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[PMID]:28469732
[Au] Autor:Cohen SA; Yu M; Baker K; Redman M; Wu C; Heinzerling TJ; Wirtz RM; Charalambous E; Pentheroudakis G; Kotoula V; Kalogeras KT; Fountzilas G; Grady WM
[Ad] Endereço:Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.
[Ti] Título:The CpG island methylator phenotype is concordant between primary colorectal carcinoma and matched distant metastases.
[So] Source:Clin Epigenetics;9:46, 2017.
[Is] ISSN:1868-7083
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The CpG island methylator phenotype (CIMP) in stage III colon cancer (CRC) has been associated with improved survival after treatment with adjuvant irinotecan-based chemotherapy. In this analysis, we determine whether CIMP status in the primary CRC is concordant with the CIMP status of matched metastases in order to determine if assessment of CIMP status in the primary tumor can be used to predict CIMP status of metastatic disease, which is relevant for patient management as well as for understanding the biology of CIMP CRCs. METHODS: We assessed the CIMP status of 70 pairs of primary CRC and matched metastases using a CRC-specific panel of five markers ( , , , , and ) where CIMP positive was defined as 3/5 positive markers at a percent methylated reference threshold of ≥10%. Concordance was compared using the Fisher's exact test and < 0.05 was considered significant. RESULTS: Sixty-nine of the pairs (98.6%) showed concordant CIMP status in the primary tumor and matched metastasis; five (7.0%) of the pairs were concordantly CIMP positive. Only one pair (1.4%) had divergent CIMP status, demonstrating CIMP positivity (4/5 markers positive) in the primary tumor, while the matched metastasis was CIMP negative (0 markers positive). CONCLUSIONS: CIMP status is generally concordant between primary CRCs and matched metastases. Thus, CIMP status in the primary tumor is maintained in matched metastases and can be used to inform CIMP-based therapy options for the metastases.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Neoplasias Colorretais/genética
Metilação de DNA
[Mh] Termos MeSH secundário: Adulto
Idoso
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Canais de Cálcio Tipo T/genética
Neoplasias Colorretais/patologia
Subunidade alfa 3 de Fator de Ligação ao Core/genética
Ilhas de CpG
Epigênese Genética
Feminino
Seres Humanos
Fator de Crescimento Insulin-Like II/genética
Masculino
Meia-Idade
Metástase Neoplásica
Proteínas do Tecido Nervoso/genética
Fenótipo
Proteína 1 Supressora da Sinalização de Citocina/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Biomarkers, Tumor); 0 (CACNA1G protein, human); 0 (Calcium Channels, T-Type); 0 (Core Binding Factor Alpha 3 Subunit); 0 (IGF2 protein, human); 0 (NEUROG1 protein, human); 0 (Nerve Tissue Proteins); 0 (Runx3 protein, human); 0 (SOCS1 protein, human); 0 (Suppressor of Cytokine Signaling 1 Protein); 67763-97-7 (Insulin-Like Growth Factor II)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1186/s13148-017-0347-1


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[PMID]:29244185
[Au] Autor:Park KS; Mitra A; Rahat B; Kim K; Pfeifer K
[Ad] Endereço:Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA.
[Ti] Título:Loss of imprinting mutations define both distinct and overlapping roles for misexpression of IGF2 and of H19 lncRNA.
[So] Source:Nucleic Acids Res;45(22):12766-12779, 2017 Dec 15.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Imprinted genes occur in discrete clusters that are coordinately regulated by shared DNA elements called Imprinting Control Regions. H19 and Igf2 are linked imprinted genes that play critical roles in development. Loss of imprinting (LOI) at the IGF2/H19 locus on the maternal chromosome is associated with the developmental disorder Beckwith Wiedemann Syndrome (BWS) and with several cancers. Here we use comprehensive genetic and genomic analyses to follow muscle development in a mouse model of BWS to dissect the separate and shared roles for misexpression of Igf2 and H19 in the disease phenotype. We show that LOI results in defects in muscle differentiation and hypertrophy and identify primary downstream targets: Igf2 overexpression results in over-activation of MAPK signaling while loss of H19 lncRNA prevents normal down regulation of p53 activity and therefore results in reduced AKT/mTOR signaling. Moreover, we demonstrate instances where H19 and Igf2 misexpression work separately, cooperatively, and antagonistically to establish the developmental phenotype. This study thus identifies new biochemical roles for the H19 lncRNA and underscores that LOI phenotypes are multigenic so that complex interactions will contribute to disease outcomes.
