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Pesquisa : D12.776.543.750.705.408.100.350 [Categoria DeCS]
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[PMID]:28957409
[Au] Autor:Moreau JM; Cen S; Berger A; Furlonger C; Paige CJ
[Ad] Endereço:Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
[Ti] Título:Bone marrow basophils provide survival signals to immature B cells in vitro but are dispensable in vivo.
[So] Source:PLoS One;12(9):e0185509, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Immature B cells are the first B cell progenitors to express a fully formed B cell receptor and are therefore subject to extensive selection processes that act to mitigate the emergence of autoreactive clones. While it is well appreciated that most B cell generation in the bone marrow is highly dependent on access to molecules present in the local milieu, the existence of extrinsically provided factors that modulate immature B cell biology is ambiguous. Nonetheless, a population of CD49b+CD90lo cells has demonstrated in vitro potential to promote immature B cell survival. Using a mouse basophil reporter strain we confirmed the identity of these CD49b+CD90lo supportive cells as basophils. However, analysis of bone marrow B cell populations following lineage specific basophil depletion demonstrates that basophils do not have a significant role in vivo in modulating immature B cell biology during steady-state conditions.
[Mh] Termos MeSH primário: Basófilos/citologia
Células da Medula Óssea/citologia
Células Precursoras de Linfócitos B/citologia
[Mh] Termos MeSH secundário: Animais
Basófilos/metabolismo
Células da Medula Óssea/metabolismo
Linhagem da Célula
Sobrevivência Celular
Técnicas de Cocultura
Citoproteção
Feminino
Proteínas de Homeodomínio/metabolismo
Cadeias lambda de Imunoglobulina/metabolismo
Integrina alfa2/metabolismo
Contagem de Linfócitos
Camundongos
Células Precursoras de Linfócitos B/metabolismo
Antígenos Thy-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Homeodomain Proteins); 0 (Immunoglobulin lambda-Chains); 0 (Integrin alpha2); 0 (Thy-1 Antigens); 128559-51-3 (RAG-1 protein)
[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.0185509


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[PMID]:28757207
[Au] Autor:Yoon SO; Shin S; Karreth FA; Buel GR; Jedrychowski MP; Plas DR; Dedhar S; Gygi SP; Roux PP; Dephoure N; Blenis J
[Ad] Endereço:Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: syoon1@uic.edu.
[Ti] Título:Focal Adhesion- and IGF1R-Dependent Survival and Migratory Pathways Mediate Tumor Resistance to mTORC1/2 Inhibition.
[So] Source:Mol Cell;67(3):512-527.e4, 2017 Aug 03.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant signaling by the mammalian target of rapamycin (mTOR) contributes to the devastating features of cancer cells. Thus, mTOR is a critical therapeutic target and catalytic inhibitors are being investigated as anti-cancer drugs. Although mTOR inhibitors initially block cell proliferation, cell viability and migration in some cancer cells are quickly restored. Despite sustained inhibition of mTORC1/2 signaling, Akt, a kinase regulating cell survival and migration, regains phosphorylation at its regulatory sites. Mechanistically, mTORC1/2 inhibition promotes reorganization of integrin/focal adhesion kinase-mediated adhesomes, induction of IGFR/IR-dependent PI3K activation, and Akt phosphorylation via an integrin/FAK/IGFR-dependent process. This resistance mechanism contributes to xenograft tumor cell growth, which is prevented with mTOR plus IGFR inhibitors, supporting this combination as a therapeutic approach for cancers.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Neoplasias da Mama/tratamento farmacológico
Movimento Celular/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos
Quinase 1 de Adesão Focal/metabolismo
Melanoma/tratamento farmacológico
Complexos Multiproteicos/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Receptores de Somatomedina/antagonistas & inibidores
Neoplasias Cutâneas/tratamento farmacológico
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Neoplasias da Mama/enzimologia
Neoplasias da Mama/genética
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Feminino
Quinase 1 de Adesão Focal/genética
Seres Humanos
Integrina alfa2/metabolismo
Alvo Mecanístico do Complexo 1 de Rapamicina
Alvo Mecanístico do Complexo 2 de Rapamicina
Melanoma/enzimologia
Melanoma/patologia
Camundongos Nus
Complexos Multiproteicos/metabolismo
Invasividade Neoplásica
Fosfatidilinositol 3-Quinase/metabolismo
Fosforilação
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Interferência de RNA
Receptores de Somatomedina/genética
Receptores de Somatomedina/metabolismo
Transdução de Sinais/efeitos dos fármacos
Neoplasias Cutâneas/enzimologia
Neoplasias Cutâneas/genética
Neoplasias Cutâneas/patologia
Serina-Treonina Quinases TOR/metabolismo
Fatores de Tempo
Transfecção
Carga Tumoral/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IGF1R protein, human); 0 (Integrin alpha2); 0 (Multiprotein Complexes); 0 (Protein Kinase Inhibitors); 0 (Receptors, Somatomedin); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 2.7.10.2 (PTK2 protein, human); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


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[PMID]:28691915
[Au] Autor:Freire-Aradas A; Phillips C; Lareu MV
[Ad] Endereço:Forensic Genetics Unit, Institute of Forensic Sciences, University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain.
