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Pesquisa : C10.228.140.163.100.937.374 [Categoria DeCS]
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[PMID]:28587924
[Au] Autor:Verma M; Charles RCM; Chakrapani B; Coumar MS; Govindaraju G; Rajavelu A; Chavali S; Dhayalan A
[Ad] Endereço:Department of Biotechnology, Pondicherry University, Puducherry 605 014, India.
[Ti] Título:PRMT7 Interacts with ASS1 and Citrullinemia Mutations Disrupt the Interaction.
[So] Source:J Mol Biol;429(15):2278-2289, 2017 Jul 21.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein arginine methyltransferase 7 (PRMT7) catalyzes the introduction of monomethylation marks at the arginine residues of substrate proteins. PRMT7 plays important roles in the regulation of gene expression, splicing, DNA damage, paternal imprinting, cancer and metastasis. However, little is known about the interaction partners of PRMT7. To address this, we performed yeast two-hybrid screening of PRMT7 and identified argininosuccinate synthetase (ASS1) as a potential interaction partner of PRMT7. We confirmed that PRMT7 directly interacts with ASS1 using pull-down studies. ASS1 catalyzes the rate-limiting step of arginine synthesis in urea cycle and citrulline-nitric oxide cycle. We mapped the interface of PRMT7-ASS1 complex through computational approaches and validated the predicted interface in vivo by site-directed mutagenesis. Evolutionary analysis revealed that the ASS1 residues important for PRMT7-ASS1 interaction have co-evolved with PRMT7. We showed that ASS1 mutations linked to type I citrullinemia disrupt the ASS1-PRMT7 interaction, which might explain the molecular pathogenesis of the disease.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/genética
Argininossuccinato Sintase/metabolismo
Proteína-Arginina N-Metiltransferases/metabolismo
[Mh] Termos MeSH secundário: Centrifugação
Citrulinemia/fisiopatologia
Análise Mutacional de DNA
Seres Humanos
Simulação de Dinâmica Molecular
Mutagênese Sítio-Dirigida
Ligação Proteica
Mapeamento de Interação de Proteínas
Técnicas do Sistema de Duplo-Híbrido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.1.1.319 (PRMT7 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE


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[PMID]:28302489
[Au] Autor:Yoshitoshi-Uebayashi EY; Toyoda T; Yasuda K; Kotaka M; Nomoto K; Okita K; Yasuchika K; Okamoto S; Takubo N; Nishikubo T; Soga T; Uemoto S; Osafune K
[Ad] Endereço:Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Department of Hepatobiliary, Pancreatic, Transplantation and Pediatric Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
[Ti] Título:Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs.
[So] Source:Biochem Biophys Res Commun;486(3):613-619, 2017 May 06.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. l-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches.
[Mh] Termos MeSH primário: Arginina/farmacologia
Argininossuccinato Sintase/deficiência
Ciclo do Ácido Cítrico/efeitos dos fármacos
Citrulinemia/genética
Hepatócitos/efeitos dos fármacos
Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Argininossuccinato Sintase/genética
Sequência de Bases
Diferenciação Celular
Ciclo do Ácido Cítrico/genética
Citrulinemia/enzimologia
Citrulinemia/patologia
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Hepatócitos/metabolismo
Hepatócitos/patologia
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Pluripotentes Induzidas/patologia
Cariotipagem
Metaboloma
Camundongos
Camundongos Endogâmicos NOD
Modelos Biológicos
Cultura Primária de Células
Transdução de Sinais
Ureia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
8W8T17847W (Urea); 94ZLA3W45F (Arginine); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE


