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Ugrinowitsch, Carlos
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[PMID]:29324825
[Au] Autor:Damas F; Libardi CA; Ugrinowitsch C; Vechin FC; Lixandrão ME; Snijders T; Nederveen JP; Bacurau AV; Brum P; Tricoli V; Roschel H; Parise G; Phillips SM
[Ad] Endereço:School of Physical Education and Sport, University of São Paulo, São Paulo, São Paulo, Brazil.
[Ti] Título:Early- and later-phases satellite cell responses and myonuclear content with resistance training in young men.
[So] Source:PLoS One;13(1):e0191039, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Satellite cells (SC) are associated with skeletal muscle remodelling after muscle damage and/or extensive hypertrophy resulting from resistance training (RT). We recently reported that early increases in muscle protein synthesis (MPS) during RT appear to be directed toward muscle damage repair, but MPS contributes to hypertrophy with progressive muscle damage attenuation. However, modulations in acute-chronic SC content with RT during the initial (1st-wk: high damage), early (3rd-wk: attenuated damage), and later (10th-wk: no damage) stages is not well characterized. Ten young men (27 ± 1 y, 23.6 ± 1.0 kg·m-2) underwent 10-wks of RT and muscle biopsies (vastus-lateralis) were taken before (Pre) and post (48h) the 1st (T1), 5th (T2) and final (T3) RT sessions to evaluate fibre type specific SC content, cross-sectional area (fCSA) and myonuclear number by immunohistochemistry. We observed RT-induced hypertrophy after 10-wks of RT (fCSA increased ~16% in type II, P < 0.04; ~8% in type I [ns]). SC content increased 48h post-exercise at T1 (~69% in type I [P = 0.014]; ~42% in type II [ns]), and this increase was sustained throughout RT (pre T2: ~65%, ~92%; pre T3: ~30% [ns], ~87%, for the increase in type I and II, respectively, vs. pre T1 [P < 0.05]). Increased SC content was not coupled with changes in myonuclear number. SC have a more pronounced role in muscle repair during the initial phase of RT than muscle hypertrophy resulted from 10-wks RT in young men. Chronic elevated SC pool size with RT is important providing proper environment for future stresses or larger fCSA increases.
[Mh] Termos MeSH primário: Núcleo Celular/metabolismo
Proteínas Musculares/metabolismo
Células Satélites de Músculo Esquelético/fisiologia
Levantamento de Peso
[Mh] Termos MeSH secundário: Adulto
Seres Humanos
Masculino
Células Satélites de Músculo Esquelético/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Muscle Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191039


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[PMID]:29287879
[Au] Autor:Niu Z; Yan D; Bressler S; Mei L; Feng Y; Liu X
[Ad] Endereço:Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
[Ti] Título:A novel splicing mutation in SMPX is linked to nonsyndromic progressive hearing loss.
[So] Source:Int J Pediatr Otorhinolaryngol;104:47-50, 2018 Jan.
[Is] ISSN:1872-8464
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: X-linked nonsyndromic hearing impairment is the rarest form of genetic hearing loss and represents only a minor fraction of all cases. The aim of this study was to investigate the cause of X-linked nonsyndromic sensorineural hearing loss in a three-generation American family. METHODS: Whole-exome sequencing and co-segregation analysis were used to identify disease-causing genes. RESULTS: In this study, we described in detail the clinical characteristics of the family and identified a novel frameshift mutation creating a premature stop codon (c.133-1 G > A, p.(Gly45fs*36)) of SMPX. The loss-of-function mutation was co-segregated with the progressive hearing loss phenotype and was absent in 200 normal controls. CONCLUSIONS: We report the first SMPX (DFNX4) mutation in a North American family. Our findings contribute to the existing genotypic and phenotypic spectrum of SMPX associated hearing loss. Furthermore, our data suggest that exome sequencing is promising in the genetic diagnosis of hearing loss.