[Ti] Título:Forensic individual age estimation with DNA: From initial approaches to methylation tests.
[So] Source:Forensic Sci Rev;29(2):121-144, 2017 Jul.
[Is] ISSN:1042-7201
[Cp] País de publicação:China (Republic : 1949- )
[La] Idioma:eng
[Ab] Resumo:Individual age estimation is a key factor in forensic science analysis that can provide very useful information applicable to criminal, legal, and anthropological investigations. Forensic age inference was initially based on morphological inspection or radiography and only later began to adopt molecular approaches. However, a lack of accuracy or technical problems hampered the introduction of these DNA-based methodologies in casework analysis. A turning point occurred when the epigenetic signature of DNA methylation was observed to gradually change during an individual´s lifespan. In the last four years, the number of publications reporting DNA methylation age-correlated changes has gradually risen and the forensic community now has a range of age methylation tests applicable to forensic casework. Most forensic age predictor models have been developed based on blood DNA samples, but additional tissues are now also being explored. This review assesses the most widely adopted genes harboring methylation sites, detection technologies, statistical age-predictive analyses, and potential causes of variation in age estimates. Despite the need for further work to improve predictive accuracy and establishing a broader range of tissues for which tests can analyze the most appropriate methylation sites, several forensic age predictors have now been reported that provide consistency in their prediction accuracies (predictive error of ±4 years); this makes them compelling tools with the potential to contribute key information to help guide criminal investigations.
[Mh] Termos MeSH primário: Envelhecimento/genética
Metilação de DNA
Genética Forense/métodos
[Mh] Termos MeSH secundário: Acetiltransferases/genética
Amidoidrolases/genética
Ilhas de CpG/genética
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética
Proteína de Domínio de Morte Associada a Edar/genética
Epigenômica
Seres Humanos
Integrina alfa2/genética
Proteínas com Homeodomínio LIM/genética
Proteínas Musculares/genética
Análise de Sequência de DNA
Sulfitos/química
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Edar-Associated Death Domain Protein); 0 (FHL2 protein, human); 0 (ITGA2B protein, human); 0 (Integrin alpha2); 0 (LIM-Homeodomain Proteins); 0 (Muscle Proteins); 0 (Sulfites); 0 (Transcription Factors); EC 2.3.1.- (Acetyltransferases); EC 2.3.1.- (fatty acid elongases); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4); EC 3.1.4.17 (PDE4C protein, human); EC 3.5.- (Amidohydrolases); EC 3.5.1.15 (aspartoacylase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE


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[PMID]:28652408
[Au] Autor:Hirbawi J; Bialkowska K; Bledzka KM; Liu J; Fukuda K; Qin J; Plow EF
[Ad] Endereço:From the Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
[Ti] Título:The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation.