[Mh] Termos MeSH primário: Síndrome de Beckwith-Wiedemann/genética
Impressão Genômica
Fator de Crescimento Insulin-Like II/genética
Mutação
RNA Longo não Codificante/genética
[Mh] Termos MeSH secundário: Animais
Síndrome de Beckwith-Wiedemann/metabolismo
Diferenciação Celular/genética
Células Cultivadas
Modelos Animais de Doenças
Perfilação da Expressão Gênica/métodos
Seres Humanos
Fator de Crescimento Insulin-Like II/metabolismo
Camundongos
Músculo Esquelético/metabolismo
Mioblastos/citologia
Mioblastos/metabolismo
RNA Longo não Codificante/metabolismo
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (H19 long non-coding RNA); 0 (RNA, Long Noncoding); 67763-97-7 (Insulin-Like Growth Factor II)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180115
[Lr] Data última revisão:
180115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx896


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[PMID]:29175438
[Au] Autor:Ahmed RG; El-Gareib AW; Shaker HM
[Ad] Endereço:Division of Anatomy and Embryology, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt. Electronic address: r_g_a_ahmed@science.bsu.edu.eg.
[Ti] Título:Gestational 3,3',4,4',5-pentachlorobiphenyl (PCB 126) exposure disrupts fetoplacental unit: Fetal thyroid-cytokines dysfunction.
[So] Source:Life Sci;192:213-220, 2018 Jan 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Exposure to polychlorinated biphenyls (PCBs) is related to several endocrine disorders. This study examined the effect of maternal exposure of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on the fetoplacental unit and fetal thyroid-cytokine axis during the pregnancy. Pregnant albino rats received PCB 126 (20 or 40µg/kgb.wt.) by oral gavage from gestation day (GD) 1 to 20. Potential effects of PCB 126 were evaluated by following the histopathological changes in the placenta by Haematoxylin and Eosin (H&E) stain and measuring the maternofetal thyroid axis (ELIZA), maternofetal body weight, and fetal growth markers (ELIZA), and cytokines (ELIZA) at embryonic day (ED) 20. Placental tissues of both treated groups showed hyperemia, hemorrhage, degeneration and apoptosis in labyrinth layer and spiral artery at GD 20. Both administrations of PCB 126 elevated serum thyrotropin (TSH) concentration, and decreased free thyroxine (FT4) and free triiodothyronine (FT3) concentrations, resulting in a maternofetal hypothyroidism. The presence of hypothyroidism increased fetal serum concentration of transforming growth factor-ß (TGF-ß), leptin (LEP), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and decreased the fetal serum insulin growth factor-I (IGF-I), IGF-II, insulin, adiponectin (ADP), and growth hormone (GH) in both treated groups at ED 20. However, the increase in resistin (RETN) and interferon-γ (IFN-γ) was non-significant in low-dose group and highly significant in high-dose group. Simultaneously, the reduction in body weight of the dams and fetuses was observed in both PCB 126 groups of examined day with respect to the control group. The maternal PCB 126 distorted the fetoplacental unit might disrupt the fetal thyroid-cytokines axis and prenatal development.