[Mh] Termos MeSH primário: Surdez/genética
Doenças Genéticas Ligadas ao Cromossomo X/genética
Perda Auditiva Neurossensorial/genética
Proteínas Musculares/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Criança
Códon sem Sentido
Feminino
Mutação da Fase de Leitura
Genótipo
Seres Humanos
Masculino
Meia-Idade
Linhagem
Processamento de RNA
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Codon, Nonsense); 0 (Muscle Proteins); 0 (SMPX protein, human)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171231
[St] Status:MEDLINE


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Registro de Ensaios Clínicos
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[PMID]:29200982
[Au] Autor:Hamarsland H; Nordengen AL; Nyvik Aas S; Holte K; Garthe I; Paulsen G; Cotter M; Børsheim E; Benestad HB; Raastad T
[Ad] Endereço:Department of Physical Performance, Norwegian School of Sport Sciences, P.O. Box 4014 Ullevål Stadion, 0806 Oslo, Norway.
[Ti] Título:Native whey protein with high levels of leucine results in similar post-exercise muscular anabolic responses as regular whey protein: a randomized controlled trial.
[So] Source:J Int Soc Sports Nutr;14:43, 2017.
[Is] ISSN:1550-2783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Protein intake is essential to maximally stimulate muscle protein synthesis, and the amino acid leucine seems to possess a superior effect on muscle protein synthesis compared to other amino acids. Native whey has higher leucine content and thus a potentially greater anabolic effect on muscle than regular whey (WPC-80). This study compared the acute anabolic effects of ingesting 2 × 20 g of native whey protein, WPC-80 or milk protein after a resistance exercise session. Methods: 24 young resistance trained men and women took part in this double blind, randomized, partial crossover, controlled study. Participants received either WPC-80 and native whey ( = 10), in a crossover design, or milk ( = 12). Supplements were ingested immediately (20 g) and two hours after (20 g) a bout of heavy-load lower body resistance exercise. Blood samples and muscle biopsies were collected to measure plasma concentrations of amino acids by gas-chromatography mass spectrometry, muscle phosphorylation of p70S6K, 4E-BP1 and eEF-2 by immunoblotting, and mixed muscle protein synthesis by use of [ H ]phenylalanine-infusion, gas-chromatography mass spectrometry and isotope-ratio mass spectrometry. Being the main comparison, differences between native whey and WPC-80 were analysed by a one-way ANOVA and comparisons between the whey supplements and milk were analysed by a two-way ANOVA. Results: Native whey increased blood leucine concentrations more than WPC-80 and milk ( < 0.05). Native whey ingestion induced a greater phosphorylation of p70S6K than milk 180 min after exercise ( = 0.03). Muscle protein synthesis rates increased 1-3 h hours after exercise with WPC-80 (0.119%), and 1-5 h after exercise with native whey (0.112%). Muscle protein synthesis rates were higher 1-5 h after exercise with native whey than with milk (0.112% vs. 0.064, = 0.023). Conclusions: Despite higher-magnitude increases in blood leucine concentrations with native whey, it was not superior to WPC-80 concerning effect on muscle protein synthesis and phosphorylation of p70S6K during a 5-h post-exercise period. Native whey increased phosphorylation of p70S6K and muscle protein synthesis rates to a greater extent than milk during the 5-h post exercise period. Trial registration: This study was retrospectively registered at clinicaltrials.gov as NCT02968888.