[So] Source:J Biol Chem;292(34):14258-14269, 2017 Aug 25.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kindlin-2 (K2), a 4.1R-ezrin-radixin-moesin (FERM) domain adaptor protein, mediates numerous cellular responses, including integrin activation. The C-terminal 15-amino acid sequence of K2 is remarkably conserved across species but is absent in canonical FERM proteins, including talin. In CHO cells expressing integrin αIIbß3, co-expression of K2 with talin head domain resulted in robust integrin activation, but this co-activation was lost after deletion of as few as seven amino acids from the K2 C terminus. This dependence on the C terminus was also observed in activation of endogenous αIIbß3 in human erythroleukemia (HEL) cells and ß1 integrin activation in macrophage-like RAW264.1 cells. Kindlin-1 (K1) exhibited a similar dependence on its C terminus for integrin activation. Expression of the K2 C terminus as an extension of membrane-anchored P-selectin glycoprotein ligand-1 (PSGL-1) inhibited integrin-dependent cell spreading. Deletion of the K2 C terminus did not affect its binding to the integrin ß3 cytoplasmic tail, but combined biochemical and NMR analyses indicated that it can insert into the F2 subdomain. We suggest that this insertion determines the topology of the K2 FERM domain, and its deletion may affect the positioning of the membrane-binding functions of the F2 subdomain and the integrin-binding properties of its F3 subdomain. Free C-terminal peptide can still bind to K2 and displace the endogenous K2 C terminus but may not restore the conformation needed for integrin co-activation. Our findings indicate that the extreme C terminus of K2 is essential for integrin co-activation and highlight the importance of an atypical architecture of the K2 FERM domain in regulating integrin activation.
[Mh] Termos MeSH primário: Integrina alfa2/metabolismo
Integrina beta3/metabolismo
Leucemia Eritroblástica Aguda/metabolismo
Macrófagos/metabolismo
Proteínas de Membrana/metabolismo
Proteínas de Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Células CHO
Linhagem Celular Tumoral
Cricetulus
Deleção de Genes
Seres Humanos
Integrina alfa2/química
Integrina alfa2/genética
Integrina beta3/química
Integrina beta3/genética
Leucemia Eritroblástica Aguda/patologia
Proteínas Luminescentes/genética
Proteínas Luminescentes/metabolismo
Macrófagos/citologia
Proteínas de Membrana/química
Proteínas de Membrana/genética
Camundongos
Mutação
Proteínas de Neoplasias/agonistas
Proteínas de Neoplasias/química
Proteínas de Neoplasias/genética
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Células RAW 264.7
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Talina/química
Talina/genética
Talina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (Luminescent Proteins); 0 (MIG2B protein, human); 0 (Membrane Proteins); 0 (Neoplasm Proteins); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (Talin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.776195


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[PMID]:28618934
[Au] Autor:Li H; Wu H; Zhang H; Li Y; Li S; Hou Q; Wu S; Yang SY
[Ad] Endereço:1 Department of Respiratory Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
[Ti] Título:Identification of curcumin-inhibited extracellular matrix receptors in non-small cell lung cancer A549 cells by RNA sequencing.