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[PMID]:28259708
[Au] Autor:Saheki T; Inoue K; Ono H; Fujimoto Y; Furuie S; Yamamura KI; Kuroda E; Ushikai M; Asakawa A; Inui A; Eto K; Kadowaki T; Moriyama M; Sinasac DS; Yamamoto T; Furukawa T; Kobayashi K
[Ad] Endereço:Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan; Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan; Department of Molecular Oncology, Kagoshima University Graduate School of Medical and D
[Ti] Título:Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency.
[So] Source:Mol Genet Metab;120(4):306-316, 2017 Apr.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mice carrying simultaneous homozygous mutations in the genes encoding citrin, the mitochondrial aspartate-glutamate carrier 2 (AGC2) protein, and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), are a phenotypically representative model of human citrin (a.k.a., AGC2) deficiency. In this study, we investigated the voluntary oral intake and preference for sucrose, glycerol or ethanol solutions by wild-type, citrin (Ctrn)-knockout (KO), mGPD-KO, and Ctrn/mGPD double-KO mice; all substances that are known or suspected precipitating factors in the pathogenesis of human citrin deficiency. The double-KO mice showed clear suppressed intake of sucrose, consuming less with progressively higher concentrations compared to the other mice. Similar observations were made when glycerol or ethanol were given. The preference of Ctrn-KO and mGPD-KO mice varied with the different treatments; essentially no differences were observed for sucrose, while an intermediate intake or similar to that of the double-KO mice was observed for glycerol and ethanol. We next examined the hepatic glycerol 3-phosphate, citrate, citrulline, lysine, glutamate and adenine nucleotide levels following forced enteral administration of these solutions. A strong correlation between the simultaneous increased hepatic glycerol 3-phosphate and decreased ATP or total adenine nucleotide content and observed aversion of the mice during evaluation of their voluntary preferences was found. Overall, our results suggest that the aversion observed in the double-KO mice to these solutions is initiated and/or mediated by hepatic metabolic perturbations, resulting in a behavioral response to increased hepatic cytosolic NADH and a decreased cellular adenine nucleotide pool. These findings may underlie the dietary predilections observed in human citrin deficient patients.
[Mh] Termos MeSH primário: Citrulinemia/metabolismo
Sacarose na Dieta/administração & dosagem
Etanol/administração & dosagem
Glicerol/administração & dosagem
Fígado/química
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Sistemas de Transporte de Aminoácidos Acídicos/genética
Animais
Antiporters/genética
Modelos Animais de Doenças
Glicerolfosfato Desidrogenase/genética
Glicerofosfatos/metabolismo
Seres Humanos
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Acidic); 0 (Antiporters); 0 (Dietary Sucrose); 0 (Glycerophosphates); 0 (aspartate-glutamate carrier); 3K9958V90M (Ethanol); 8L70Q75FXE (Adenosine Triphosphate); 9NTI6P3O4X (alpha-glycerophosphoric acid); EC 1.1.- (Glycerolphosphate Dehydrogenase); PDC6A3C0OX (Glycerol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170306
[St] Status:MEDLINE


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[PMID]:28132756
[Au] Autor:Kose E; Unal O; Bulbul S; Gunduz M; Häberle J; Arslan N
[Ad] Endereço:Dokuz Eylul University, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey.
[Ti] Título:Identification of three novel mutations in fourteen patients with citrullinemia type 1.
[So] Source:Clin Biochem;50(12):686-689, 2017 Aug.
[Is] ISSN:1873-2933
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Citrullinemia type 1 (CTLN1) is an autosomal recessive genetic disorder caused by mutations in the argininosuccinate synthetase 1 (ASS1) gene, which encodes for the argininosuccinate synthetase enzyme. Here, we report genetic and clinical characterizations of 14 patients with citrullinemia type 1. DESIGN & METHODS: The study group consisted of 14 patients (4 females, 10 males) diagnosed with citrullinemia type 1 from three centers in Turkey. Age of onset, clinical presentation, initial citrulline and ammonia levels, family history and molecular genetic analysis were retrospectively evaluated. RESULTS: The mean age of the cohort and the mean age at the time of diagnosis were 48.3±36.5months (min: 12days, max: 10years) and 11.6±26.2months (min: 3days, max: 8years), respectively. In four patients, a homozygous p.Gly390Arg pathogenic variant was detected. All patients homozygous for p.Gly390Arg were diagnosed during the newborn period with the clinical presentation of classical citrullinemia. In each two patients, homozygous p.Arg86His, c.773+49C>T and p.Gly362Val pathogenic variants were detected. Clinical presentation was compatible with the mild form of the disease in patients homozygous for c.773+49C>T and for Gly362Val. Novel compound heterozygous genotypes (p.Ala164Pro/p.Gly390Arg; p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in five patients. Of these, three siblings with CTLN1 were diagnosed with the compound heterozygous genotype p.Ala164Pro/p.Gly390Arg at the age of 4days, 5days and 2years, respectively. The other two patients with novel compound heterozygous genotypes (p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in the first month of life as neonatal onset form and were born to non-consanguineous parents. CONCLUSION: In our study, consistent with the literature, a correlation was found between homozygous p.Gly390Arg mutation and the classic neonatal onset form. Mild citrullinemia was detected in patients with c.773+49C>T or p.Gly362Val pathogenic variants. This study adds to our understanding of the molecular genetic background of patients with CTLN1, and allows to infer on the correlation between the genotype and phenotype of the disease.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/genética
Citrulinemia/genética
Mutação
[Mh] Termos MeSH secundário: Idade de Início
Amônia/sangue
Argininossuccinato Sintase/sangue
Criança
Pré-Escolar
Citrulina/sangue
Citrulinemia/sangue
Citrulinemia/diagnóstico
Citrulinemia/patologia
Expressão Gênica
Genes Recessivos
Genótipo
Heterozigoto
Homozigoto
Seres Humanos
Lactente
Recém-Nascido
Linhagem
Fenótipo
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
29VT07BGDA (Citrulline); 7664-41-7 (Ammonia); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170131
[St] Status:MEDLINE


