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  1 / 2409 MEDLINE  
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[PMID]:28712454
[Au] Autor:Gasperini M; Findlay GM; McKenna A; Milbank JH; Lee C; Zhang MD; Cusanovich DA; Shendure J
[Ad] Endere鏾:Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: gasperim@uw.edu.
[Ti] T韙ulo:CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions.
[So] Source:Am J Hum Genet;101(2):192-205, 2017 Aug 03.
[Is] ISSN:1537-6605
[Cp] Pa韘 de publica玢o:United States
[La] Idioma:eng
[Ab] Resumo:The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation.
[Mh] Termos MeSH prim醨io: Sistemas CRISPR-Cas/gen閠ica
Regula玢o da Express鉶 G阯ica/gen閠ica
Hipoxantina Fosforribosiltransferase/gen閠ica
Sequ阯cias Reguladoras de 羉ido Nucleico/gen閠ica
Dele玢o de Sequ阯cia/gen閠ica
[Mh] Termos MeSH secund醨io: Linhagem Celular
C閘ulas HEK293
Seres Humanos
Hipoxantina Fosforribosiltransferase/bioss韓tese
S韓drome de Lesch-Nyhan/gen閠ica
RNA Guia/gen閠ica
Tioguanina/metabolismo
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
0 (RNA, Guide); EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1709
[Cu] Atualiza玢o por classe:170907
[Lr] Data 鷏tima revis鉶:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


  2 / 2409 MEDLINE  
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[PMID]:28710878
[Au] Autor:Pranzatelli MR; Tate ED; Allison TJ
[Ad] Endere鏾:National Pediatric Neuroinflammation Organization, Inc., the National Pediatric Myoclonus Center, Orlando, FL, USA.
[Ti] T韙ulo:6-Mercaptopurine modifies cerebrospinal fluid T cell abnormalities in paediatric opsoclonus-myoclonus as steroid sparer.
[So] Source:Clin Exp Immunol;190(2):217-225, 2017 Nov.
[Is] ISSN:1365-2249
[Cp] Pa韘 de publica玢o:England
[La] Idioma:eng
[Ab] Resumo:The purpose of this study was to evaluate the capacity of 6-mercaptopurine (6-MP), a known immunosuppressant, to normalize cerebrospinal fluid (CSF) lymphocyte frequencies in opsoclonus-myoclonus syndrome (OMS) and function as a steroid sparer. CSF and blood lymphocytes were immunophenotyped in 11 children with OMS (without CSF B cell expansion) using a comprehensive panel of cell surface adhesion, activation and maturation markers by flow cytometry, and referenced to 18 paediatric controls. Drug metabolites, lymphocyte counts and liver function tests were used clinically to monitoring therapeutic range and toxicity. In CSF, adjunctive oral 6-MP was associated with a 21% increase in the low percentage of CD4 T cells in OMS, restoring the CD4/CD8 ratio. The percentage of CD4 T cells that were interferon (IFN)-纬 was reduced by 66%, shifting the cytokine balance away from T helper type 1 (Th1) (proinflammatory) predominance. The percentage of natural killer (NK) cells decreased significantly in CSF (-32%) and blood (-67 to -82%). Low blood absolute lymphocyte count was more predictive of improvement in CSF lymphocyte proportions (correlated with % CD4 T cells) than the 6-thioguanine level (no correlation). 6-MP was difficult to titrate: 50% achieved the target absolute lymphocyte count (<񁪍 K/mm); 20%, the 'therapeutic' 6-thioguanine level; and 40% the non-toxic 6-methylmercaptopurine level. Side effects and transaminase elevation were mild and reversible. Clinical steroid-sparing properties and lowered relapse frequency were demonstrated. 6-MP displayed unique pharmacodynamic properties that may be useful in OMS and other autoimmune disorders. Its steroid sparer capacity is limited to children in whom the therapeutic window can be reached without limiting pharmacokinetic factors or side effects.
[Mh] Termos MeSH prim醨io: Linf骳itos T CD4-Positivos/efeitos dos f醨macos
L韖uido Cefalorraquidiano/citologia
Mercaptopurina/farmacologia
S韓drome de Opsoclonia-Mioclonia/l韖uido cefalorraquidiano
[Mh] Termos MeSH secund醨io: Administra玢o Oral
Linf骳itos T CD4-Positivos/imunologia
Linf骳itos T CD4-Positivos/patologia
Linf骳itos T CD8-Positivos/imunologia
L韖uido Cefalorraquidiano/imunologia
Pr-Escolar
Feminino
Seres Humanos
Imunofenotipagem
Inflama玢o
Interferon gama/bioss韓tese
Interferon gama/imunologia
C閘ulas Matadoras Naturais/imunologia
Contagem de Linf骳itos
Masculino
Mercaptopurina/administra玢o & dosagem
Mercaptopurina/an醠ogos & derivados
Mercaptopurina/sangue
Mercaptopurina/farmacocin閠ica
Neuroblastoma/imunologia
C閘ulas Th1/imunologia
Tioguanina/sangue
Transaminases/sangue
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
6V404DV25O (6-methylthiopurine); 82115-62-6 (Interferon-gamma); E7WED276I5 (Mercaptopurine); EC 2.6.1.- (Transaminases); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1710
[Cu] Atualiza玢o por classe:171116
[Lr] Data 鷏tima revis鉶:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170716
[St] Status:MEDLINE
[do] DOI:10.1111/cei.13015


