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[PMID]:29185092
[Au] Autor:Ma M; Dai J; Xu T; Yu S; Yu H; Tang H; Yan J; Wu X; Yu J; Chi Z; Si L; Cui C; Sheng X; Kong Y; Guo J
[Ad] Endereço:Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
[Ti] Título:Analysis of TSC1 mutation spectrum in mucosal melanoma.
[So] Source:J Cancer Res Clin Oncol;144(2):257-267, 2018 Feb.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma. METHODS: We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1. RESULTS: The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007). CONCLUSIONS: Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.
[Mh] Termos MeSH primário: Melanoma/genética
Mutação
Proteínas Supressoras de Tumor/genética
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Análise Mutacional de DNA
Feminino
Seres Humanos
Masculino
Melanoma/metabolismo
Melanoma/patologia
Meia-Idade
Membrana Mucosa/patologia
Estadiamento de Neoplasias
Fosfoproteínas/metabolismo
Prognóstico
Proteína S6 Ribossômica/metabolismo
Serina-Treonina Quinases TOR/metabolismo
Proteínas Supressoras de Tumor/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (EIF4EBP1 protein, human); 0 (Phosphoproteins); 0 (Ribosomal Protein S6); 0 (Tumor Suppressor Proteins); 0 (tuberous sclerosis complex 1 protein); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-017-2550-z


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[PMID]:28506734
[Au] Autor:Kerr DA; Busarla SVP; Gimbel DC; Sohani AR; Nazarian RM
[Ad] Endereço:Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Electronic address: dkerr@med.miami.edu.
[Ti] Título:mTOR, VEGF, PDGFR, and c-kit signaling pathway activation in Kaposi sarcoma.
[So] Source:Hum Pathol;65:157-165, 2017 Jul.
[Is] ISSN:1532-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates, and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (N=274), most (90%) associated with human immunodeficiency virus. Tissue microarray slides were stained with human herpes virus-8, Friend leukemia integration 1 transcription factor, CD117 (c-kit), phospho-S6 (pS6), PDGF receptor-ß, VEGF, and phospho-mTOR. Both intensity and extent of staining were scored. Multiplying these scores for each core yielded total staining H-scores. Human herpes virus-8 was positive in 87% and Friend leukemia integration 1 transcription factor in 95.7% of cases. Most were also VEGF+ (97.6%), pS6+ (95.7%), CD117+ (92.5%), and PDGFRB+ (87.4%). Approximately half (55.6%) were phospho-mTOR+. There was no significant difference in staining among patients with low (<500 cells/mm ) or preserved CD4 T-cell counts. Immunohistochemistry confirms upregulation of the mTOR, PDGF, VEGF, and c-kit pathways in a large cohort of KS samples. Of proteins tested, pS6, downstream of mTOR, demonstrated the highest proportion of strong positivity (67.1%). These results support the possibility of using targeted inhibitors in KS. Overexpression was independent of CD4 count, suggesting that even patients with low counts may be targeted therapy candidates.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/análise
Proteínas Proto-Oncogênicas c-kit/análise
Receptores do Fator de Crescimento Derivado de Plaquetas/análise
Sarcoma de Kaposi/química
Transdução de Sinais
Serina-Treonina Quinases TOR/análise
Fator A de Crescimento do Endotélio Vascular/análise
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Antineoplásicos/uso terapêutico
Contagem de Linfócito CD4
Criança
Pré-Escolar
Feminino
Infecções por HIV/imunologia
Infecções por HIV/virologia
Herpesvirus Humano 8/isolamento & purificação
Seres Humanos
Imuno-Histoquímica
Masculino
Meia-Idade
Terapia de Alvo Molecular
Fosforilação
Valor Preditivo dos Testes
Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores
Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores
Estudos Retrospectivos
Proteína S6 Ribossômica/análise
Sarcoma de Kaposi/tratamento farmacológico
Sarcoma de Kaposi/patologia
Sarcoma de Kaposi/virologia
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/antagonistas & inibidores
Análise Serial de Tecidos
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Ribosomal Protein S6); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.1 (Proto-Oncogene Proteins c-kit); EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE


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[PMID]:28445558
[Au] Autor:Bongiorno MA; Nathan N; Oyerinde O; Wang JA; Lee CR; Brown GT; Moss J; Darling TN
[Ad] Endereço:Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland2Naval Health Clinic, Pearl Harbor, Hawaii.
