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Pesquisa : D08.811.520.650.600.500.250 [Categoria DeCS]
Referências encontradas : 394 [refinar]
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[PMID]:29370189
[Au] Autor:Gallery M; Zhang J; Bradley DP; Brauer P; Cvet D; Estevam J; Danaee H; Greenfield E; Li P; Manfredi M; Loke HK; Rabino C; Stringer B; Williamson M; Wyant T; Yang J; Zhu Q; Abu-Yousif A; Veiby OP
[Ad] Endereço:Molecular & Cellular Oncology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, United States of America.
[Ti] Título:A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo.
[So] Source:PLoS One;13(1):e0191046, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/imunologia
Imunoconjugados/farmacologia
Oligopeptídeos/metabolismo
Receptores de Enterotoxina/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/metabolismo
Western Blotting
Neoplasias Colorretais/enzimologia
Neoplasias Colorretais/patologia
Feminino
Células HEK293
Seres Humanos
Mucosa Intestinal/enzimologia
Camundongos
Camundongos SCID
Receptores de Enterotoxina/genética
Receptores de Enterotoxina/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Immunoconjugates); 0 (Oligopeptides); 0 (indusatumab); EC 4.6.1.2 (Receptors, Enterotoxin); V7I58RC5EJ (monomethyl auristatin E)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180126
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191046


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[PMID]:29261789
[Au] Autor:Danaee H; Kalebic T; Wyant T; Fassan M; Mescoli C; Gao F; Trepicchio WL; Rugge M
[Ad] Endereço:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts, United States of America.
[Ti] Título:Consistent expression of guanylyl cyclase-C in primary and metastatic gastrointestinal cancers.
[So] Source:PLoS One;12(12):e0189953, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The transmembrane receptor guanylate cyclase-C (GCC) has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues. METHODS: GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627) with gastrointestinal tumors, including esophageal (n = 130), gastric (n = 276), pancreatic (n = 136), and colorectal (n = 85) primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors. RESULT: Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients. CONCLUSION: This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease.
[Mh] Termos MeSH primário: Neoplasias Gastrointestinais/enzimologia
Neoplasias Gastrointestinais/patologia
Receptores de Enterotoxina/metabolismo
[Mh] Termos MeSH secundário: Adenocarcinoma/enzimologia
Adenocarcinoma/patologia
Seres Humanos
Metástase Neoplásica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 4.6.1.2 (Receptors, Enterotoxin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189953


  3 / 394 MEDLINE  
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[PMID]:28957388
[Au] Autor:von Volkmann HL; Brønstad I; Gilja OH; R Tronstad R; Sangnes DA; Nortvedt R; Hausken T; Dimcevski G; Fiskerstrand T; Nylund K
[Ad] Endereço:National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway.
[Ti] Título:Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.
[So] Source:PLoS One;12(9):e0185496, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Increased intestinal hydration by activation of the epithelial enzyme linked receptor guanylate cyclase C (GC-C) is a pharmacological principle for treating constipation. Activating mutations in the GUCY2C gene encoding GC-C cause Familial GUCY2C diarrhea syndrome (FGDS) which has been diagnosed with severe dysmotility. AIM: To investigate gut motility and hormones before and after a meal in FGDS patients and compare with healthy controls (HC). SUBJECTS AND METHODS: Bristol stool chart and stool frequency was assessed. Before and after a meal occlusive and non-occlusive contractions were obtained using ultrasound. A wireless motility capsule (WMC) recorded gut transit time, pH, contractions and pressure. Plasma levels of selected gut hormones were measured at different time points. RESULTS: The FGDS patients had 4 (range 1-10) loose stools/day and prolonged total gut transit time compared to HC, 55.5 h vs 28.5 h, respectively,with significantly increased colon transit time. In FGDS patients, pH in duodenum, small bowel and colon was increased and the number of contractions and the intraluminal pressure were significantly decreased, measured by WMC. Ultrasound showed in small bowel increased number of non-occlusive contractions in the FGDS patients. Serotonin (5-HT) plasma levels in the HC peaked 30 min after the meal, while the FGDS patients had no response. CONCLUSION: Despite having diarrhea, the FGDS patients have prolonged transit time through the gut compared to HC, particularly in colon. The reduced number of intestinal contractions and lack of 5-HT release after a meal in FGDS patients surprisingly resemble colonic motility disturbances seen in patients with constipation.
[Mh] Termos MeSH primário: Diarreia/genética
Diarreia/fisiopatologia
Trânsito Gastrointestinal/fisiologia
Mutação/genética
Receptores Acoplados a Guanilato Ciclase/genética
Receptores de Peptídeos/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Líquidos Corporais
Endoscopia por Cápsula
Diarreia/sangue
Diarreia/diagnóstico por imagem
Feminino
Hormônios/sangue
Seres Humanos
Concentração de Íons de Hidrogênio
Intestinos/patologia
Intestinos/fisiopatologia
Masculino
Meia-Idade
Contração Muscular
Variações Dependentes do Observador
Pressão
Receptores de Enterotoxina
Fatores de Tempo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hormones); 0 (Receptors, Peptide); EC 4.6.1.2 (GUCY2C protein, human); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185496