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[PMID]:28111830
[Au] Autor:Diez-Fernandez C; Rüfenacht V; Häberle J
[Ad] Endereço:Division of Metabolism, University Children´s Hospital and Children's Research Center, Zurich, Switzerland.
[Ti] Título:Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations.
[So] Source:Hum Mutat;38(5):471-484, 2017 May.
[Is] ISSN:1098-1004
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Citrullinemia type 1 is an autosomal recessive urea cycle disorder caused by defects in the argininosuccinate synthetase (ASS) enzyme due to mutations in ASS1 gene. An impairment of ASS function can lead to a wide spectrum of phenotypes, from life-threatening neonatal hyperammonemia to a later onset with mild symptoms, and even some asymptomatic patients exhibiting an only biochemical phenotype. The disease is panethnic. In this update, we report 137 mutations (64 of which are novel), consisting of 89 missense mutations, 19 nonsense mutations, 17 mutations that affect splicing, and 12 deletions. The change p.Gly390Arg is by far the most common mutation and is widely spread throughout the world. Other frequent mutations (p.Arg157His, p.Trp179Arg, p.Val263Met, p.Arg304Trp, p.Gly324Ser, p.Gly362Val, and p.Arg363Trp), each found in at least 12 independent families, are mainly carried by patients from the Indian subcontinent, Turkey, Germany, and Japan. To better understand the disease, we collected clinical data of >360 patients, including all published information available. This information is related to the patients' genetic background, the conservation of the mutated residues and a structural rationalization of the effect of the most frequent mutations. In addition, we review ASS regulation, animal models, diagnostic strategies, newborn screening, and treatment options.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/genética
Citrulinemia/diagnóstico
Citrulinemia/genética
Mutação
[Mh] Termos MeSH secundário: Alelos
Sequência de Aminoácidos
Animais
Argininossuccinato Sintase/química
Argininossuccinato Sintase/metabolismo
Citrulinemia/epidemiologia
Citrulinemia/terapia
Modelos Animais de Doenças
Ativação Enzimática
Estudos de Associação Genética
Genótipo
Geografia Médica
Seres Humanos
Modelos Moleculares
Fenótipo
Matrizes de Pontuação de Posição Específica
Diagnóstico Pré-Natal
Conformação Proteica
Índice de Gravidade de Doença
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170124
[St] Status:MEDLINE
[do] DOI:10.1002/humu.23184


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[PMID]:28041819
[Au] Autor:Nagasaka H; Komatsu H; Inui A; Nakacho M; Morioka I; Tsukahara H; Kaji S; Hirayama S; Miida T; Kondou H; Ihara K; Yagi M; Kizaki Z; Bessho K; Kodama T; Iijima K; Saheki T; Yorifuji T; Honda A
[Ad] Endereço:Department of Pediatrics, Takarazuka City Hospital, 4-5-1, Kohama, Takarazuka 665-0827, Japan. Electronic address: nagasaka@cnt-osaka.com.
[Ti] Título:Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment.
[So] Source:Mol Genet Metab;120(3):207-212, 2017 Mar.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid ß-oxidation cycle between 22 citrin-deficient children (age, 3-13years) with normal liver functions and 37 healthy controls (age, 5-13years). TCA cycle analysis showed that basal plasma citrate and α-ketoglutarate levels were significantly higher in the affected than the control group (p<0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p<0.001). The plasma level of 3-OH-butyrate derived from fatty acid ß-oxidation was significantly higher in the affected group (p<0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p<0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.
[Mh] Termos MeSH primário: Ciclo do Ácido Cítrico
Citrulinemia/tratamento farmacológico
Citrulinemia/metabolismo
Ácidos Graxos/metabolismo
Piruvatos/administração & dosagem
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Ácido Cítrico/sangue
Ciclo do Ácido Cítrico/efeitos dos fármacos
Feminino
Fumaratos/sangue
Seres Humanos
Ácidos Cetoglutáricos/sangue
Malatos/sangue
Masculino
Estresse Oxidativo/efeitos dos fármacos
Piruvatos/farmacologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Fumarates); 0 (Ketoglutaric Acids); 0 (Malates); 0 (Pyruvates); 2968PHW8QP (Citric Acid); 817L1N4CKP (malic acid); 8ID597Z82X (alpha-ketoglutaric acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170103
[St] Status:MEDLINE