[So] Source:Tumour Biol;39(6):1010428317705334, 2017 Jun.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Curcumin is a potent anti-cancer drug in several types of human cancers. Despite of several preclinical and clinical studies of curcumin, the precise mechanism of curcumin in cancer prevention has remained unclear. In our study, we for the first time investigated whole transcriptome alteration in A549 non-small cell lung cancer (NSCLC) cell lines after treatment with curcumin using RNA sequencing. We found that lots of genes and signaling pathways were significantly altered after curcumin treatment in A549 cells. With bioinformatics approaches (gene ontology, Kyoto Encyclopedia of Genes and Genomes, and STRING), we found that those curcumin altered genes were not only the genes that induce cell death but also those extracellular matrix receptors and mitogen-activated protein kinase signaling pathway genes which regulate cell migration and proliferation. Among those significantly altered genes, eight genes ( COL1A1, COL4A1, COL5A1, LAMA5, ITGA3, ITGA2B, DDIT3, and DUSP1) were further examined by quantitative reverse transcription polymerase chain reaction and western blot analysis in four non-small cell lung cancer cell lines. Both in cell lines and in mouse model, the extracellular matrix receptors including the integrin ( ITGA3 and ITGA2B), collagen ( COL5A1), and laminin ( LAMA5) were significantly inhibited by curcumin at messenger RNA and protein levels. Functional studies confirmed that curcumin not only induced A549 cell death but also repressed cell proliferation and migration by regulating extracellular matrix receptors. Collectively, our study suggests that curcumin may be used as a promising drug candidate for intervening lung cancer in future studies.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Colágeno Tipo V/biossíntese
Curcumina/administração & dosagem
Integrina alfa2/biossíntese
Integrina alfa3/biossíntese
Laminina/biossíntese
[Mh] Termos MeSH secundário: Células A549
Animais
Apoptose/efeitos dos fármacos
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma Pulmonar de Células não Pequenas/patologia
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Colágeno Tipo V/genética
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Integrina alfa2/genética
Integrina alfa3/genética
Laminina/genética
Camundongos
RNA Mensageiro/biossíntese
Receptores de Superfície Celular/antagonistas & inibidores
Receptores de Superfície Celular/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (COL5A1 protein, human); 0 (Collagen Type V); 0 (ITGA2B protein, human); 0 (ITGA3 protein, human); 0 (Integrin alpha2); 0 (Integrin alpha3); 0 (Laminin); 0 (RNA, Messenger); 0 (Receptors, Cell Surface); 0 (extracellular matrix receptor); 0 (laminin alpha5); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317705334


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[PMID]:28487468
[Au] Autor:Ye F; Yang C; Kim J; MacNevin CJ; Hahn KM; Park D; Ginsberg MH; Kim C
[Ad] Endereço:From the Department of Medicine, University of California San Diego School of Medicine, La Jolla, California 92093.
[Ti] Título:Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains.
[So] Source:J Biol Chem;292(24):9858-9864, 2017 Jun 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epigallocatechin gallate (EGCG) is the principal bioactive ingredient in green tea and has been reported to have many health benefits. EGCG influences multiple signal transduction pathways related to human diseases, including redox, inflammation, cell cycle, and cell adhesion pathways. However, the molecular mechanisms of these varying effects are unclear, limiting further development and utilization of EGCG as a pharmaceutical compound. Here, we examined the effect of EGCG on two representative transmembrane signaling receptors, integrinαIIbß3 and epidermal growth factor receptor (EGFR). We report that EGCG inhibits talin-induced integrin αIIbß3 activation, but it activates αIIbß3 in the absence of talin both in a purified system and in cells. This apparent paradox was explained by the fact that the activation state of αIIbß3 is tightly regulated by the topology of ß3 transmembrane domain (TMD); increases or decreases in TMD embedding can activate integrins. Talin increases the embedding of integrin ß3 TMD, resulting in integrin activation, whereas we observed here that EGCG decreases the embedding, thus opposing talin-induced integrin activation. In the absence of talin, EGCG decreases the TMD embedding, which can also disrupt the integrin α-ß TMD interaction, leading to integrin activation. EGCG exhibited similar paradoxical behavior in EGFR signaling. EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF, but inhibits EGF-induced EGFR activation. Thus, this widely ingested polyphenol exhibits pleiotropic effects on transmembrane signaling by modifying the topology of TMDs.