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[PMID]:28916678
[Au] Autor:Li P; Wuthrick E; Rappaport JA; Kraft C; Lin JE; Marszalowicz G; Snook AE; Zhan T; Hyslop TM; Waldman SA
[Ad] Endereço:Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, The University of Florida, Gainesville, Florida.
[Ti] Título:GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.
[So] Source:Cancer Res;77(18):5095-5106, 2017 Sep 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. .
[Mh] Termos MeSH primário: Raios gama/efeitos adversos
Trato Gastrointestinal/efeitos da radiação
Síndrome do Intestino Irritável/prevenção & controle
Lesões Experimentais por Radiação/prevenção & controle
Receptores Acoplados a Guanilato Ciclase/metabolismo
Receptores de Peptídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos da radiação
Proliferação Celular/efeitos da radiação
Neoplasias do Colo/enzimologia
Neoplasias do Colo/patologia
Neoplasias do Colo/radioterapia
Feminino
Hormônios Gastrointestinais/metabolismo
Seres Humanos
Síndrome do Intestino Irritável/enzimologia
Síndrome do Intestino Irritável/etiologia
Linfoma/enzimologia
Linfoma/patologia
Linfoma/radioterapia
Masculino
Melanoma Experimental/enzimologia
Melanoma Experimental/patologia
Melanoma Experimental/radioterapia
Camundongos
Camundongos Endogâmicos C57BL
Peptídeos Natriuréticos/metabolismo
Comunicação Parácrina/efeitos da radiação
Lesões Experimentais por Radiação/enzimologia
Lesões Experimentais por Radiação/etiologia
Receptores de Enterotoxina
Transdução de Sinais/efeitos da radiação
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gastrointestinal Hormones); 0 (Natriuretic Peptides); 0 (Receptors, Peptide); 140653-38-9 (guanylin); 152175-68-3 (uroguanylin); EC 4.6.1.2 (GUCY2C protein, human); EC 4.6.1.2 (Gucy2c protein, mouse); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-17-0859


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[PMID]:28341670
[Au] Autor:Xiang B; Baybutt TR; Berman-Booty L; Magee MS; Waldman SA; Alexeev VY; Snook AE
[Ad] Endereço:Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107.
[Ti] Título:Prime-Boost Immunization Eliminates Metastatic Colorectal Cancer by Producing High-Avidity Effector CD8 T Cells.
[So] Source:J Immunol;198(9):3507-3514, 2017 May 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Heterologous prime-boost immunization with plasmid DNA and viral vector vaccines is an emerging approach to elicit CD8 T cell-mediated immunity targeting pathogens and tumor Ags that is superior to either monotherapy. Yet, the mechanisms underlying the synergy of prime-boost strategies remain incompletely defined. In this study, we examine a DNA and adenovirus (Ad5) combination regimen targeting guanylyl cyclase C (GUCY2C), a receptor expressed by intestinal mucosa and universally expressed by metastatic colorectal cancer. DNA immunization efficacy was optimized by i.m. delivery via electroporation, yet it remained modest compared with Ad5. Sequential immunization with DNA and Ad5 produced superior antitumor efficacy associated with increased TCR avidity, whereas targeted disruption of TCR avidity enhancement eliminated GUCY2C-specific antitumor efficacy, without affecting responding T cell number or cytokine profile. Indeed, functional TCR avidity of responding GUCY2C-specific CD8 T cells induced by various prime or prime-boost regimens correlated with antitumor efficacy, whereas T cell number and cytokine profile were not. Importantly, although sequential immunization with DNA and Ad5 maximized antitumor efficacy through TCR avidity enhancement, it produced no autoimmunity, reflecting sequestration of GUCY2C to intestinal apical membranes and segregation of mucosal and systemic immunity. Together, TCR avidity enhancement may be leveraged by prime-boost immunization to improve GUCY2C-targeted colorectal cancer immunotherapeutic efficacy and patient outcomes without concomitant autoimmune toxicity.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/metabolismo
Linfócitos T CD8-Positivos/fisiologia
Neoplasias Colorretais/terapia
Imunoterapia Adotiva/métodos
Mucosa Intestinal/fisiologia
Receptores Acoplados a Guanilato Ciclase/metabolismo
Receptores de Peptídeos/metabolismo
Vacinas de DNA/imunologia
[Mh] Termos MeSH secundário: Adenoviridae/genética
Animais
Biomarcadores Tumorais/genética
Linfócitos T CD8-Positivos/transplante
Células Cultivadas
Neoplasias Colorretais/imunologia
Citotoxicidade Imunológica
Imunidade nas Mucosas
Imunização Secundária
Camundongos
Camundongos Endogâmicos BALB C
Metástase Neoplásica
Receptores de Antígenos de Linfócitos T/metabolismo
Receptores de Enterotoxina
Receptores Acoplados a Guanilato Ciclase/genética
Receptores de Peptídeos/genética
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Receptors, Antigen, T-Cell); 0 (Receptors, Peptide); 0 (Vaccines, DNA); EC 4.6.1.2 (Gucy2c protein, mouse); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170326
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1502672