[Mh] Termos MeSH primário: Citocinas/metabolismo
Poluentes Ambientais/toxicidade
Feto/efeitos dos fármacos
Placenta/efeitos dos fármacos
Bifenilos Policlorados/toxicidade
Doenças da Glândula Tireoide/induzido quimicamente
[Mh] Termos MeSH secundário: Adiponectina/biossíntese
Animais
Peso Corporal/efeitos dos fármacos
Feminino
Peso Fetal/efeitos dos fármacos
Feto/metabolismo
Hormônio do Crescimento/biossíntese
Fator de Crescimento Insulin-Like I/biossíntese
Fator de Crescimento Insulin-Like II/biossíntese
Placenta/metabolismo
Placenta/patologia
Gravidez
Ratos
Ratos Wistar
Tireotropina/sangue
Tiroxina/sangue
Tri-Iodotironina/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adiponectin); 0 (Cytokines); 0 (Environmental Pollutants); 0 (insulin-like growth factor II, rat); 0 (insulin-like growth factor-1, rat); 06LU7C9H1V (Triiodothyronine); 67763-96-6 (Insulin-Like Growth Factor I); 67763-97-7 (Insulin-Like Growth Factor II); 9002-71-5 (Thyrotropin); 9002-72-6 (Growth Hormone); DFC2HB4I0K (Polychlorinated Biphenyls); Q51BO43MG4 (Thyroxine); TSH69IA9XF (3,4,5,3',4'-pentachlorobiphenyl)
[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:171128
[St] Status:MEDLINE


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[PMID]:29244844
[Au] Autor:Gschwantler-Kaulich D; Weingartshofer S; Rappaport-Fürhauser C; Zeilinger R; Pils D; Muhr D; Braicu EI; Kastner MT; Tan YY; Semmler L; Sehouli J; Singer CF
[Ad] Endereço:Department of Obstetrics and Gynecology, Cancer Comprehensive Center, Medical University Vienna, Vienna, Austria.
[Ti] Título:Diagnostic markers for the detection of ovarian cancer in BRCA1 mutation carriers.
[So] Source:PLoS One;12(12):e0189641, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Screening for ovarian cancer (OC) in women at high risk consists of a combination of carbohydrate antigen 125 (CA125) and transvaginal ultrasound, despite their low sensitivity and specificity. This could be improved by the combination of several biomarkers, which has been shown in average risk patients but has not been investigated until now in female BRCA mutation carriers. METHODS: Using a multiplex, bead-based, immunoassay system, we analyzed the concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, CA125 and human epididymis antigen 4 in 26 healthy wild type women, 26 healthy BRCA1 mutation carriers, 28 wildtype OC patients and 26 OC patients with BRCA1 mutation. RESULTS: Using the ROC analysis, we found a high overall sensitivity of 94.3% in differentiating healthy controls from OC patients with comparable results in the wildtype subgroup (sensitivity 92.8%, AUC = 0.988; p = 5.2e-14) as well as in BRCA1 mutation carriers (sensitivity 95.2%, AUC = 0.978; p = 1.7e-15) at an overall specificity of 92.3%. The used algorithm also allowed to identify healthy BRCA1 mutation carriers when compared to healthy wildtype women (sensitivity 88.4%, specificity 80.7%, AUC = 0.895; p = 6e-08), while this was less pronounced in patients with OC (sensitivity 66.7%, specificity 67.8%, AUC = 0.724; p = 0.00065). CONCLUSION: We have developed an algorithm, which can differentiate between healthy women and OC patients and have for the first time shown, that such an algorithm can also be used in BRCA mutation carriers. To clarify a suggested benefit to the existing early detection program, large prospective trials with mainly early stage OC cases are warranted.
[Mh] Termos MeSH primário: Proteína BRCA1/genética
Biomarcadores Tumorais/sangue
Detecção Precoce de Câncer
Neoplasias Ovarianas/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Biomarcadores Tumorais/genética
Antígeno Ca-125/sangue
Feminino
Seres Humanos
Fator de Crescimento Insulin-Like II/genética
Leptina/sangue
Meia-Idade
Mutação
Osteopontina/sangue
Neoplasias Ovarianas/sangue
Neoplasias Ovarianas/patologia
Prolactina/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (Biomarkers, Tumor); 0 (CA-125 Antigen); 0 (Leptin); 0 (SPP1 protein, human); 0 (human epithelial antigen-125); 106441-73-0 (Osteopontin); 67763-97-7 (Insulin-Like Growth Factor II); 9002-62-4 (Prolactin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189641


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[PMID]:28987236
[Au] Autor:Perng W; Rifas-Shiman SL; McCulloch S; Chatzi L; Mantzoros C; Hivert MF; Oken E
[Ad] Endereço:Department of Nutritional Sciences, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. Electronic address: perngwei@umich.edu.
