node positive M0: no metastases M0: no metastases High >20% >20 M1: metastases M1: metastases S L I D E 3 Classification Based on Functionality • Nonfunctioning tumors – No clinical symptoms (can still produce hormone) – Accounts for 40% of tumors – 60-85% -
An Exploration of Non-Coding RNA in Exosomes Delivered by Swine Anterior Pituitary
An exploration of non-coding RNA in exosomes delivered by swine anterior pituitary Jiali Xiong South China Agricultural University Haojie Zhang South China Agricultural University Bin Zeng South China Agricultural University Jie Liu South China Agricultural University Junyi Luo South China Agricultural University Ting Chen South China Agricultural University Jiajie Sun South China Agricultural University Qianyun Xi South China Agricultural University Yong-Liang Zhang ( [email protected] ) South China Agricultural University Research article Keywords: Anterior pituitary exosomes, MiRNA, LncRNA, CircRNA, Cross-talk Posted Date: July 29th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-36112/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/26 Abstract Background: The anterior pituitary is a key endocrine organ both in animal and human being drawing much concern. Exosomes are extracellular secretory vesicles carrying proteins, lipids and small RNAs. Previous studies have demonstrated that they had regulatory function both physiologically and pathologically. However, information on exosomes from anterior pituitary remains unknown. Results: In this study, we separated and identied exosomes from anterior pituitary of Duroc swine model for the rst time. Total RNA was extracted and RNA-seq was performed, followed by a comprehensive analysis of miRNAs, lncRNAs and circRNAs. Resultantly, we obtained 343 known miRNAs and 73 novel miRNAs, 15545 lncRNAs and 494 circRNAs. Furthermore, GO and KEGG enrichment analysis showed that the ncRNAs in exosomes may participate in regulating intracellular signal transduction, cellular component organization or biogenesis, small molecule binding, transferase activity. The cross-talk between them also suggested that they may play an important role in signaling process and the biological regulation. -
Primary Neuroendocrine Neoplasms of the Kidney, a Distinct Entity but Classifiable- Like the Gastroenteropancreatic Neuroendocrine Neoplasms
C-60 Primary Neuroendocrine Neoplasms of the Kidney, A Distinct Entity but Classifiable- Like the Gastroenteropancreatic Neuroendocrine Neoplasms Manik Amin1; Deyali Chatterjee2 1Washington University in St Louis; 2Washington University School of Medicine BACKGROUND: Primary neuroendocrine neoplasms of the kidney are a distinct and rare entity, but classifiable-like the gastroenteropancreatic neuroendocrine neoplasms. Due to rarity of these tumors, not much is known about histopathology and behaviors of these tumors. We attempted to review pathology of primary kidney neuroendocrine tumor patients at our institution. METHODS: Retrospective chart review identified 8 primary kidney neuroendocrine tumors from Siteman Cancer Registry database from 1/1/2000 until 1/1/2018. Pathology review was done for all the patients to confirm their diagnosis and other pathological features. RESULTS: In our cohort, we identified eight cases of neuroendocrine neoplasms of the kidney. Three of the cases were poorly differentiated neuroendocrine carcinoma. All cases of well-differentiated neuroendocrine tumor (either grade 1 or grade 2) were identified in females (age range 44 – 60). All the tumors characteristically extended to the perirenal fat. These tumors showed diffuse positivity for synaptophysin, variable positivity for chromogranin, and did not stain for markers specific for renal differentiation (PAX-8). The growth pattern in well differentiated neuroendocrine tumors is predominantly trabeculated, but a diffuse plasmacytoid growth is also noted, which is unusual in gastroenteropancreatic neuroendocrine neoplasms. Two patients had Primary tumor measuring 9 cm and 14 cm respectively also presented with positive lymph nodes and lymphovascular invasion developed metastatic disease in 2 years. NANETS 2019 Symposium Abstracts | 175 CONCLUSION: Primary kidney neuroendocrine tumors are very rare. -
Single Cell Transcriptomic Analysis of the Adult Mouse Pituitary Reveals a Novel Multi-Hormone Cell Cluster and Physiologic Demand-Induced Lineage Plasticity
bioRxiv preprint doi: https://doi.org/10.1101/475558; this version posted November 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Single cell transcriptomic analysis of the adult mouse pituitary reveals a novel multi-hormone cell cluster and physiologic demand-induced lineage plasticity Yugong Ho1,5,*. Peng Hu1,3,5, Michael T. Peel1, Pablo G. Camara1,4, Hao Wu1,3,* , and Stephen A. Liebhaber1,2, Departments of Genetics1 and Medicine2, Penn Epigenetics Institute3, and Penn Institute for Biomedical Informatics4, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 5 These authors contributed equally * Corresponding authors Running title: Single cell transcriptomic analysis of the adult mouse pituitary 1 bioRxiv preprint doi: https://doi.org/10.1101/475558; this version posted November 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The anterior pituitary gland drives a set of highly conserved physiologic processes in mammalian species. These hormonally-controlled processes are central to somatic growth, pubertal transformation, fertility, lactation, and metabolism. Current models, based on targeted immuno-histochemical and mRNA analyses, suggest that each of the seven hormones synthesized by the pituitary is produced by a specific and exclusive cell lineage. However, emerging evidence suggests a more complex model in which critical aspects of hormone specificity and plasticity of pituitary cells remain undefined. Here we have applied massively parallel single-cell RNA sequencing (scRNA-seq), in conjunction with a set of orthogonal imaging studies, to systematically map the cellular composition of adult male and female mouse pituitaries at single-cell resolution and in the setting of major physiologic demands.