[Mh] Termos MeSH primário: Suplementos Nutricionais
Leucina/análise
Músculo Esquelético/efeitos dos fármacos
Treinamento de Resistência
Fenômenos Fisiológicos da Nutrição Esportiva
Proteínas do Soro do Leite/química
Proteínas do Soro do Leite/farmacologia
[Mh] Termos MeSH secundário: Estudos Cross-Over
Método Duplo-Cego
Feminino
Voluntários Saudáveis
Seres Humanos
Leucina/farmacologia
Masculino
Proteínas Musculares/biossíntese
Músculo Esquelético/fisiologia
Biossíntese de Proteínas/efeitos dos fármacos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Muscle Proteins); 0 (Whey Proteins); GMW67QNF9C (Leucine)
[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:171205
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1186/s12970-017-0202-y


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[PMID]:28464919
[Au] Autor:Toth C; Funke S; Nitsche V; Liverts A; Zlachevska V; Gasis M; Wiek C; Hanenberg H; Mahotka C; Schirmacher P; Heikaus S
[Ad] Endereço:Institute of Pathology, Heinrich Heine University Hospital, Medical Faculty, Moorenstrasse 5, 40225, Düsseldorf, Germany. csaba.toth@med.uni-heidelberg.de.
[Ti] Título:The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.
[So] Source:Cell Commun Signal;15(1):16, 2017 May 02.
[Is] ISSN:1478-811X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). METHODS: Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. RESULTS: Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. CONCLUSION: Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic and intrinsic pathways of apoptosis in RCCs. In this context, ARC cooperates with anti-apoptotic Bcl-2 family members to exert its strong anti-apoptotic effects and is therefore an important factor not only in the therapeutic resistance but also in future therapy strategies (i.e., Bcl-2 inhibitors) in RCC. In sum, targeting of ARC may enhance the therapeutic response in combination therapy protocols.
[Mh] Termos MeSH primário: Proteínas Reguladoras de Apoptose/metabolismo
Apoptose/efeitos dos fármacos
Carcinoma de Células Renais/patologia
Resistência a Medicamentos Antineoplásicos
Neoplasias Renais/patologia
Proteínas Musculares/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Compostos de Anilina/farmacologia
Proteínas Reguladoras de Apoptose/deficiência
Proteínas Reguladoras de Apoptose/genética
Linhagem Celular Tumoral
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/metabolismo
Citoplasma/efeitos dos fármacos
Citoplasma/metabolismo
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Seres Humanos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/patologia
Terapia de Alvo Molecular
Proteínas Musculares/deficiência
Proteínas Musculares/genética
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Sulfonamidas/farmacologia
Topotecan/farmacologia
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Apoptosis Regulatory Proteins); 0 (Muscle Proteins); 0 (NOL3 protein, human); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Sulfonamides); 0 (Tumor Suppressor Protein p53); 7M7YKX2N15 (Topotecan); XKJ5VVK2WD (navitoclax)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12964-017-0170-5


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[PMID]:28468631
[Au] Autor:Lakhdar R; Drost EM; MacNee W; Bastos R; Rabinovich RA
[Ad] Endereço:ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
[Ti] Título:2D-DIGE proteomic analysis of vastus lateralis from COPD patients with low and normal fat free mass index and healthy controls.
[So] Source:Respir Res;18(1):81, 2017 May 03.
[Is] ISSN:1465-993X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with several extra-pulmonary effects of which skeletal muscle wasting is one of the most common and contributes to reduced quality of life, increased morbidity and mortality. The molecular mechanisms leading to muscle wasting are not fully understood. Proteomic analysis of human skeletal muscle is a useful approach for gaining insight into the molecular basis for normal and pathophysiological conditions. METHODS: To identify proteins involved in the process of muscle wasting in COPD, we searched differentially expressed proteins in the vastus lateralis of COPD patients with low fat free mass index (FFMI), as a surrogate of muscle mass (COPD n = 10) (FEV 33 ± 4.3% predicted, FFMI 15 ± 0.2 Kg.m ), in comparison to patients with COPD and normal FFMI (COPD n = 8) and a group of age, smoking history, and sex matched healthy controls (C, n = 9) using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) technology, combined with mass spectrometry (MS). The effect of silencing DOT1L protein expression on markers of cell arrest was analyzed in skeletal muscle satellite cells (HSkMSCs) in vitro and assessed by qPCR and Western blotting. RESULTS: A subset of 7 proteins was differentially expressed in COPD compared to both COPD and C. We found an increased expression of proteins associated with muscle homeostasis and protection against oxidative stress, and a decreased expression of structural muscle proteins and proteins involved in myofibrillogenesis, cell proliferation, cell cycle arrest and energy production. Among these was a decreased expression of the histone methyltransferase DOT1L. In addition, silencing of the DOT1L gene in human skeletal muscle satellite cells in vitro was significantly related to up regulation of p21 /CDKN1A, a marker of cell arrest and ageing. CONCLUSIONS: 2D-DIGE coupled with MS identified differences in the expression of several proteins in the wasted vastus lateralis that are relevant to the disease process. Down regulation of DOT1L in the vastus lateralis of COPD patients may mediate the muscle wasting process through up regulation of markers of cell arrest and senescence.
