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Acinar ductal metaplasia

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https://www.readbyqxmd.com/read/28774888/development-of-autoimmune-pancreatitis-is-independent-of-cdkn1a-p21-mediated-pancreatic-inflammation
#1
Gitta M Seleznik, Theresia Reding, Lukas Peter, Anurag Gupta, Sabrina G Steiner, Sabrina Sonda, Caroline S Verbeke, Emmanuel Dejardin, Igor Khatkov, Stephan Segerer, Mathias Heikenwalder, Rolf Graf
OBJECTIVE: Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21-a member of cyclin-dependent kinase inhibitors-can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development...
August 3, 2017: Gut
https://www.readbyqxmd.com/read/28752115/acinar-to-ductal-metaplasia-induced-by-transforming-growth-factor-beta-facilitates-kras-g12d-driven-pancreatic-tumorigenesis
#2
Nicolas Chuvin, David F Vincent, Roxane M Pommier, Lindsay B Alcaraz, Johann Gout, Cassandre Caligaris, Karam Yacoub, Victoire Cardot, Elodie Roger, Bastien Kaniewski, Sylvie Martel, Celia Cintas, Sophie Goddard-Léon, Amélie Colombe, Julie Valantin, Nicolas Gadot, Emilie Servoz, Jennifer Morton, Isabelle Goddard, Anne Couvelard, Vinciane Rebours, Julie Guillermet, Owen J Sansom, Isabelle Treilleux, Ulrich Valcourt, Stéphanie Sentis, Pierre Dubus, Laurent Bartholin
BACKGROUND & AIMS: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive...
September 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28738823/metformin-suppresses-cancer-initiation-and-progression-in-genetic-mouse-models-of-pancreatic-cancer
#3
Ke Chen, Weikun Qian, Zhengdong Jiang, Liang Cheng, Jie Li, Liankang Sun, Cancan Zhou, Luping Gao, Meng Lei, Bin Yan, Junyu Cao, Wanxing Duan, Qingyong Ma
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer...
July 24, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28701342/activating-transcription-factor-3-promotes-loss-of-the-acinar-cell-phenotype-in-response-to-cerulein-induced-pancreatitis-in-mice
#4
Elena N Fazio, Claire C Young, Jelena Toma, Michael Levy, Kurt R Berger, Charis L Johnson, Rashid Mehmood, Patrick Swan, Alphonse Chu, Sean P Cregan, F Jeffrey Dilworth, Christopher J Howlett, Christopher L Pin
Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). While down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by Next Generation Sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of more than 30% of differentially expressed genes during the initiation of pancreatitis...
July 12, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28639695/glycogen-synthase-kinase-3%C3%AE-ablation-limits-pancreatitis-induced-acinar-to-ductal-metaplasia
#5
Li Ding, Geou-Yarh Liou, Daniel M Schmitt, Peter Storz, Jin-San Zhang, Daniel D Billadeau
Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models...
June 22, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28593186/origin-of-barrett-s-epithelium-esophageal-submucosal-glands
#6
Katherine S Garman
The origin of the progenitor cell for Barrett's esophagus remains a major unsolved mystery. Understanding the source of this progenitor may improve strategies to prevent the development of esophageal adenocarcinoma. Esophageal submucosal glands (ESMGs) and ducts may serve as a potential source of progenitor cells that respond to esophageal injury. Through the use of human histologic and molecular analysis, ESMGs and ducts have been described in physical continuity with areas of columnar esophagus, and shared mutations have been described between ESMG ducts and Barrett's esophagus...
July 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28572084/ductular-and-proliferative-response-of-esophageal-submucosal-glands-in-a-porcine-model-of-esophageal-injury-and-repair
#7
Leandi Krüger, Liara M Gonzalez, Tiffany A Pridgen, Shannon J McCall, Richard von Furstenberg, Ivan Harnden, Gwendolyn E Carnighan, Abigail M Cox, Anthony T Blikslager, Katherine Schuver Garman
Esophageal injury is a risk factor for diseases such as Barrett's Esophagus (BE) and Esophageal Adenocarcinoma. In order to improve understanding of signaling pathways associated with both normal and abnormal repair, animal models are needed. Traditional rodent models of esophageal repair are limited by the absence of esophageal submucosal glands (ESMGs), which are present in human esophagus. Previously, we identified acinar ductal metaplasia in human ESMGs in association with both esophageal injury and cancer...