[Ti] Título:Associations of cord blood metabolites with perinatal characteristics, newborn anthropometry, and cord blood hormones in project viva.
[So] Source:Metabolism;76:11-22, 2017 Nov.
[Is] ISSN:1532-8600
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Metabolomics has emerged as a powerful tool to characterize biomarkers and elucidate physiological processes underlying adverse health outcomes. Little is known of these relationships during gestation and infancy, which are critical period for development of metabolic disease risk. OBJECTIVES: To identify cord blood metabolite patterns associated with birth size; and to investigate relations of the birth size-associated metabolite patterns, and a branched chain amino acid (BCAA) metabolite pattern with a range of newborn and perinatal characteristics. METHODS: Using untargeted mass-spectrometry, we quantified metabolites in cord blood of 126 mother-child pairs. After excluding 103 xenobiotics, we used principal components analysis (PCA) to consolidate the remaining 606 metabolites into principal components ("factors"). Next, we identified factors associated with gestational age-and sex-standardized birthweight z-score (BW/GA) and examined associations of the BW/GA-associated pattern(s) and the BCAA pattern with cord blood insulin, leptin, adiponectin, insulin-like growth factor (IGF)-1, IGF-2, and IGF binding protein 3 (IGFBP-3) using multivariable linear regression. Finally, we examined associations of maternal/perinatal characteristics with the cord blood metabolite patterns. RESULTS: Mean BW/GA z-score was 0.27±0.98 units. About half of the infants were male (52.4%) and white (57.1%). Of the 6 factors identified from PCA, one was associated with higher BW/GA: Factor 5, which comprised metabolites involved in energy production (malate, succinate, fumarate) and nucleotide turnover (inosine 5-monophosphate, adenosine 5-monophosphate, cytidine 5-monophosphate) pathways. In multivariable analysis, Factor 5 was related to higher cord blood leptin (1.64 [95% CI: 0.42, 2.87] ng/mL) and IGF-1 even after adjusting for IGFBP-3 (3.35 [0.25, 6.44] ng/mL). The BCAA pattern was associated with higher BW/GA (0.20 [0.03, 0.36] z-scores) and IGFBP-3 (106.5 [44.7, 168.2] ng/mL). No maternal characteristics were associated with either metabolite pattern; however, infants born via Cesarean delivery exhibited a higher score for Factor 5, and gestation length was inversely associated with the BCAA pattern. CONCLUSIONS: Metabolites in energy production and DNA/RNA turnover pathways in cord blood are associated with larger size at birth, and higher leptin and IGF-1. Similarly, the BCAA pattern was associated with larger birth size and IGFBP-3.
[Mh] Termos MeSH primário: Adiponectina/sangue
Peso ao Nascer/fisiologia
Sangue Fetal/metabolismo
Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue
Fator de Crescimento Insulin-Like II/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Insulina/sangue
Leptina/sangue
[Mh] Termos MeSH secundário: Antropometria
Índice de Massa Corporal
Feminino
Idade Gestacional
Seres Humanos
Recém-Nascido
Masculino
Espectrometria de Massas
Metabolômica
Gravidez
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adiponectin); 0 (Insulin); 0 (Insulin-Like Growth Factor Binding Protein 3); 0 (Leptin); 67763-96-6 (Insulin-Like Growth Factor I); 67763-97-7 (Insulin-Like Growth Factor II)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171009
[St] Status:MEDLINE


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[PMID]:28974642
[Au] Autor:Uchimura T; Hollander JM; Nakamura DS; Liu Z; Rosen CJ; Georgakoudi I; Zeng L
[Ad] Endereço:Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, 136 Harrison Avenue, Boston, MA 02111, USA.
[Ti] Título:An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth.