[Ti] Título:Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches.
[So] Source:JAMA Dermatol;153(7):660-665, 2017 Jul 01.
[Is] ISSN:2168-6084
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Patients with tuberous sclerosis complex (TSC) frequently develop collagenous connective tissue nevi. The prototypical lesion is a large shagreen patch located on the lower back, but some patients only manifest small collagenomas or have lesions elsewhere on the body. The ability to recognize these variable presentations can be important for the diagnosis of TSC. Objective: To describe the clinical characteristics of connective tissue nevi on the trunk and extremities of patients with tuberous sclerosis complex. Design, Setting, and Participants: A retrospective analysis of patient medical records and skin photography was performed; 104 adult patients with TSC were enrolled in an observational cohort study that was enriched for those with pulmonary lymphangioleiomyomatosis, and was therefore composed mostly of women (99 women, 5 men). All patients included were examined at the National Institutes of Health (NIH) in Bethesda, Maryland, from 1998 to 2013. Connective tissue nevi were categorized per anatomic location and size. Lesions less than 1 cm in diameter were termed collagenomas. Shagreen patches were characterized as small (1 to <4 cm), medium (4 to <8 cm), and large (≥8 cm). Main Outcome and Measures: Frequency, anatomic location, size, and histological appearance of connective tissue nevi in patients with TSC. Results: Overall, 58 of 104 patients (median [range] age, 42 [19-70] years) with TSC (56%) had at least 1 connective tissue nevus on the trunk or thighs; of these, 28 of 58 patients (48%) had a solitary lesion, and 30 of 58 patients (52%) had 2 or more lesions. Overall, 120 lesions from 55 patients were classified by size; 46 lesions (38%) were collagenomas; 39 lesions (32%) were small shagreen patches; 21 lesions (18%), medium shagreen patches; and 14 lesions (12%), large shagreen patches. The distribution of lesions was 9% (n = 11), upper back; 29% (n = 35), middle back; 51% (n = 61), lower back; and 11% (n = 13), other locations. All 26 shagreen patches that were analyzed histopathologically had coarse collagen fibers and 24 of 26 stained with Miller elastic stain had decreased elastic fibers. On immunoblot analysis, fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin. Conclusions and Relevance: Tuberous sclerosis complex-related connective tissue nevi are not limited to the lower back, and occasionally present on the central or upper back, buttocks, or thighs. Elastic fibers are typically decreased. Recognition of these variable presentations can be important for TSC diagnosis.
[Mh] Termos MeSH primário: Nevo/patologia
Proteína S6 Ribossômica/metabolismo
Esclerose Tuberosa/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Estudos de Coortes
Feminino
Seres Humanos
Masculino
Meia-Idade
Nevo/diagnóstico
Nevo/etiologia
Fosforilação
Estudos Retrospectivos
Esclerose Tuberosa/complicações
Esclerose Tuberosa/diagnóstico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Ribosomal Protein S6)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1001/jamadermatol.2017.0298


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[PMID]:28409828
[Au] Autor:Martin NRW; Turner MC; Farrington R; Player DJ; Lewis MP
[Ad] Endereço:School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
[Ti] Título:Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro.
[So] Source:J Cell Physiol;232(10):2788-2797, 2017 Oct.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The amino acid leucine is thought to be important for skeletal muscle growth by virtue of its ability to acutely activate mTORC1 and enhance muscle protein synthesis, yet little data exist regarding its impact on skeletal muscle size and its ability to produce force. We utilized a tissue engineering approach in order to test whether supplementing culture medium with leucine could enhance mTORC1 signaling, myotube growth, and muscle function. Phosphorylation of the mTORC1 target proteins 4EBP-1 and rpS6 and myotube hypertrophy appeared to occur in a dose dependent manner, with 5 and 20 mM of leucine inducing similar effects, which were greater than those seen with 1 mM. Maximal contractile force was also elevated with leucine supplementation; however, although this did not appear to be enhanced with increasing leucine doses, this effect was completely ablated by co-incubation with the mTOR inhibitor rapamycin, showing that the augmented force production in the presence of leucine was mTOR sensitive. Finally, by using electrical stimulation to induce chronic (24 hr) contraction of engineered skeletal muscle constructs, we were able to show that the effects of leucine and muscle contraction are additive, since the two stimuli had cumulative effects on maximal contractile force production. These results extend our current knowledge of the efficacy of leucine as an anabolic nutritional aid showing for the first time that leucine supplementation may augment skeletal muscle functional capacity, and furthermore validates the use of engineered skeletal muscle for highly-controlled investigations into nutritional regulation of muscle physiology.