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[PMID]:28271055
[Au] Autor:Tse Y; Armstrong D; Andrews CN; Bitton A; Bressler B; Marshall J; Liu LW
[Ad] Endereço:University of Toronto, Toronto, ON, Canada.
[Ti] Título:Treatment Algorithm for Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome Derived from a Canadian National Survey and Needs Assessment on Choices of Therapeutic Agents.
[So] Source:Can J Gastroenterol Hepatol;2017:8612189, 2017.
[Is] ISSN:2291-2797
[Cp] País de publicação:Egypt
[La] Idioma:eng
[Ab] Resumo:. Chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) are common functional lower gastrointestinal disorders that impair patients' quality of life. In a national survey, we aimed to evaluate (1) Canadian physician practice patterns in the utilization of therapeutic agents listed in the new ACG and AGA guidelines; (2) physicians satisfaction with these agents for their CIC and IBS-C patients; and (3) the usefulness of these new guidelines in their clinical practice. . A 9-item questionnaire was sent to 350 Canadian specialists to evaluate their clinical practice for the management of CIC and IBS-C. . The response rate to the survey was 16% ( = 55). Almost all (96%) respondents followed a standard, stepwise approach for management while they believed that only 24% of referring physicians followed the same approach. Respondents found guanylyl cyclase C (GCC) agonist most satisfying when treating their patients. Among the 69% of respondents who were aware of published guidelines, only 50% found them helpful in prioritizing treatment choices and 69% of respondents indicated that a treatment algorithm, applicable to Canadian practice, would be valuable. . Based on this needs assessment, a treatment algorithm was developed to provide clinical guidance in the management of IBS-C and CIC in Canada.
[Mh] Termos MeSH primário: Algoritmos
Constipação Intestinal/tratamento farmacológico
Fibras na Dieta/uso terapêutico
Fármacos Gastrointestinais/uso terapêutico
Síndrome do Intestino Irritável/tratamento farmacológico
Laxantes/uso terapêutico
Padrões de Prática Médica/estatística & dados numéricos
Agonistas de Receptores 5-HT4 de Serotonina/uso terapêutico
[Mh] Termos MeSH secundário: Benzofuranos/uso terapêutico
Canadá
Doença Crônica
Suplementos Nutricionais
Gerenciamento Clínico
Gastroenterologistas
Seres Humanos
Determinação de Necessidades de Cuidados de Saúde
Peptídeos/uso terapêutico
Guias de Prática Clínica como Assunto
Receptores de Enterotoxina
Receptores Acoplados a Guanilato Ciclase/agonistas
Receptores de Peptídeos/agonistas
Inquéritos e Questionários
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzofurans); 0 (Dietary Fiber); 0 (Gastrointestinal Agents); 0 (Laxatives); 0 (Peptides); 0 (Receptors, Peptide); 0 (Serotonin 5-HT4 Receptor Agonists); 0A09IUW5TP (prucalopride); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled); N0TXR0XR5X (linaclotide)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170309
[St] Status:MEDLINE
[do] DOI:10.1155/2017/8612189