June 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28542719/ibuprofen-and-diclofenac-treatments-reduce-proliferation-of-pancreatic-acinar-cells-upon-inflammatory-injury-and-mitogenic-stimulation
#8
Marta Bombardo, Ermanno Malagola, Rong Chen, Alina Rudnicka, Rolf Graf, Sabrina Sonda
BACKGROUND AND PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered to manage the pain typically found in patients suffering from pancreatitis. NSAIDs also display anti-proliferative activity against cancer cells; however, their effects on normal, untransformed cells are poorly understood. Here, we evaluated whether NSAIDs inhibit the proliferation of pancreatic acinar cells during the development of acute pancreatitis. EXPERIMENTAL APPROACH: The NSAIDs ibuprofen and diclofenac were administered to C57BL/6 mice after induction of pancreatitis with serial injections of cerulein...
May 19, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28514653/the-presence-of-interleukin-13-at-pancreatic-adm-panin-lesions-alters-macrophage-populations-and-mediates-pancreatic-tumorigenesis
#9
Geou-Yarh Liou, Ligia Bastea, Alicia Fleming, Heike Döppler, Brandy H Edenfield, David W Dawson, Lizhi Zhang, Nabeel Bardeesy, Peter Storz
The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28461470/grp78-haploinsufficiency-suppresses-acinar-to-ductal-metaplasia-signaling-and-mutant-kras-driven-pancreatic-tumorigenesis-in-mice
#10
Jieli Shen, Dat P Ha, Genyuan Zhu, Daisy F Rangel, Agnieszka Kobielak, Parkash S Gill, Susan Groshen, Louis Dubeau, Amy S Lee
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras(G12D/+);p53(f/+) (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28368927/heterotopic-pancreas-of-the-gastrointestinal-tract-and-associated-precursor-and-cancerous-lesions-systematic-pathologic-studies-of-165-cases
#11
Sun-Young Jun, Dahye Son, Mi-Ju Kim, Sung Joo Kim, Soyeon An, Young Soo Park, Sook Ryun Park, Kee Don Choi, Hwoon-Yong Jung, Song Cheol Kim, Jeong Hwan Yook, Byung-Sik Kim, Seung-Mo Hong
Heterotopic pancreas (HP) can be detected by accompanying symptoms or incidentally during gastrointestinal (GI) tract tumor resection. We compared clinicopathologic features among 165 resected HPs (57 gastric [35%], 56 duodenal [34%], 30 omental [18%], and 22 jejunal [13%]). Symptomatic HPs (79/135 GI tract wall HPs, 59%) were larger (P=0.05), more common in younger patients and in a gastric location (both P<0.001), and more frequently associated with lymphoid cuffs (P=0.03) than incidentally found HPs. Gastric/jejunal HPs were more frequently symptomatic (P<0...
June 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28270694/acinar-cell-plasticity-and-development-of-pancreatic-ductal-adenocarcinoma
#12
REVIEW
Peter Storz
Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. Data from animal models show that cells that undergo ADM in response to oncogenic signalling are precursors for pancreatic intraepithelial neoplasia lesions, which can further progress to pancreatic ductal adenocarcinoma (PDAC). As human pancreatic adenocarcinoma is often diagnosed at a stage of metastatic disease, understanding the processes that lead to its initiation is important for the discovery of markers for early detection, as well as options that enable an early intervention...
May 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28162998/common-telomere-changes-during-in%C3%A2-vivo-reprogramming-and-early-stages-of-tumorigenesis
#13
Rosa M Marión, Isabel López de Silanes, Lluc Mosteiro, Benjamin Gamache, María Abad, Carmen Guerra, Diego Megías, Manuel Serrano, Maria A Blasco
Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length...
February 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28099259/smad2-3-linker-phosphorylation-is-a-possible-marker-of-pancreatic-stem-progenitor-cells-in-the-regenerative-phase-of-acute-pancreatitis
#14
Masayuki Sakao, Yutaku Sakaguchi, Ryo Suzuki, Yu Takahashi, Masanobu Kishimoto, Toshiro Fukui, Kazushige Uchida, Akiyoshi Nishio, Koichi Matsuzaki, Kazuichi Okazaki
OBJECTIVES: The aims of this study are to characterize cell proliferation and differentiation during regeneration after pancreatitis and pancreatic buds during development to evaluate the role of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr) in positive cells. METHODS: Male C57BL/6 mice received hourly intraperitoneal injections of cerulein and were analyzed after induced pancreatitis. Pancreatitis-affected tissue sections and pancreatic buds were immunostained for pSmad2/3L-Thr, with other markers thought to be stem/progenitor markers of the pancreas...