  3 / 2409 MEDLINE  
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[PMID]:28531214
[Au] Autor:Houlleberghs H; Goverde A; Lusseveld J; Dekker M; Bruno MJ; Menko FH; Mensenkamp AR; Spaander MCW; Wagner A; Hofstra RMW; Te Riele H
[Ad] Endere鏾:Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
[Ti] T韙ulo:Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.
[So] Source:PLoS Genet;13(5):e1006765, 2017 May.
[Is] ISSN:1553-7404
[Cp] Pa韘 de publica玢o:United States
[La] Idioma:eng
[Ab] Resumo:Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG) allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.
[Mh] Termos MeSH prim醨io: Neoplasias Colorretais Heredit醨ias sem Polipose/gen閠ica
Prote韓as de Liga玢o a DNA/gen閠ica
Testes Gen閠icos/m閠odos
Muta玢o de Sentido Incorreto
Fen髏ipo
[Mh] Termos MeSH secund醨io: Animais
C閘ulas Cultivadas
C閘ulas-Tronco Embrion醨ias/metabolismo
Seres Humanos
Camundongos
Mutag阯ese S韙io-Dirigida
Tioguanina/toxicidade
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
0 (DNA-Binding Proteins); 0 (G-T mismatch-binding protein); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1706
[Cu] Atualiza玢o por classe:170615
[Lr] Data 鷏tima revis鉶:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006765


  4 / 2409 MEDLINE  
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[PMID]:28498075
[Au] Autor:Kirsanova OV; Sergeev AV; Yasko IS; Gromova ES
[Ad] Endere鏾:a Department of Chemistry , M. V. Lomonosov Moscow State University , Moscow , Russia.
[Ti] T韙ulo:The impact of 6-thioguanine incorporation into DNA on the function of DNA methyltransferase Dnmt3a.
[So] Source:Nucleosides Nucleotides Nucleic Acids;36(6):392-405, 2017 Jun 03.
[Is] ISSN:1532-2335
[Cp] Pa韘 de publica玢o:United States
[La] Idioma:eng
[Ab] Resumo:The incorporation of chemotherapeutic agent 6-thioguanine ( G) into DNA is a prerequisite for its cytotoxic action. This modification of DNA impedes the activity of enzymes involved in DNA repair and replication. Here, using hemimethylated DNA substrates we demonstrated that DNA methylation by Dnmt3a-CD is reduced if DNA is damaged by the incorporation of G into one or two CpG sites separated by nine base pairs. An increase in the number of G substitutions did not enhance the effect. Dnmt3a-CD binding to either of G-containing DNA substrates was not distorted. Our results suggest that G incorporation into DNA may influence epigenetic regulation via DNA methylation.
[Mh] Termos MeSH prim醨io: DNA (Citosina-5-)-Metiltransferases/metabolismo
DNA/metabolismo
Tioguanina/metabolismo
[Mh] Termos MeSH secund醨io: Animais
Sequ阯cia de Bases
Ilhas de CpG/gen閠ica
DNA/gen閠ica
Metila玢o de DNA/efeitos dos f醨macos
Cin閠ica
Camundongos
Liga玢o Proteica
Tioguanina/farmacologia
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
9007-49-2 (DNA); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases); EC 2.1.1.37 (DNA methyltransferase 3A); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1711
[Cu] Atualiza玢o por classe:171116
[Lr] Data 鷏tima revis鉶:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2017.1287921