[Mh] Termos MeSH primário: Leucina/farmacologia
Contração Muscular/efeitos dos fármacos
Fibras Musculares Esqueléticas/efeitos dos fármacos
Força Muscular/efeitos dos fármacos
Engenharia Tecidual/métodos
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/metabolismo
Linhagem Celular
Relação Dose-Resposta a Droga
Estimulação Elétrica
Hipertrofia
Alvo Mecanístico do Complexo 1 de Rapamicina
Camundongos
Complexos Multiproteicos/metabolismo
Fibras Musculares Esqueléticas/metabolismo
Fibras Musculares Esqueléticas/patologia
Fosfoproteínas/metabolismo
Fosforilação
Inibidores de Proteínas Quinases/farmacologia
Proteína S6 Ribossômica/metabolismo
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/antagonistas & inibidores
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Eif4ebp1 protein, mouse); 0 (Multiprotein Complexes); 0 (Phosphoproteins); 0 (Protein Kinase Inhibitors); 0 (Ribosomal Protein S6); 0 (ribosomal protein S6, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25960


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[PMID]:28228357
[Au] Autor:Temiz-Resitoglu M; Kucukkavruk SP; Guden DS; Cecen P; Sari AN; Tunctan B; Gorur A; Tamer-Gumus L; Buharalioglu CK; Malik KU; Sahan-Firat S
[Ad] Endereço:Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
[Ti] Título:Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats.
[So] Source:Eur J Pharmacol;802:7-19, 2017 May 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic diseases, and inflammation. Although mTOR participates in Toll-like receptor 4 signalling in different cell types, the role of this enzyme in sepsis pathogenesis and its effects on hypotension and inflammation in endotoxemic rats remains unclear. In this study we investigated the effects of mTOR inhibition on lipopolysaccharide (LPS)-induced changes on expressions and/or activities of ribosomal protein S6 (rpS6), an mTOR substrate, nuclear factor-κB (NF-κB) p65, inhibitor κB (IκB)-α, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 with production of nitric oxide, peroxynitrite, prostacyclin, and tumor necrosis factor (TNF)-α and activity of myeloperoxidase (MPO), which results in hypotension and inflammation. Injection of LPS (10mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate that were associated with elevated nitrotyrosine, 6-keto-PGF , and TNF-α levels and MPO activity, and increased expressions and/or activities of rpS6, NF-κB p65, iNOS, and COX-2 and decreased expression of IκB-α in renal, cardiac, and vascular tissues. LPS also increased serum and tissue nitrite levels. Rapamycin (1mg/kg, i.p.) given one h after injection of LPS reversed these effects of LPS. These data suggest that the activation of mTOR/IκB-α/NF-κB pathway associated with vasodilator and proinflammatory mediator formation contributes to LPS-induced hypotension and inflammation.
[Mh] Termos MeSH primário: Hipotensão/induzido quimicamente
Hipotensão/patologia
Proteínas I-kappa B/metabolismo
Lipopolissacarídeos/farmacologia
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/metabolismo
Fator de Transcrição RelA/metabolismo
[Mh] Termos MeSH secundário: 6-Cetoprostaglandina F1 alfa/metabolismo
Animais
Pressão Arterial/efeitos dos fármacos
Ciclo-Oxigenase 2/metabolismo
Epoprostenol/biossíntese
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Frequência Cardíaca/efeitos dos fármacos
Hipotensão/metabolismo
Hipotensão/fisiopatologia
Inflamação/induzido quimicamente
Inflamação/patologia
Masculino
Óxido Nítrico/biossíntese
Óxido Nítrico Sintase Tipo II/metabolismo
Peroxidase/metabolismo
Ácido Peroxinitroso/biossíntese
Ratos
Ratos Wistar
Proteína S6 Ribossômica/metabolismo
Fator de Necrose Tumoral alfa/biossíntese
Tirosina/análogos & derivados
Tirosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (I-kappa B Proteins); 0 (Lipopolysaccharides); 0 (Ribosomal Protein S6); 0 (Transcription Factor RelA); 0 (Tumor Necrosis Factor-alpha); 14691-52-2 (Peroxynitrous Acid); 31C4KY9ESH (Nitric Oxide); 3604-79-3 (3-nitrotyrosine); 42HK56048U (Tyrosine); 58962-34-8 (6-Ketoprostaglandin F1 alpha); DCR9Z582X0 (Epoprostenol); EC 1.11.1.7 (Peroxidase); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 1.14.99.1 (Cyclooxygenase 2); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE


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[PMID]:28119058
[Au] Autor:Klingebiel M; Dinekov M; Köhler C
[Ad] Endereço:Institute II for Anatomy, Medical Faculty, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
[Ti] Título:Analysis of ribosomal protein S6 baseline phosphorylation and effect of tau pathology in the murine brain and human hippocampus.