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[PMID]:28162021
[Au] Autor:Aka AA; Rappaport JA; Pattison AM; Sato T; Snook AE; Waldman SA
[Ad] Endereço:a Department of Pharmacology and Experimental Therapeutics , Sidney Kimmel Medical College at Thomas Jefferson University , Philadelphia , PA , USA.
[Ti] Título:Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer.
[So] Source:Expert Rev Clin Pharmacol;10(5):549-557, 2017 May.
[Is] ISSN:1751-2441
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the GUCY2C ligand, linaclotide, and two more synthetic ligands in the pipeline, this strategy can be tested in human trials. In addition to primary tumor prevention, we also review immunotherapies targeting GUCY2C expressed by metastatic lesions, and platforms using GUCY2C as a biomarker for detection and patient staging. Expert commentary: Results of the first GUCY2C targeting schemes in patients will become available in the coming years. The identification of GUCY2C ligand loss as a requirement for colorectal tumorigenesis has the potential to change the treatment paradigm from an irreversible disease of genetic mutation, to a treatable disease of ligand insufficiency.
[Mh] Termos MeSH primário: Neoplasias Colorretais/tratamento farmacológico
Terapia de Alvo Molecular
Receptores Acoplados a Guanilato Ciclase/metabolismo
Receptores de Peptídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores Tumorais/metabolismo
Neoplasias Colorretais/diagnóstico
Neoplasias Colorretais/patologia
Desenho de Drogas
Seres Humanos
Imunoterapia/métodos
Ligantes
Estadiamento de Neoplasias
Receptores de Enterotoxina
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Ligands); 0 (Receptors, Peptide); EC 4.6.1.2 (GUCY2C protein, human); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170207
[St] Status:MEDLINE
[do] DOI:10.1080/17512433.2017.1292124


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[PMID]:27688649
[Au] Autor:Pattison AM; Merlino DJ; Blomain ES; Waldman SA
[Ad] Endereço:Amanda M Pattison, Dante J Merlino, Erik S Blomain, Scott A Waldman, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States.
[Ti] Título:Guanylyl cyclase C signaling axis and colon cancer prevention.
[So] Source:World J Gastroenterol;22(36):8070-7, 2016 Sep 28.
[Is] ISSN:2219-2840
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C's role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.
[Mh] Termos MeSH primário: Neoplasias do Colo/metabolismo
Neoplasias do Colo/prevenção & controle
Receptores Acoplados a Guanilato Ciclase/metabolismo
Receptores de Peptídeos/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Carcinogênese
Ciclo Celular
GMP Cíclico/química
Enterotoxinas/química
Hormônios Gastrointestinais/metabolismo
Genômica
Homeostase
Hormônios/metabolismo
Seres Humanos
Inflamação
Ligantes
Mutação
Peptídeos Natriuréticos/metabolismo
Comunicação Parácrina
Receptores de Enterotoxina
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enterotoxins); 0 (Gastrointestinal Hormones); 0 (Hormones); 0 (Ligands); 0 (Natriuretic Peptides); 0 (Receptors, Peptide); 140653-38-9 (guanylin); 152175-68-3 (uroguanylin); EC 4.6.1.2 (GUCY2C protein, human); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161001
[St] Status:MEDLINE
[do] DOI:10.3748/wjg.v22.i36.8070


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[PMID]:27481254
[Au] Autor:Pattison AM; Blomain ES; Merlino DJ; Wang F; Crissey MA; Kraft CL; Rappaport JA; Snook AE; Lynch JP; Waldman SA
[Ad] Endereço:Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
[Ti] Título:Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins.
[So] Source:Infect Immun;84(10):3083-91, 2016 Oct.
[Is] ISSN:1098-5522
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Enterotoxigenic Escherichia coli (ETEC) causes ∼20% of the acute infectious diarrhea (AID) episodes worldwide, often by producing heat-stable enterotoxins (STs), which are peptides structurally homologous to paracrine hormones of the intestinal guanylate cyclase C (GUCY2C) receptor. While molecular mechanisms mediating ST-induced intestinal secretion have been defined, advancements in therapeutics have been hampered for decades by the paucity of disease models that integrate molecular and functional endpoints amenable to high-throughput screening. Here, we reveal that mouse and human intestinal enteroids in three-dimensional ex vivo cultures express the components of the GUCY2C secretory signaling axis. ST and its structural analog, linaclotide, an FDA-approved oral secretagog, induced fluid accumulation quantified simultaneously in scores of enteroid lumens, recapitulating ETEC-induced intestinal secretion. Enteroid secretion depended on canonical molecular signaling events responsible for ETEC-induced diarrhea, including cyclic GMP (cGMP) produced by GUCY2C, activation of cGMP-dependent protein kinase (PKG), and opening of the cystic fibrosis transmembrane conductance regulator (CFTR). Importantly, pharmacological inhibition of CFTR abrogated enteroid fluid secretion, providing proof of concept for the utility of this model to screen antidiarrheal agents. Intestinal enteroids offer a unique model, integrating the GUCY2C signaling axis and luminal fluid secretion, to explore the pathophysiology of, and develop platforms for, high-throughput drug screening to identify novel compounds to prevent and treat ETEC diarrheal disease.
[Mh] Termos MeSH primário: Toxinas Bacterianas/metabolismo
Escherichia coli Enterotoxigênica/fisiologia
Enterotoxinas/fisiologia
Infecções por Escherichia coli/microbiologia
Intestinos/metabolismo
Receptores Acoplados a Guanilato Ciclase/metabolismo
Receptores de Peptídeos/metabolismo
[Mh] Termos MeSH secundário: Análise de Variância
Animais
GMP Cíclico/metabolismo
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo
Diarreia/metabolismo
Modelos Animais de Doenças
Escherichia coli Enterotoxigênica/metabolismo
Enterotoxinas/metabolismo
Ensaio de Imunoadsorção Enzimática
Infecções por Escherichia coli/fisiopatologia
Proteínas de Escherichia coli/metabolismo
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Receptores de Enterotoxina
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Toxins); 0 (Enterotoxins); 0 (Escherichia coli Proteins); 0 (Receptors, Peptide); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); EC 4.6.1.2 (GUCY2C protein, human); EC 4.6.1.2 (Gucy2c protein, mouse); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160803
[St] Status:MEDLINE
[do] DOI:10.1128/IAI.00639-16