[So] Source:Development;144(19):3533-3546, 2017 10 01.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Postnatal bone growth involves a dramatic increase in length and girth. Intriguingly, this period of growth is independent of growth hormone and the underlying mechanism is poorly understood. Recently, an mutation was identified in humans with early postnatal growth restriction. Here, we show that IGF2 is essential for longitudinal and appositional murine postnatal bone development, which involves proper timing of chondrocyte maturation and perichondrial cell differentiation and survival. Importantly, the null mouse model does not represent a simple delay of growth but instead uncoordinated growth plate development. Furthermore, biochemical and two-photon imaging analyses identified elevated and imbalanced glucose metabolism in the null mouse. Attenuation of glycolysis rescued the mutant phenotype of premature cartilage maturation, thereby indicating that IGF2 controls bone growth by regulating glucose metabolism in chondrocytes. This work links glucose metabolism with cartilage development and provides insight into the fundamental understanding of human growth abnormalities.
[Mh] Termos MeSH primário: Desenvolvimento Ósseo/genética
Cartilagem/embriologia
Cartilagem/metabolismo
Condrogênese
Glucose/metabolismo
Fator de Crescimento Insulin-Like II/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Diferenciação Celular
Condrócitos/metabolismo
Condrócitos/patologia
Condrogênese/genética
Regulação da Expressão Gênica no Desenvolvimento
Glicólise
Lâmina de Crescimento/metabolismo
Lâmina de Crescimento/patologia
Hipertrofia
Camundongos
Modelos Biológicos
Mutação/genética
Técnicas de Cultura de Órgãos
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
67763-97-7 (Insulin-Like Growth Factor II); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1242/dev.155598


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[PMID]:28972999
[Au] Autor:Mohammed RH; Anderton H; Brameld JM; Sweetman D
[Ad] Endereço:School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom.
[Ti] Título:Effects of insulin like growth factors on early embryonic chick limb myogenesis.
[So] Source:PLoS One;12(10):e0185775, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Limb muscles derive from pax3 expressing precursor cells that migrate from the hypaxial somite into the developing limb bud. Once there they begin to differentiate and express muscle determination genes such as MyoD. This process is regulated by a combination of inductive or inhibitory signals including Fgf18, retinoic acid, HGF, Notch and IGFs. IGFs are well known to affect late stages of muscle development and to promote both proliferation and differentiation. We examined their roles in early stage limb bud myogenesis using chicken embryos as an experimental model. Grafting beads soaked in purified recombinant IGF-I, IGF-II or small molecule inhibitors of specific signaling pathways into developing chick embryo limbs showed that both IGF-I and IGF-II induce expression of the early stage myogenic markers pax3 and MyoD as well as myogenin. Their effects on pax3 and MyoD expression were blocked by inhibitors of both the IGF type I receptor (picropodophyllotoxin, PPP) and MEK (U0126). The PI3K inhibitor LY294002 blocked IGF-II, but not IGF-I, induction of pax3 mRNA as well as the IGF-I, but not IGF-II, induction of MyoD mRNA. In addition SU5402, an FGFR/ VEGFR inhibitor, blocked the induction of MyoD by both IGFs but had no effect on pax3 induction, suggesting a role for FGF or VEGF signaling in their induction of MyoD. This was confirmed by in situ hybridization showing that FGF18, a known regulator of MyoD in limb myoblasts, was induced by IGF-I. In addition to their well-known effects on later stages of myogenesis via their induction of myogenin expression, both IGF-I and IGF-II induced pax3 and MyoD expression in developing chick embryos, indicating that they also regulate early stages of myogenesis. The data suggests that the IGFs may have slightly different effects on IGF1R signal transduction via PI3K and that their stimulatory effects on MyoD expression may be indirect, possibly via induction of FGF18 expression.