[So] Source:Brain Res;1659:121-135, 2017 Mar 15.
[Is] ISSN:1872-6240
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:We examined the distribution pattern of the phosphorylated 40S ribosomal subunit protein S6, a downstream target of the mTOR pathway, in the brains of 24-months-old human tau transgenic pR5 mice, non-transgenic littermates and in human hippocampi. We studied baseline levels of phosphorylated S6 and a possible effect of tau pathology. S6 phosphorylated at Ser235/236 (pS6Ser235/236) or Ser240/244 (pS6Ser240/244) has been used as a read-out of mTOR activity in several studies. The mTOR pathway regulates a wide variety of cellular functions including cell growth, ribosome biosynthesis, translational control and autophagy. Its dysregulation might underlie the neurodegenerative pathology of Alzheimer's disease and other tauopathies. pS6Ser235/236 and pS6Ser240/244 immunoreactivity in the mouse brain were widespread and similar distributed, but intensive pS6Ser235/236 immunoreactivity was more selective, especially highlighting certain brainstem regions. In the human hippocampus mainly granulovacuolar inclusions in neurons displayed pS6Ser235/236 immunoreactivity. In contrast, a considerable number of neurons displayed pS6Ser240/244 immunoreactivity in the cytoplasm without labeling of granulovacuolar inclusions. Except for a tendency of lower numbers of intensely phosphorylated S6-positive neurons in pR5 mice, the pattern of distribution of pS6Ser235/236 and pS6Ser240/244 immunoreactivity was largely unchanged when compared with non-transgenic mice and also when human hippocampi from AD cases and controls were compared. Similar to pR5 mice most neurons with hyper-phosphorylated tau in human hippocampi displayed no or only weak labeling for phosphorylated S6, suggesting that phosphorylated S6 is not especially associated with pathological tau, but is rather a feature of unaffected neurons.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Encéfalo/patologia
Proteína S6 Ribossômica/metabolismo
Proteínas tau/metabolismo
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Animais
Feminino
Imunofluorescência
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neurônios/metabolismo
Neurônios/patologia
Fosforilação
Proteína S6 Ribossômica/genética
Transdução de Sinais
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MAPT protein, human); 0 (Mapt protein, mouse); 0 (Ribosomal Protein S6); 0 (tau Proteins); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE


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[PMID]:27448205
[Au] Autor:Dieterlen MT; John K; Haase S; Garbade J; Tarnok A; Mohr FW; Bittner HB; Barten MJ
[Ad] Endereço:a HELIOS Clinic, Department of Cardiac Surgery , University Hospital Leipzig, Heart Center , Leipzig , Germany.
[Ti] Título:Effect of confounding factors on a phospho-flow assay of ribosomal S6 protein for therapeutic drug monitoring of the mTOR-inhibitor everolimus in heart transplanted patients.
[So] Source:Biomarkers;22(1):86-92, 2017 Feb.
[Is] ISSN:1366-5804
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Several assays of monitoring immune cell function have been developed to enhance therapeutic drug monitoring. OBJECTIVE: An in vitro-validated whole-blood assay of phosphorylated ribosomal protein S6 (pS6RP) was evaluated for confounders to monitor the mTOR-inhibitor everolimus (ERL). MATERIALS AND METHODS: Whole blood samples from 87 heart transplant recipients were analyzed for pS6RP-expression in CD3-positive T-cells by phospho-flow analysis. RESULTS: ERL blood concentration, laboratory parameters, co-medications, demographic and clinical data were reviewed. CONCLUSION: Evaluating the pS6RP-assay revealed that pS6RP is influenced by cyclosporine A (CsA) blood concentration, duration of ERL treatment, co-medication with thiazide diuretics and different metabolic parameters.