[Mh] Termos MeSH primário: Índice de Massa Corporal
Proteínas Musculares/metabolismo
Atrofia Muscular/metabolismo
Proteoma/metabolismo
Doença Pulmonar Obstrutiva Crônica/metabolismo
Músculo Quadríceps/metabolismo
Eletroforese em Gel Diferencial Bidimensional/métodos
[Mh] Termos MeSH secundário: Idoso
Biomarcadores/metabolismo
Feminino
Seres Humanos
Masculino
Atrofia Muscular/etiologia
Atrofia Muscular/patologia
Tamanho do Órgão
Doença Pulmonar Obstrutiva Crônica/complicações
Doença Pulmonar Obstrutiva Crônica/patologia
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Muscle Proteins); 0 (Proteome)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1186/s12931-017-0525-x


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[PMID]:28464882
[Au] Autor:Ceelen JJM; Schols AMWJ; van Hoof SJ; de Theije CC; Verhaegen F; Langen RCJ
[Ad] Endereço:Department of Respiratory Medicine, Maastricht University Medical Center, PO box 5800, 6202 AZ, Maastricht, The Netherlands.
[Ti] Título:Differential regulation of muscle protein turnover in response to emphysema and acute pulmonary inflammation.
[So] Source:Respir Res;18(1):75, 2017 May 02.
[Is] ISSN:1465-993X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Exacerbations in COPD are often accompanied by pulmonary and systemic inflammation, and associated with increased susceptibility to and prevalence of weight loss and muscle wasting. Muscle mass loss during disease exacerbations may contribute to emphysema-associated muscle atrophy. However, whether pulmonary inflammation in presence of emphysema differentially affects skeletal muscle, including protein synthesis and degradation signaling pathways has not previously been addressed. The aims of this study were to 1) develop a mouse model of disease exacerbation-associated muscle wasting, 2) evaluate whether emphysema and muscle wasting can be monitored non-invasively and 3) assess alterations in muscle protein turnover regulation. METHODS: Emphysema was induced by three, weekly intra-tracheal (IT) elastase (E) or vehicle control (vc) instillations, followed by one single IT-LPS bolus (L) or vc instillation to mimic pulmonary inflammation-driven disease exacerbation. Consequently, four experimental groups were defined: vc/vc ('C'), E/vc ('E'), vc/LPS ('L'), E/LPS ('E + L'). Using micro cone-beam CT-scans, emphysema development and muscle mass changes were monitored, and correlated to muscle weight 48 h after LPS instillation. Protein turnover signaling was assessed in muscle tissue collected 24 h post LPS instillation. RESULTS: Micro-CT imaging correlated strongly with established invasive measurements of emphysema and muscle atrophy. Pulmonary inflammation following LPS instillation developed irrespective of emphysema and body and muscle weight were similarly reduced in the 'L' and 'E + L' groups. Accordingly, mRNA and protein expression levels of genes of the ubiquitin-proteasome pathway (UPS) and the autophagy-lysosomal pathway (ALP) were upregulated in skeletal muscle following IT-LPS ('L' and 'E + L'). In contrast, mTOR signaling, which controls ALP and protein synthesis, was reduced by pulmonary inflammation ('L' and 'E + L') as well as emphysema as a single insult ('E') compared to control. CONCLUSION: Changes in lung tissue density and muscle mass can be monitored non-invasively to evaluate emphysema and muscle atrophy longitudinally. Acute loss of muscle mass evoked by pulmonary inflammation is similar in control and emphysematous mice. Although muscle atrophy cues in response to pulmonary inflammation are not altered by emphysema, emphysema itself affects protein synthesis and ALP signaling, which may interfere with muscle mass recovery and impair maintenance of muscle mass in emphysema.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Enfisema/metabolismo