[Mh] Termos MeSH primário: Antioxidantes/metabolismo
Catequina/análogos & derivados
Integrina beta3/metabolismo
Bicamadas Lipídicas/metabolismo
Modelos Moleculares
Receptor do Fator de Crescimento Epidérmico/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Antioxidantes/química
Antioxidantes/uso terapêutico
Células CHO
Catequina/química
Catequina/metabolismo
Catequina/uso terapêutico
Cricetulus
Suplementos Nutricionais
Dimerização
Seres Humanos
Integrina alfa2/química
Integrina alfa2/genética
Integrina alfa2/metabolismo
Integrina beta3/química
Integrina beta3/genética
Ligantes
Bicamadas Lipídicas/química
Mutação
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/metabolismo
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/agonistas
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Domínios e Motivos de Interação entre Proteínas
Receptor do Fator de Crescimento Epidérmico/agonistas
Receptor do Fator de Crescimento Epidérmico/química
Receptor do Fator de Crescimento Epidérmico/genética
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Talina/antagonistas & inibidores
Talina/química
Talina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (Ligands); 0 (Lipid Bilayers); 0 (Peptide Fragments); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Recombinant Fusion Proteins); 0 (Talin); 8R1V1STN48 (Catechin); BQM438CTEL (epigallocatechin gallate); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170706
[Lr] Data última revisão:
170706
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.C117.787309


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[PMID]:28428218
[Au] Autor:Berrou E; Adam F; Lebret M; Planche V; Fergelot P; Issertial O; Coupry I; Bordet JC; Nurden P; Bonneau D; Colin E; Goizet C; Rosa JP; Bryckaert M
[Ad] Endereço:From the INSERM UMR_S 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France (E.B., F.A., M.L., V.P., O.I., J.-P.R., M.B.); INSERM UMR_S 1211, Université de Bordeaux, CHU Bordeaux UNIV EA 4576, Place Aurélie Raba-Léon, France (P.F., I.C., C.G.); CHU Bordeaux, Centre de Référ
[Ti] Título:Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin α ß Activation.
[So] Source:Arterioscler Thromb Vasc Biol;37(6):1087-1097, 2017 Jun.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Dominant mutations of the X-linked filamin A ( ) gene are responsible for filaminopathies A, which are rare disorders including brain periventricular nodular heterotopia, congenital intestinal pseudo-obstruction, cardiac valves or skeleton malformations, and often macrothrombocytopenia. APPROACH AND RESULTS: We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: ). Platelet counts were normal, with few enlarged platelets. FLNa was detectable in all platelets but at 30% of control levels. Surprisingly, all platelet functions were significantly upregulated, including platelet aggregation and secretion, as induced by ADP, collagen, or von Willebrand factor in the presence of ristocetin, as well as thrombus formation in blood flow on a collagen or on a von Willebrand factor matrix. Most importantly, patient platelets stimulated with ADP exhibited a marked increase in α ß integrin activation and a parallel increase in talin recruitment to ß , contrasting with normal Rap1 activation. These results are consistent with the mutant FLNa affecting the last step of α ß activation. Overexpression of mutant FLNa in the HEL megakaryocytic cell line correlated with an increase (compared with wild-type FLNa) in PMA-induced fibrinogen binding to and in talin and kindlin-3 recruitment by α ß . CONCLUSIONS: Altogether, our results are consistent with a less binding of mutant FLNa to ß and the facilitated recruitment of talin by ß on platelet stimulation, explaining the increased α ß activation and the ensuing gain-of-platelet functions.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Filaminas/genética
Integrina alfa2/sangue
Integrina beta3/sangue
Pseudo-Obstrução Intestinal/genética
Mutação
Heterotopia Nodular Periventricular/genética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Plaquetas/ultraestrutura
Linhagem Celular
Análise Mutacional de DNA
Filaminas/sangue
Predisposição Genética para Doença
Hereditariedade
Seres Humanos
Pseudo-Obstrução Intestinal/sangue
Pseudo-Obstrução Intestinal/diagnóstico
Masculino
Heterotopia Nodular Periventricular/sangue
Heterotopia Nodular Periventricular/diagnóstico
Fenótipo
Ativação Plaquetária
Testes de Função Plaquetária
Ligação Proteica
Transdução de Sinais
Talina/sangue
Proteínas de Ligação a Telômeros/sangue
Transfecção
Fator de von Willebrand/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FLNA protein, human); 0 (Filamins); 0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (TERF2IP protein, human); 0 (Talin); 0 (Telomere-Binding Proteins); 0 (von Willebrand Factor)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309337


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[PMID]:28388872
[Au] Autor:Vlachadis N; Tsamadias V; Vrachnis N; Kaparos G; Vitoratos N; Kouskouni E; Economou E
[Ad] Endereço:a Clinical Laboratory of Therapeutic Individualization, Second Department of Obstetrics and Gynecology , National and Kapodistrian University of Athens, School of Medicine, Aretaieio Hospital , Athens , Greece.