[Mh] Termos MeSH primário: Embrião de Galinha/efeitos dos fármacos
Membro Posterior/efeitos dos fármacos
Fator de Crescimento Insulin-Like II/farmacologia
Fator de Crescimento Insulin-Like I/farmacologia
Desenvolvimento Muscular/efeitos dos fármacos
Músculo Esquelético/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Butadienos/farmacologia
Embrião de Galinha/metabolismo
Cromonas/farmacologia
Inibidores Enzimáticos/farmacologia
Fatores de Crescimento de Fibroblastos/genética
Fatores de Crescimento de Fibroblastos/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Membro Posterior/metabolismo
Morfolinas/farmacologia
Desenvolvimento Muscular/fisiologia
Músculo Esquelético/metabolismo
Proteína MyoD/genética
Proteína MyoD/metabolismo
Miogenina/genética
Miogenina/metabolismo
Nitrilos/farmacologia
Fator de Transcrição PAX3/genética
Fator de Transcrição PAX3/metabolismo
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Podofilotoxina/análogos & derivados
Podofilotoxina/farmacologia
Pirróis/farmacologia
Receptor IGF Tipo 1/antagonistas & inibidores
Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Butadienes); 0 (Chromones); 0 (Enzyme Inhibitors); 0 (Morpholines); 0 (MyoD Protein); 0 (Myogenin); 0 (Nitriles); 0 (PAX3 Transcription Factor); 0 (Pyrroles); 0 (SU 5402); 0 (U 0126); 0 (fibroblast growth factor 18); 0F35AOI227 (picropodophyllin); 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one); 62031-54-3 (Fibroblast Growth Factors); 67763-96-6 (Insulin-Like Growth Factor I); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (Receptor, IGF Type 1); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor); L36H50F353 (Podophyllotoxin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185775


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[PMID]:28954282
[Au] Autor:Andersson MK; Afshari MK; Andrén Y; Wick MJ; Stenman G
[Ad] Endereço:Sahlgrenska Cancer Center, Department of Pathology and Genetics, University of Gothenburg, Gothenburg, Sweden; Preclinical Research, South Texas Accelerated Research Therapeutics, San Antonio, TX.
[Ti] Título:Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling.
[So] Source:J Natl Cancer Inst;109(9), 2017 Sep 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Adenoid cystic carcinoma (ACC) is an aggressive cancer with no curative treatment for patients with recurrent/metastatic disease. The MYB-NFIB gene fusion is the main genomic hallmark and a potential therapeutic target. Methods: Oncogenic signaling pathways were studied in cultured cells and/or tumors from 15 ACC patients. Phospho-receptor tyrosine kinase (RTK) arrays were used to study the activity of RTKs. Effects of RTK inhibition on cell proliferation were analyzed with AlamarBlue, sphere assays, and two ACC xenograft models (n = 4-9 mice per group). The molecular effects of MYB-NFIB knockdown and IGF1R inhibition were studied with quantitative polymerase chain reaction, immunoblot, and gene expression microarrays. All statistical tests were two-sided. Results: The MYB-NFIB fusion drives proliferation of ACC cells and is crucial for spherogenesis. Intriguingly, the fusion is regulated through AKT-dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control ± SD = 27.2 ± 1.3, P < .001). MYB-NFIB regulates genes involved in cell cycle control, DNA replication/repair, and RNA processing. The transcriptional program induced by MYB-NFIB affects critical oncogenic mediators normally controlled by MYC and is reversed by pharmacological inhibition of IGF1R. Co-activation of epidermal growth factor receptor (EGFR) and MET promoted proliferation of ACC cells, and combined targeting of IGFR1/EGFR/MET induced differentiation and synergistically inhibited the growth of patient-derived xenografted ACCs (ACCX5M1, % growth of control ± SD = 34.9 ± 20.3, P = .006; ACCX6, % growth of control ± SD = 24.1 ± 17.5, P = .04). Conclusions: MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.