Proteínas Musculares/metabolismo
Músculo Esquelético/metabolismo
Atrofia Muscular/metabolismo
Pneumonia/metabolismo
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Enfisema/complicações
Enfisema/patologia
Regulação da Expressão Gênica
Camundongos
Camundongos Endogâmicos C57BL
Atrofia Muscular/etiologia
Atrofia Muscular/patologia
Pneumonia/complicações
Pneumonia/patologia
Proteólise
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Muscle Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12931-017-0531-z


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[PMID]:28464817
[Au] Autor:Sigurdsson MI; Saddic L; Heydarpour M; Chang TW; Shekar P; Aranki S; Couper GS; Shernan SK; Muehlschlegel JD; Body SC
[Ad] Endereço:Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital/Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA. martiningi@gmail.com.
[Ti] Título:Post-operative atrial fibrillation examined using whole-genome RNA sequencing in human left atrial tissue.
[So] Source:BMC Med Genomics;10(1):25, 2017 May 02.
[Is] ISSN:1755-8794
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Both ambulatory atrial fibrillation (AF) and post-operative AF (poAF) are associated with substantial morbidity and mortality. Analyzing the tissue-specific gene expression in the left atrium (LA) can identify novel genes associated with AF and further the understanding of the mechanism by which previously identified genetic variants associated with AF mediate their effects. METHODS: LA free wall samples were obtained intraoperatively immediately prior to mitral valve surgery in 62 Caucasian individuals. Gene expression was quantified on mRNA harvested from these samples using RNA sequencing. An expression quantitative trait loci (eQTL) analysis was performed, comparing gene expression between different genotypes of 1.0 million genetic markers, emphasizing genomic regions and genes associated with AF. RESULTS: Comparison of whole-genome expression between patients who later developed poAF and those who did not identified 23 differentially expressed genes. These included genes associated with the resting membrane potential modified by potassium currents, as well as genes within Wnt signaling and cyclic GMP metabolism. The eQTL analysis identified 16,139 cis eQTL relationships in the LA, including several involving genes and single nucleotide polymorphisms (SNPs) linked to AF. A previous relationship between rs3744029 and MYOZ1 expression was confirmed, and a novel relationship between rs6795970 and the expression of the SCN10A gene was identified. CONCLUSIONS: The current study is the first analysis of the human LA expression landscape using high-throughput RNA sequencing. Several novel genes and variants likely involved in AF pathogenesis were identified, thus furthering the understanding of how variants associated with AF mediate their effects via altered gene expression. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00833313 , registered 5. January 2009.