[Ti] Título:Associations of combined polymorphisms of the platelet membrane glycoproteins Ia and IIIa and the platelet-endothelial cell adhesion molecule-1 and P-Selectin genes with IVF implantation failures.
[So] Source:J Obstet Gynaecol;37(3):363-369, 2017 Apr.
[Is] ISSN:1364-6893
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The aim of the study was to investigate the combined impact of the genetic heterogeneity of the glycoproteins Ia (GpIa) and IIIa (GpIIIa) and the platelet-endothelial cell adhesion molecule-1 (PECAM-1) and P-Selectin genes on IVF embryo transfer implantation failures (IVF-ET failures). Sixty nulligravida women with previous IVF-ET failures and 60 fertile controls were genotyped for the GpIa-C807T, GpIIIa-PlA1/PA2, PECAM-1-C373G (Leu125Val) and P-Selectin-A37674C (Thr715Pro) polymorphisms by pyrosequencing. Compared with wild-type combined homozygotes, carriers of combinations of risk alleles in two gene loci were at significantly increased risk for IVF-ET failure, whereas carriers of the combination of GpIa-807T, GpIIIa-PlA2 and PECAM-1-373G alleles had OR = 52.50 (95%CI: 4.05-680.95, p < .001). The area under the receiver-operating characteristic curve (AUC) based on the number of polymorphisms and the number of risk alleles per subject was 75.4% (95%CI: 66.7%-82.8%, p < .001) and 72.5% (95%CI: 63.6%-80.3%, p < .001), respectively. The OR per polymorphism and risk allele increase was 4.26 (95%CI: 2.15-8.41, p < .001) and 2.85 (95%CI: 1.71-4.76, p < .001), respectively. The above associations were more robust among younger women. The combined analysis of these polymorphisms revealed strong association of combined carriers with IVF-ET failures especially for younger women and provided a genetic risk score with good diagnostic accuracy in the prediction of IVF-ET failures.
[Mh] Termos MeSH primário: Implantação do Embrião/genética
Fertilização In Vitro
Integrina alfa2/genética
Integrina beta3/genética
Selectina-P/genética
Molécula-1 de Adesão Celular Endotelial de Plaquetas/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Adulto
Fatores Etários
Área Sob a Curva
Biomarcadores/sangue
Estudos de Casos e Controles
Feminino
Heterozigoto
Seres Humanos
Integrina alfa2/sangue
Integrina beta3/sangue
Risco
Sensibilidade e Especificidade
Falha de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (P-Selectin); 0 (Platelet Endothelial Cell Adhesion Molecule-1)
[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:170409
[St] Status:MEDLINE
[do] DOI:10.1080/01443615.2016.1256978


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[PMID]:28358707
[Au] Autor:Simou M; Kouskouni E; Vitoratos N; Economou E; Creatsas G
[Ad] Endereço:Second Department of Obstetrics and Gynecology, Medical School, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece maria.simou@ymail.com.
[Ti] Título:Polymorphisms of Platelet Glycoprotein Receptors and Cell Adhesion Molecules in Fetuses with Fetal Growth Restriction and Their Mothers As Detected with Pyrosequencing.
[So] Source:In Vivo;31(2):243-249, 2017 Mar-Apr.