[Mh] Termos MeSH primário: Carcinoma Adenoide Cístico/genética
Carcinoma Adenoide Cístico/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas c-myb/metabolismo
Receptores de Somatomedina/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Apoptose
Biomarcadores Tumorais
Carcinoma Adenoide Cístico/tratamento farmacológico
Carcinoma Adenoide Cístico/patologia
Ciclo Celular
Proliferação Celular/genética
Análise por Conglomerados
Modelos Animais de Doenças
Feminino
Perfilação da Expressão Gênica
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Fator de Crescimento Insulin-Like II/farmacologia
Masculino
Meia-Idade
Gradação de Tumores
Proteínas de Fusão Oncogênicas/genética
Proteínas de Fusão Oncogênicas/metabolismo
Fosforilação
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-myb/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-myb/genética
Transdução de Sinais/efeitos dos fármacos
Transcrição Genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (IGF1R protein, human); 0 (MYB-NFIB fusion protein, human); 0 (Oncogene Proteins, Fusion); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins c-myb); 0 (Receptors, Somatomedin); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx017


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[PMID]:28934637
[Au] Autor:Liefers-Visser JAL; Meijering RAM; Reyners AKL; van der Zee AGJ; de Jong S
[Ad] Endereço:Department of Medical Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
[Ti] Título:IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.
[So] Source:Cancer Treat Rev;60:90-99, 2017 Nov.
[Is] ISSN:1532-1967
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Fator de Crescimento Insulin-Like II/efeitos dos fármacos
Terapia de Alvo Molecular/métodos
Neoplasias Ovarianas/tratamento farmacológico
[Mh] Termos MeSH secundário: Feminino
Seres Humanos
Fator de Crescimento Insulin-Like II/metabolismo
Neoplasias Ovarianas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (IGF2 protein, human); 67763-97-7 (Insulin-Like Growth Factor II)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE


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[PMID]:28873464
[Au] Autor:Cedano Prieto DM; Cheng Y; Chang CC; Yu J; Takada YK; Takada Y
[Ad] Endereço:Department of Dermatology, Biochemistry and Molecular Medicine, UC Davis School of Medicine, Research III Suite, 4645 Second Avenue, Sacramento, CA, United States of America.
[Ti] Título:Direct integrin binding to insulin-like growth factor-2 through the C-domain is required for insulin-like growth factor receptor type 1 (IGF1R) signaling.
[So] Source:PLoS One;12(9):e0184285, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have reported that integrins crosstalk with growth factors through direct binding to growth factors (e.g., fibroblast growth factor-1, insulin-like growth factor 1 (IGF1), neuregulin-1, fractalkine) and subsequent ternary complex formation with cognate receptor [e.g., integrin/IGF1/IGF1 receptor (IGF1R)]. IGF1 and IGF2 are overexpressed in cancer and major therapeutic targets. We previously reported that IGF1 binds to integrins ανß3 and α6ß4, and the R36E/R37E mutant in the C-domain of IGF1 is defective integrin binding and signaling functions of IGF1, and acts as an antagonist of IGF1R. We studied if integrins play a role in the signaling functions of IGF2, another member of the IGF family. Here we describe that IGF2 specifically binds to integrins ανß3 and α6ß4, and induced proliferation of CHO cells (IGF1R+) that express ανß3 or α6ß4 (ß3- or α6ß4-CHO cells). Arg residues to Glu at positions 24, 34, 37 and/or 38 in or close to the C-domain of IGF2 play a critical role in binding to integrins and signaling functions. The R24E/R37E/R38E, R34E/R37E/R38E, and R24E/R34E/R37E/R38E mutants were defective in integrin binding and IGF2 signaling. These mutants suppressed proliferation induced by WT IGF2, suggesting that they are dominant-negative antagonists of IGF1R. These results suggest that IGF2 also requires integrin binding for signaling functions, and the IGF2 mutants that cannot bind to integrins act as antagonists of IGF1R. The present study defines the role of the C-domain in integrin binding and signaling.
[Mh] Termos MeSH primário: Fator de Crescimento Insulin-Like II/química
Fator de Crescimento Insulin-Like II/metabolismo
Integrina alfa6beta4/metabolismo
Integrina alfaVbeta3/metabolismo
Receptor IGF Tipo 1/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Células CHO
Linhagem Celular Tumoral
Proliferação Celular
Cricetinae
Cricetulus
Seres Humanos
Proteínas Mutantes
Ligação Proteica
Domínios Proteicos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin alpha6beta4); 0 (Integrin alphaVbeta3); 0 (Mutant Proteins); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184285



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