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[PMID]:27829683
[Au] Autor:Oh SH; Lee BH; Kim GH; Choi JH; Kim KM; Yoo HW
[Ad] Endereço:Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
[Ti] Título:Biochemical and molecular characteristics of citrin deficiency in Korean children.
[So] Source:J Hum Genet;62(2):305-307, 2017 Feb.
[Is] ISSN:1435-232X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in SLC25A13 cause citrin deficiency, which has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and adult-onset type 2 citrullinemia (CTLN2). The purpose of this study was to determine the mutation spectrum and the clinical and biochemical characteristics of citrin deficiency in Korean patients. Thirty-four patients were diagnosed with citrin deficiency based on mutations in SLC25A13, as verified by direct sequencing and long PCR screening of a large transposon insertion. A total of 66 alleles from 33 unrelated families of 34 patients with citrin deficiency (27 NICCD, 2 FTTDCD and 5 CTLN2) were retrospectively identified. The common pathogenic alleles were IVS16ins3kb (33%), c.851_854del (30%) and c.1177+1G>A (12%), and three novel variants were identified. Levels of citrulline, threonine, methionine, tyrosine and arginine and the threonine-to-serine ratio were higher in children with neonatal intrahepatic cholestasis caused by NICCD compared with that in patients with idiopathic neonatal hepatitis (INH). We concluded that Korean patients with citrin deficiency showed the highest frequency of the IVS16ins3kb mutation and that plasma amino-acid profiles can be used to differentiate between NICCD and INH.
[Mh] Termos MeSH primário: Citrulinemia/genética
Insuficiência de Crescimento/genética
Proteínas de Transporte da Membrana Mitocondrial/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Alelos
Aminoácidos/metabolismo
Grupo com Ancestrais do Continente Asiático/genética
Sequência de Bases
Citrulinemia/metabolismo
Insuficiência de Crescimento/metabolismo
Feminino
Frequência do Gene/genética
Seres Humanos
Lactente
Recém-Nascido
Masculino
Proteínas de Transporte da Membrana Mitocondrial/metabolismo
Mutação
Reação em Cadeia da Polimerase
República da Coreia
Estudos Retrospectivos
Análise de Sequência de DNA
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Mitochondrial Membrane Transport Proteins); 0 (SLC25A13 protein, human)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170524
[Lr] Data última revisão:
170524
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161111
[St] Status:MEDLINE
[do] DOI:10.1038/jhg.2016.131


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[PMID]:27584578
[Au] Autor:Szlosarek PW; Steele JP; Nolan L; Gilligan D; Taylor P; Spicer J; Lind M; Mitra S; Shamash J; Phillips MM; Luong P; Payne S; Hillman P; Ellis S; Szyszko T; Dancey G; Butcher L; Beck S; Avril NE; Thomson J; Johnston A; Tomsa M; Lawrence C; Schmid P; Crook T; Wu BW; Bomalaski JS; Lemoine N; Sheaff MT; Rudd RM; Fennell D; Hackshaw A
[Ad] Endereço:Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England2Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
[Ti] Título:Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial.
[So] Source:JAMA Oncol;3(1):58-66, 2017 Jan 01.
[Is] ISSN:2374-2445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. Objective: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. Design, Setting, and Participants: A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. Interventions: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. Results: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. Conclusions and Relevance: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. Trial Registration: clinicaltrials.gov Identifier: NCT01279967.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/sangue
Biomarcadores Tumorais/sangue
Citrulinemia/tratamento farmacológico
Hidrolases/administração & dosagem
Neoplasias Pulmonares/tratamento farmacológico
Mesotelioma/tratamento farmacológico
Polietilenoglicóis/administração & dosagem
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Arginina/metabolismo
Biomarcadores Tumorais/genética
Citrulinemia/sangue
Citrulinemia/genética
Citrulinemia/patologia
Metilação de DNA/genética
Intervalo Livre de Doença
Determinação de Ponto Final
Feminino
Seres Humanos
Neoplasias Pulmonares/sangue
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
Masculino
Mesotelioma/sangue
Mesotelioma/genética
Mesotelioma/patologia
Meia-Idade
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 30IQX730WE (Polyethylene Glycols); 94ZLA3W45F (Arginine); EC 3.- (Hydrolases); EC 3.5.3.6 (ADI PEG20); EC 6.3.4.5 (Argininosuccinate Synthase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160902
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1001/jamaoncol.2016.3049