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[PMID]:27338166
[Au] Autor:von Volkmann HL; Nylund K; Tronstad RR; Hovdenak N; Hausken T; Fiskerstrand T; Gilja OH
[Ad] Endereço:a National Centre for Ultrasound in Gastroenterology , Haukeland University Hospital , Bergen , Norway ;
[Ti] Título:An activating gucy2c mutation causes impaired contractility and fluid stagnation in the small bowel.
[So] Source:Scand J Gastroenterol;51(11):1308-15, 2016 Nov.
[Is] ISSN:1502-7708
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Familial GUCY2C diarrhoea syndrome (FGDS) is caused by an activating mutation in the GUCY2C gene encoding the receptor guanylate cyclase C in enterocytes. Activation leads to increased secretion of fluid into the intestinal lumen. Twenty percent of the patients have increased risk of Crohn's disease and intestinal obstruction (CD, 20%) and the condition resembles irritable bowel syndrome with diarrhoea. We aimed to describe fluid content, contractility, peristaltic activity and bowel wall thickness in the intestine in fasting FGDS patients, using ultrasound, with healthy volunteers serving as controls. METHODS: Twenty-three patients with FGDS and 22 healthy controls (HC) were examined with a Logiq E9 scanner in a fasting state. Bowel wall thickness was measured and fluid-filled small bowel loops were counted using three-dimensional (3D) magnetic positioning navigation. The HC ingested 500 ml PEG solution, an electrolyte balanced, non-absorbable solution, in order to investigate the contractions of the small bowel. RESULTS: The fasting 23 FGDS patients had significantly higher number of fluid-filled small bowel segments compared to 22 fasting HC, p < 0.001. A high number of non-occlusive contractions in the ileum was observed, which was significant when compared to HC after ingesting PEG solution, p < 0.016. An increase in intestinal wall thickness or other signs of CD were not observed. CONCLUSIONS: FGDS is characterised by multiple, fluid-filled small bowel loops with incomplete contractions and fluid stagnation in fasting state. These findings may play a role in the increased risk of bowel obstruction as well as IBS-like symptoms observed in these patients.
[Mh] Termos MeSH primário: Diarreia/fisiopatologia
Íleo/fisiopatologia
Enteropatias/genética
Intestino Delgado/fisiopatologia
Peristaltismo
Receptores Acoplados a Guanilato Ciclase/genética
Receptores de Peptídeos/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Estudos de Casos e Controles
Doença de Crohn/diagnóstico por imagem
Diarreia/etiologia
Feminino
Seres Humanos
Íleo/diagnóstico por imagem
Enteropatias/diagnóstico por imagem
Obstrução Intestinal/diagnóstico por imagem
Intestino Delgado/diagnóstico por imagem
Modelos Lineares
Masculino
Meia-Idade
Mutação
Receptores de Enterotoxina
Ultrassonografia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Peptide); EC 4.6.1.2 (GUCY2C protein, human); EC 4.6.1.2 (Receptors, Enterotoxin); EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160625
[St] Status:MEDLINE
[do] DOI:10.1080/00365521.2016.1200139



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