[Mh] Termos MeSH primário: Everolimo/sangue
Transplante de Coração
Proteína S6 Ribossômica/sangue
[Mh] Termos MeSH secundário: Complexo CD3/análise
Monitoramento de Medicamentos/métodos
Citometria de Fluxo/métodos
Transplante de Coração/efeitos adversos
Seres Humanos
Imunossupressores/sangue
Meia-Idade
Fosforilação
Linfócitos T/imunologia
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD3 Complex); 0 (Immunosuppressive Agents); 0 (Ribosomal Protein S6); 9HW64Q8G6G (Everolimus); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160723
[St] Status:MEDLINE
[do] DOI:10.1080/1354750X.2016.1210676


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[PMID]:27729247
[Au] Autor:Osman I; Poulose N; Ganapathy V; Segar L
[Ad] Endereço:Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
[Ti] Título:High fructose-mediated attenuation of insulin receptor signaling does not affect PDGF-induced proliferative signaling in vascular smooth muscle cells.
[So] Source:Eur J Pharmacol;791:703-710, 2016 Nov 15.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Insulin resistance is associated with accelerated atherosclerosis. Although high fructose is known to induce insulin resistance, it remains unclear as to how fructose regulates insulin receptor signaling and proliferative phenotype in vascular smooth muscle cells (VSMCs), which play a major role in atherosclerosis. Using human aortic VSMCs, we investigated the effects of high fructose treatment on insulin receptor substrate-1 (IRS-1) serine phosphorylation, insulin versus platelet-derived growth factor (PDGF)-induced phosphorylation of Akt, S6 ribosomal protein, and extracellular signal-regulated kinase (ERK), and cell cycle proteins. In comparison with PDGF (a potent mitogen), neither fructose nor insulin enhanced VSMC proliferation and cyclin D1 expression. d-[ C(U)]fructose uptake studies revealed a progressive increase in fructose uptake in a time-dependent manner. Concentration-dependent studies with high fructose (5-25mM) showed marked increases in IRS-1 serine phosphorylation, a key adapter protein in insulin receptor signaling. Accordingly, high fructose treatment led to significant diminutions in insulin-induced phosphorylation of downstream signaling components including Akt and S6. In addition, high fructose significantly diminished insulin-induced ERK phosphorylation. Nevertheless, high fructose did not affect PDGF-induced key proliferative signaling events including phosphorylation of Akt, S6, and ERK and expression of cyclin D1 protein. Together, high fructose dysregulates IRS-1 phosphorylation state and proximal insulin receptor signaling in VSMCs, but does not affect PDGF-induced proliferative signaling. These findings suggest that systemic insulin resistance rather than VSMC-specific dysregulation of insulin receptor signaling by high fructose may play a major role in enhancing atherosclerosis and neointimal hyperplasia.
[Mh] Termos MeSH primário: Frutose/farmacologia
Músculo Liso Vascular/citologia
Receptor de Insulina/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Aorta/citologia
Proliferação Celular/efeitos dos fármacos
Ciclina D1/metabolismo
Inibidor de Quinase Dependente de Ciclina p27/metabolismo
Relação Dose-Resposta a Droga
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Proteínas Substratos do Receptor de Insulina/química
Proteínas Substratos do Receptor de Insulina/metabolismo
Músculo Liso Vascular/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Fator de Crescimento Derivado de Plaquetas/farmacologia
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteína S6 Ribossômica/metabolismo
Serina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IRS1 protein, human); 0 (IRS2 protein, human); 0 (Insulin Receptor Substrate Proteins); 0 (Platelet-Derived Growth Factor); 0 (Ribosomal Protein S6); 136601-57-5 (Cyclin D1); 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27); 30237-26-4 (Fructose); 452VLY9402 (Serine); EC 2.7.10.1 (Receptor, Insulin); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161013
[St] Status:MEDLINE


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[PMID]:27699948
[Au] Autor:Hirashita Y; Tsukamoto Y; Yanagihara K; Fumoto S; Hijiya N; Nakada C; Uchida T; Matsuura K; Kodama M; Okimoto T; Daa T; Seike M; Iha H; Shirao K; Murakami K; Moriyama M
[Ad] Endereço:Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.
[Ti] Título:Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells.
[So] Source:Cancer Sci;107(12):1919-1928, 2016 Dec.