[Mh] Termos MeSH primário: Fibrilação Atrial/genética
Regulação da Expressão Gênica
Predisposição Genética para Doença
Átrios do Coração/metabolismo
Polimorfismo de Nucleotídeo Único
Locos de Características Quantitativas
[Mh] Termos MeSH secundário: Idoso
Fibrilação Atrial/metabolismo
Fibrilação Atrial/fisiopatologia
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
GMP Cíclico/metabolismo
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Estudos de Associação Genética
Átrios do Coração/fisiopatologia
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Potenciais da Membrana/genética
Meia-Idade
Proteínas Musculares/genética
Proteínas Musculares/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.8/genética
Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo
Período Pós-Operatório
Análise de Sequência de RNA
Transdução de Sinais/genética
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (MYOZ1 protein, human); 0 (Muscle Proteins); 0 (NAV1.8 Voltage-Gated Sodium Channel); 0 (SCN10A protein, human); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1186/s12920-017-0270-5


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[PMID]:29248133
[Au] Autor:Mikkilineni L; Whitaker-Menezes D; Domingo-Vidal M; Sprandio J; Avena P; Cotzia P; Dulau-Florea A; Gong J; Uppal G; Zhan T; Leiby B; Lin Z; Pro B; Sotgia F; Lisanti MP; Martinez-Outschoorn U
[Ad] Endereço:Department of Medical Oncology, National Cancer Institute, Bethesda, MD.
[Ti] Título:Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment.
[So] Source:Semin Oncol;44(3):218-225, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. METHODS: A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells. RESULTS: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature. CONCLUSION: Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease.
[Mh] Termos MeSH primário: Glicólise
Doença de Hodgkin/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Mitocôndrias/metabolismo
Transportadores de Ácidos Monocarboxílicos/metabolismo
Recidiva Local de Neoplasia/metabolismo
Fosforilação Oxidativa
Receptores de Superfície Celular/metabolismo
Células de Reed-Sternberg/metabolismo
Simportadores/metabolismo
Microambiente Tumoral
[Mh] Termos MeSH secundário: Adulto
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Bleomicina/administração & dosagem
Estudos de Casos e Controles
Dacarbazina/administração & dosagem
Doxorrubicina/administração & dosagem
Feminino
Doença de Hodgkin/tratamento farmacológico
Seres Humanos
Imuno-Histoquímica
Linfócitos do Interstício Tumoral/metabolismo
Macrófagos/metabolismo
Masculino
Meia-Idade
Proteínas Musculares/metabolismo
Indução de Remissão
Vimblastina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Membrane Transport Proteins); 0 (Monocarboxylic Acid Transporters); 0 (Muscle Proteins); 0 (Receptors, Cell Surface); 0 (SLC16A4 protein, human); 0 (Symporters); 0 (TOMM20 protein, human); 0 (monocarboxylate transport protein 1); 11056-06-7 (Bleomycin); 5V9KLZ54CY (Vinblastine); 7GR28W0FJI (Dacarbazine); 80168379AG (Doxorubicin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


  9 / 27492 MEDLINE  
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[PMID]:29248134
[Au] Autor:Monti D; Sotgia F; Whitaker-Menezes D; Tuluc M; Birbe R; Berger A; Lazar M; Cotzia P; Draganova-Tacheva R; Lin Z; Domingo-Vidal M; Newberg A; Lisanti MP; Martinez-Outschoorn U
[Ad] Endereço:Marcus Institute of Integrative Health at Thomas Jefferson University, Philadelphia, PA.
[Ti] Título:Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer.
[So] Source:Semin Oncol;44(3):226-232, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models. N-Acetylcysteine (NAC) is an antioxidant that reduces oxidative stress and reverses stromal catabolism and stromal-carcinoma cell metabolic heterogeneity, resulting in reduced proliferation and increased apoptosis of cancer cells in experimental models of breast cancer. The purpose of this clinical trial was to determine if NAC could reduce markers of stromal-cancer metabolic heterogeneity and markers of cancer cell aggressiveness in human breast cancer. METHODS: Subjects with newly diagnosed stage 0 and I breast cancer who were not going to receive neoadjuvant therapy prior to surgical resection were treated with NAC before definitive surgery to assess intra-tumoral metabolic markers. NAC was administered once a week intravenously at a dose of 150 mg/kg and 600 mg twice daily orally on the days not receiving intravenous NAC. Histochemistry for the stromal metabolic markers monocarboxylate transporter 4 (MCT4) and caveolin-1 (CAV1) and the Ki67 proliferation assay and TUNEL apoptosis assay in carcinoma cells were performed in pre- and post-NAC specimens. RESULTS: The range of days on NAC was 14-27 and the mean was 19 days. Post-treatment biopsies showed significant decrease in stromal MCT4 and reduced Ki67 in carcinoma cells. NAC did not significantly change stromal CAV1 and carcinoma TUNEL staining. NAC was well tolerated. CONCLUSIONS: NAC as a single agent reduces MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation. This study suggests that modulating metabolism in the tumor microenvironment has the potential to impact breast cancer proliferation.