May 2017: Pancreas
https://www.readbyqxmd.com/read/28090569/mitogen-activated-protein-kinase-kinase-activity-maintains-acinar-to-ductal-metaplasia-and-is-required-for-organ-regeneration-in-pancreatitis
#15
Christopher J Halbrook, Hui-Ju Wen, Jeanine M Ruggeri, Kenneth K Takeuchi, Yaqing Zhang, Marina Pasca di Magliano, Howard C Crawford
BACKGROUND & AIMS: Mitogen-activated protein kinase (MAPK) signaling in the exocrine pancreas has been extensively studied in the context of pancreatic cancer, where its potential as a therapeutic target is limited by acquired drug resistance. However, its role in pancreatitis is less understood. We investigated the role of mitogen-activated protein kinase kinase (MEK)-initiated MAPK signaling in pancreatitis to determine the potential for MEK inhibition in treating pancreatitis patients...
January 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28089234/oncogenic-kras-induced-increase-in-fluid-phase-endocytosis-is-dependent-on-n-wasp-and-is-required-for-the-formation-of-pancreatic-preneoplastic-lesions
#16
Clara Lubeseder-Martellato, Katharina Alexandrow, Ana Hidalgo-Sastre, Irina Heid, Sophie Luise Boos, Thomas Briel, Roland M Schmid, Jens T Siveke
Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRas(G12D), which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRas(G12D)-induced ADM is dependent on RAC1 and EGF receptor (EGFR) by a not fully clarified mechanism. Using three-dimensional mouse and human acinar tissue cultures and genetically engineered mouse models, we provide evidence that (i) KRas(G12D) leads to EGFR-dependent sustained fluid-phase endocytosis (FPE) during acinar metaplasia; (ii) variations in plasma membrane tension increase FPE and lead to ADM in vitro independently of EGFR; and (iii) that RAC1 regulates ADM formation partially through actin-dependent regulation of FPE...
December 24, 2016: EBioMedicine
https://www.readbyqxmd.com/read/28057438/oncogenic-kras-induced-increase-in-fluid-phase-endocytosis-is-dependent-on-n-wasp-and-is-required-for-the-formation-of-pancreatic-preneoplastic-lesions
#17
Clara Lubeseder-Martellato, Katharina Alexandrow, Ana Hidalgo-Sastre, Irina Heid, Sophie Luise Boos, Thomas Briel, Roland M Schmid, Jens T Siveke
Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRas(G12D), which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRas(G12D)-induced ADM is dependent on RAC1 and EGF receptor (EGFR) by a not fully clarified mechanism. Using three-dimensional mouse and human acinar tissue cultures and genetically engineered mouse models, we provide evidence that (i) KRas(G12D) leads to EGFR-dependent sustained fluid-phase endocytosis (FPE) during acinar metaplasia; (ii) variations in plasma membrane tension increase FPE and lead to ADM in vitro independently of EGFR; and (iii) that RAC1 regulates ADM formation partially through actin-dependent regulation of FPE...
February 2017: EBioMedicine
https://www.readbyqxmd.com/read/27851966/pancreatic-inflammation-redirects-acinar-to-%C3%AE-cell-reprogramming
#18
Hannah W Clayton, Anna B Osipovich, Jennifer S Stancill, Judsen D Schneider, Pedro G Vianna, Carolyn M Shanks, Weiping Yuan, Guoqiang Gu, Elisabetta Manduchi, Christian J Stoeckert, Mark A Magnuson
Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages...
November 15, 2016: Cell Reports
https://www.readbyqxmd.com/read/27798096/chronic-pancreatitis-and-lipomatosis-are-associated-with-defective-function-of-ciliary-genes-in-pancreatic-ductal-cells
#19
Cécile Augereau, Louis Collet, Pierfrancesco Vargiu, Carmen Guerra, Sagrario Ortega, Frédéric P Lemaigre, Patrick Jacquemin
Genetic diseases associated with defects in primary cilia are classified as ciliopathies. Pancreatic lesions and ductal cysts are found in patients with ciliopathic polycystic kidney diseases suggesting a close connection between pancreatic defects and primary cilia. Here we investigate the role of two genes whose deletion is known to cause primary cilium defects, namely Hnf6 and Lkb1, in pancreatic ductal homeostasis. We find that mice with postnatal duct-specific deletion of Hnf6 or Lkb1 show duct dilations...
October 7, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27788482/reg-proteins-promote-acinar-to-ductal-metaplasia-and-act-as-novel-diagnostic-and-prognostic-markers-in-pancreatic-ductal-adenocarcinoma
#20
Qing Li, Hao Wang, George Zogopoulos, Qin Shao, Kun Dong, Fudong Lv, Karam Nwilati, Xian-Yong Gui, Adeline Cuggia, Jun-Li Liu, Zu-Hua Gao
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry...
November 22, 2016: Oncotarget
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