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[PMID]:27938561
[Au] Autor:Zhang J; Wang XH; Ye YZ; Xie XB; Lu Y; Ye LJ; Yu H
[Ad] Endereço:Department of Infectious Diseases, Children's Hospital of Fudan University, Shanghai 201102, China.
[Ti] Título:[Value of albumin in diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency].
[So] Source:Zhonghua Gan Zang Bing Za Zhi;24(10):755-760, 2016 Oct 20.
[Is] ISSN:1007-3418
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:To investigate the clinical value of albumin (Alb) in the diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). A retrospective analysis was performed for the clinical data of 90 children with NICCD who visited Children's Hospital of Fudan University from January 2007 to December 2014, and according to the content of Alb, these children were divided into Alb < 30 g/L (LA) group with 20 children and Alb ≥30 g/L (NA) group with 70 children. The clinical manifestations, results of laboratory examination, results of blood tandem mass spectrometry and urine gas chromatography-mass spectrometry, and gene detection results were compared between the two groups. The t-test and the chi-square test were used for statistical analysis.. There were significant differences between the LA group and the NA group in splenomegaly degree (3.28±1.95 cm vs 1.92±1.06 cm, = 0.030), aspartate aminotransferase/alanine aminotransferase ratio [3.15 (0.38-5.93) vs 2.14 (0.26-6.67), = 0.010], activated partial thromboplastin time (53.27±11.68 s vs 45.06±9.79 s, = 0.003), and international normalized ratio (1.92±1.35 vs 1.29±0.33, = 0.001). The SLC25A13 mutation I 851_854del4 was associated with Alb ( = 4.76, = 0.025). As for the children with Alb < 30g/L who are highly suspected of having NICCD, SLC25A13 gene detection and blood/urine mass spectrometry should be performed as early as possible, in order to initiate intervention treatment as soon as possible, prevent and treat complications, and improve prognosis.
[Mh] Termos MeSH primário: Albuminas
Proteínas de Ligação ao Cálcio/deficiência
Citrulinemia/diagnóstico
Transportadores de Ânions Orgânicos/deficiência
[Mh] Termos MeSH secundário: Citrulinemia/sangue
Feminino
Cromatografia Gasosa-Espectrometria de Massas
Seres Humanos
Proteínas de Transporte da Membrana Mitocondrial/genética
Mutação
Estudos Retrospectivos
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Albumins); 0 (Calcium-Binding Proteins); 0 (Mitochondrial Membrane Transport Proteins); 0 (Organic Anion Transporters)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.1007-3418.2016.10.008


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[PMID]:27724842
[Au] Autor:Choi JJ; Kim HS; Lee KC; Shin Y; Jo YY
[Ad] Endereço:Department of Anesthesiology and Pain Medicine, Gachon University Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760, South Korea.
[Ti] Título:Anesthetic experience of an adult male with citrullinemia type II: a case report.
[So] Source:BMC Anesthesiol;16(1):92, 2016 Oct 11.
[Is] ISSN:1471-2253
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Citrullinemia type II is an autosomal recessive urea cycle disorder and a subtype of citrin deficiency. However, the management of recurrent hyperammonemia with neurologic symptoms in patients with citrullinemia type II is quite different from the management of other types of urea cycle disorders. In pats with citrullinemia type II, regional anesthesia might be a good choice for the early detection of hyperammonemic symptoms and addressing psychic stress. CASE PRESENTATION: A 48-year-old male with adult onset citrullinemia type II was scheduled for urethral scrotal fistula repair. During the first operation, spinal anesthesia with conscious sedation using dexmedetomidine was used, a second operation was performed after confirmation of infection control and a stable neurologic condition. In this patient, dietary planning with close monitoring of serum ammonia level and close observation of neurologic conditions might lead to successful perioperative care. CONCLUSION: For anesthesia of patients with adult onset citrullinemia type II, close monitoring of neurologic signs and serum ammonia are important to reduce neurologic complications induced by hyperammonemia. Regional anesthesia with a proper dietary plan might reduce patient stress and prevent metabolic tragedy.
[Mh] Termos MeSH primário: Raquianestesia
Encefalopatias/prevenção & controle
[Mh] Termos MeSH secundário: Amônia/sangue
Encefalopatias/sangue
Encefalopatias/complicações
Citrulinemia/sangue
Citrulinemia/complicações
Seres Humanos
Hiperamonemia/sangue
Hiperamonemia/complicações
Masculino
Meia-Idade
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
7664-41-7 (Ammonia)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161012
[St] Status:MEDLINE



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