[Mh] Termos MeSH primário: Acetilcisteína/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Carcinoma Ductal de Mama/tratamento farmacológico
Carcinoma Intraductal não Infiltrante/tratamento farmacológico
Depuradores de Radicais Livres/uso terapêutico
Mastectomia
[Mh] Termos MeSH secundário: Adulto
Apoptose
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Carcinoma Ductal de Mama/metabolismo
Carcinoma Ductal de Mama/patologia
Carcinoma Intraductal não Infiltrante/metabolismo
Carcinoma Intraductal não Infiltrante/patologia
Carcinoma Papilar/tratamento farmacológico
Carcinoma Papilar/metabolismo
Carcinoma Papilar/patologia
Caveolina 1/metabolismo
Proliferação Celular
Feminino
Seres Humanos
Imuno-Histoquímica
Marcação In Situ das Extremidades Cortadas
Antígeno Ki-67/metabolismo
Meia-Idade
Transportadores de Ácidos Monocarboxílicos/metabolismo
Proteínas Musculares/metabolismo
Terapia Neoadjuvante
Estadiamento de Neoplasias
Projetos Piloto
Células Estromais/metabolismo
Resultado do Tratamento
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (CAV1 protein, human); 0 (Caveolin 1); 0 (Free Radical Scavengers); 0 (Ki-67 Antigen); 0 (Monocarboxylic Acid Transporters); 0 (Muscle Proteins); 0 (SLC16A4 protein, human); WYQ7N0BPYC (Acetylcysteine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


  10 / 27492 MEDLINE  
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[PMID]:29248131
[Au] Autor:Wilde L; Roche M; Domingo-Vidal M; Tanson K; Philp N; Curry J; Martinez-Outschoorn U
[Ad] Endereço:Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA.
[Ti] Título:Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development.
[So] Source:Semin Oncol;44(3):198-203, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis, or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation. Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize oxidative phosphorylation. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation, and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate, and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism, are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.
[Mh] Termos MeSH primário: Trifosfato de Adenosina/metabolismo
Glucose/metabolismo
Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos
Proliferação Celular
Descoberta de Drogas
Fibroblastos/metabolismo
Glicólise
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Corpos Cetônicos/metabolismo
Ácido Láctico/metabolismo
Transportadores de Ácidos Monocarboxílicos/metabolismo
Proteínas Musculares/metabolismo
NF-kappa B/metabolismo
Neoplasias/tratamento farmacológico
Proteínas Proto-Oncogênicas c-myc/metabolismo
Ácido Pirúvico/metabolismo
Células Estromais/metabolismo
Simportadores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (C12orf5 protein, human); 0 (HIF1A protein, human); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Intracellular Signaling Peptides and Proteins); 0 (Ketone Bodies); 0 (MYC protein, human); 0 (Monocarboxylic Acid Transporters); 0 (Muscle Proteins); 0 (NF-kappa B); 0 (Proto-Oncogene Proteins c-myc); 0 (SLC16A4 protein, human); 0 (Symporters); 0 (monocarboxylate transport protein 1); 33X04XA5AT (Lactic Acid); 8558G7RUTR (Pyruvic Acid); 8L70Q75FXE (Adenosine Triphosphate); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE



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