[Is] ISSN:1791-7549
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Vascular thrombotic tendency may lead to fetal growth restriction (FGR). Altered platelet function and genetic heterogeneity may play a role in this procedure. We investigated whether maternal or fetal genotypic frequencies of genes polymorphisms for certain platelet receptor and cell adhesion molecules are altered in FGR. MATERIALS AND METHODS: We compared the maternal and fetal genotypic frequencies of single nucleotide polymorphisms (SNPs) in four genes coding for platelet receptors and cell adhesion molecules [integrin alpha subunit 2 (ITGA2)C807T, integrin subunit beta 3(ITGB3) T1565C, platelet cell adhesion protein 1 (PECAM1) CTG-GTG and selectin P(SELP)A/C]. A total of 32 fetuses with fetal growth restriction and their mothers were matched with 18 normal controls. Using maternal venous blood and umbilical cord blood samples, nucleotide sequences were determined from pyrograms. Genotypic frequencies were calculated and analyzed using appropriate tests and logistic regression. RESULTS: There was no statistical difference in the proportion of heterozygotes or homozygotes for any of the genotypic frequencies between FGR and control groups in mothers or fetuses. CONCLUSION: Our study demonstrated no association of maternal or fetal ITGA2 C807T SNP, ITGB3 T1565C SNP, PECAM1 CTG - GTG and SELP A/C polymorphisms with FGR.
[Mh] Termos MeSH primário: Moléculas de Adesão Celular/genética
Retardo do Crescimento Fetal/genética
Glicoproteínas da Membrana de Plaquetas/genética
Polimorfismo de Nucleotídeo Único
Análise de Sequência de DNA/métodos
[Mh] Termos MeSH secundário: Adulto
Feminino
Feto/metabolismo
Frequência do Gene
Genótipo
Seres Humanos
Integrina alfa2/genética
Integrina beta3/genética
Modelos Logísticos
Mães
Selectina-P/genética
Molécula-1 de Adesão Celular Endotelial de Plaquetas/genética
Estudos Prospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Adhesion Molecules); 0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (P-Selectin); 0 (Platelet Endothelial Cell Adhesion Molecule-1); 0 (Platelet Membrane Glycoproteins); 0 (SELP protein, human)
[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:170331
[St] Status:MEDLINE


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[PMID]:28324020
[Au] Autor:Moravek MB; Yin P; Coon JS; Ono M; Druschitz SA; Malpani SS; Dyson MT; Rademaker AW; Robins JC; Wei JJ; Kim JJ; Bulun SE
[Ad] Endereço:Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
[Ti] Título:Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A.
[So] Source:J Clin Endocrinol Metab;102(5):1588-1595, 2017 May 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown. Objective: To define differential gene expression and signaling pathways in leiomyoma cell populations. Design: Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b-, and CD34-/CD49b-. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2'-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma. Setting: Research laboratory. Patients: Eight African American women. Interventions: None. Main Outcomes Measures: Gene expression patterns, cell proliferation, and differentiation. Results: A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b- intermediary cells, which then terminally differentiate to CD34-/CD49b- cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b- vs CD34-/CD49b- cells (83-fold; P < 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD34-/CD49b- cells (15-fold and 0.35-fold, respectively; P < 0.05). IGF2 significantly increased cell number (1.4-fold; P < 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation. Conclusions: IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas.
[Mh] Termos MeSH primário: Antígenos CD/genética
Diferenciação Celular/genética
Proliferação Celular/genética
Fator de Crescimento Insulin-Like II/genética
Leiomioma/genética
Células-Tronco Neoplásicas/citologia
Comunicação Parácrina/genética
Receptor de Insulina/genética
Neoplasias Uterinas/genética
[Mh] Termos MeSH secundário: Adulto
Afroamericanos
Antígenos CD/metabolismo
Antígenos CD34/metabolismo
Feminino
Citometria de Fluxo
Perfilação da Expressão Gênica
Seres Humanos
Immunoblotting
Fator de Crescimento Insulin-Like II/metabolismo
Integrina alfa2/metabolismo
Leiomioma/metabolismo
Sistema de Sinalização das MAP Quinases
Meia-Idade
Células-Tronco Neoplásicas/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Receptor de Insulina/metabolismo
Análise Serial de Tecidos
Neoplasias Uterinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Antigens, CD34); 0 (IGF2 protein, human); 0 (Integrin alpha2); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.10.1 (INSR protein, human); EC 2.7.10.1 (Receptor, Insulin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3497



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