[Is] ISSN:1349-7006
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, therefore, targeting of the RTK/KRAS downstream pathways could help to broaden the applicability of molecular targeted therapy for GC. We assembled a panel of 48 GC cell lines and screened predictors of responsiveness to inhibition of the RAF/MEK/ERK pathway, one of the RTK/KRAS downstream pathways. We found that GC cells with MET amplification or KRAS mutation, but not amplification, tended to be sensitive to MEK inhibition. However, several cell lines without RTK/KRAS alterations also showed high sensitivity to MEK inhibition. We then focused on the phosphorylation of RTK/KRAS downstream molecules to screen for predictors' sensitivity to MEK inhibition. We found that the phosphorylation level of mammalian target of rapamycin complex 1 (mTORC1) downstream molecules, including p70S6K, 4EBP1, and S6, was significantly associated with sensitivity to MEK inhibition in GC cells (P < 0.05), suggesting that mTORC1 activity is related to the sensitivity to MEK inhibition. Furthermore, the change in mTORC1 activity after MEK inhibition was also significantly associated with this sensitivity (P < 0.001). Among the mTORC1 downstream molecules, the change in S6 phosphorylation (pS6) showed the most significant correlation with sensitivity. Using xenograft models derived from highly sensitive and resistant cell lines, we found specific reduction of pS6 in xenografts from highly sensitive cell lines after 6 h of treatment with an MEK inhibitor. Thus, our data suggest the potential clinical applicability of an MEK inhibitor for a proportion of GC patients who could be selected on the basis of pS6 change after MEK inhibition.
[Mh] Termos MeSH primário: MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Proteína S6 Ribossômica/metabolismo
Neoplasias Gástricas/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/genética
Expressão Gênica
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
Camundongos
Complexos Multiproteicos/metabolismo
Fosforilação
Proteínas Quinases S6 Ribossômicas 70-kDa/genética
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Transdução de Sinais/efeitos dos fármacos
Neoplasias Gástricas/genética
Neoplasias Gástricas/patologia
Serina-Treonina Quinases TOR/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Multiprotein Complexes); 0 (Protein Kinase Inhibitors); 0 (Ribosomal Protein S6); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE
[do] DOI:10.1111/cas.13094


  10 / 782 MEDLINE  
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[PMID]:27616062
[Au] Autor:Tan CL; Cooke EK; Leib DE; Lin YC; Daly GE; Zimmerman CA; Knight ZA
[Ad] Endereço:Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
[Ti] Título:Warm-Sensitive Neurons that Control Body Temperature.
[So] Source:Cell;167(1):47-59.e15, 2016 Sep 22.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thermoregulation is one of the most vital functions of the brain, but how temperature information is converted into homeostatic responses remains unknown. Here, we use an unbiased approach for activity-dependent RNA sequencing to identify warm-sensitive neurons (WSNs) within the preoptic hypothalamus that orchestrate the homeostatic response to heat. We show that these WSNs are molecularly defined by co-expression of the neuropeptides BDNF and PACAP. Optical recordings in awake, behaving mice reveal that these neurons are selectively activated by environmental warmth. Optogenetic excitation of WSNs triggers rapid hypothermia, mediated by reciprocal changes in heat production and loss, as well as dramatic cold-seeking behavior. Projection-specific manipulations demonstrate that these distinct effectors are controlled by anatomically segregated pathways. These findings reveal a molecularly defined cell type that coordinates the diverse behavioral and autonomic responses to heat. Identification of these warm-sensitive cells provides genetic access to the core neural circuit regulating the body temperature of mammals. PAPERCLIP.
[Mh] Termos MeSH primário: Regulação da Temperatura Corporal/genética
Fator Neurotrófico Derivado do Encéfalo/genética
Regulação da Expressão Gênica
Temperatura Alta
Neurônios/fisiologia
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética
Núcleo Hipotalâmico Ventromedial/citologia
[Mh] Termos MeSH secundário: Animais
Comportamento Animal
Camundongos
Microdissecção
Neurônios/metabolismo
Optogenética
RNA Mensageiro/genética
Proteína S6 Ribossômica/metabolismo
Análise de Sequência de RNA
Núcleo Hipotalâmico Ventromedial/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Brain-Derived Neurotrophic Factor); 0 (Pituitary Adenylate Cyclase-Activating Polypeptide); 0 (RNA, Messenger); 0 (Ribosomal Protein S6)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160913
[St] Status:MEDLINE



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