  5 / 2409 MEDLINE  
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[PMID]:28339328
[Au] Autor:Landier W; Hageman L; Chen Y; Kornegay N; Evans WE; Bostrom BC; Casillas J; Dickens DS; Angiolillo AL; Lew G; Maloney KW; Mascarenhas L; Ritchey AK; Termuhlen AM; Carroll WL; Relling MV; Wong FL; Bhatia S
[Ad] Endere鏾:Wendy Landier, Lindsey Hageman, Yanjun Chen, and Smita Bhatia, University of Alabama at Birmingham, Birmingham, AL; Nancy Kornegay, William E. Evans, and Mary V. Relling, St. Jude Children's Research Hospital, Memphis, TN; Bruce C. Bostrom, Children's Hospitals and Clinics of Minnesota, Minneapolis,
[Ti] T韙ulo:Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.
[So] Source:J Clin Oncol;35(15):1730-1736, 2017 May 20.
[Is] ISSN:1527-7755
[Cp] Pa韘 de publica玢o:United States
[La] Idioma:eng
[Ab] Resumo:Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 107.1 v 220.6 121.6; P = .5), with dairy versus without (220.1 87.8 v 216.3 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 119.7 v 195.5 82.3 v 174.8 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.
[Mh] Termos MeSH prim醨io: Antimetab髄itos Antineopl醩icos/administra玢o & dosagem
Ades鉶 Medica玢o
Mercaptopurina/administra玢o & dosagem
Leucemia-Linfoma Linfobl醩tico de C閘ulas Precursoras/sangue
Leucemia-Linfoma Linfobl醩tico de C閘ulas Precursoras/tratamento farmacol骻ico
Tioguanina/sangue
Tionucleot韉eos/sangue
[Mh] Termos MeSH secund醨io: Administra玢o Oral
Adolescente
Adulto
Crian鏰
Pr-Escolar
Latic韓ios
Esquema de Medica玢o
Monitoramento de Medicamentos/m閠odos
Eritr骳itos/metabolismo
Feminino
Intera珲es Alimento-Droga
Seres Humanos
Masculino
Metiltransferases/gen閠ica
Metiltransferases/metabolismo
Adulto Jovem
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
0 (Antimetabolites, Antineoplastic); 0 (Thionucleotides); E7WED276I5 (Mercaptopurine); EC 2.1.1.- (Methyltransferases); EC 2.1.1.67 (thiopurine methyltransferase); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1708
[Cu] Atualiza玢o por classe:171116
[Lr] Data 鷏tima revis鉶:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE
[do] DOI:10.1200/JCO.2016.71.7579


  6 / 2409 MEDLINE  
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[PMID]:28276819
[Au] Autor:Taylor KM; Ward MG; Blaker PA; Sparrow MP
[Ad] Endere鏾:a Department of Gastroenterology , Alfred Hospital and Monash University , Melbourne , Australia.
[Ti] T韙ulo:Is there a role for thioguanine therapy in IBD in 2017 and beyond?
[So] Source:Expert Rev Gastroenterol Hepatol;11(5):473-486, 2017 May.
[Is] ISSN:1747-4132
[Cp] Pa韘 de publica玢o:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.
[Mh] Termos MeSH prim醨io: Antimetab髄itos/uso terap陁tico
Colite Ulcerativa/tratamento farmacol骻ico
Doen鏰 de Crohn/tratamento farmacol骻ico
F醨macos Gastrointestinais/uso terap陁tico
Tioguanina/uso terap陁tico
[Mh] Termos MeSH secund醨io: Animais
Antimetab髄itos/efeitos adversos
Doen鏰 Hep醫ica Induzida por Subst鈔cias e Drogas/etiologia
Colite Ulcerativa/diagn髎tico
Doen鏰 de Crohn/diagn髎tico
Monitoramento de Medicamentos
Hiperplasia Nodular Focal do F韌ado/induzido quimicamente
F醨macos Gastrointestinais/efeitos adversos
Seres Humanos
Pancreatite/induzido quimicamente
Fatores de Risco
Tioguanina/efeitos adversos
Resultado do Tratamento
[Pt] Tipo de publica玢o:JOURNAL ARTICLE; REVIEW
[Nm] Nome de subst鈔cia:
0 (Antimetabolites); 0 (Gastrointestinal Agents); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1710
[Cu] Atualiza玢o por classe:171023
[Lr] Data 鷏tima revis鉶:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE
[do] DOI:10.1080/17474124.2017.1294062


  7 / 2409 MEDLINE  
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[PMID]:28258828
[Au] Autor:Nielsen SN; Grell K; Nersting J; Abrahamsson J; Lund B; Kanerva J; J髇sson 覩; Vaitkeviciene G; Pruunsild K; Hjalgrim LL; Schmiegelow K
[Ad] Endere鏾:Department of Pediatrics and Adolescent Medicine, University Hospital, Rigshospitalet, Copenhagen, Denmark.
[Ti] T韙ulo:DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.
[So] Source:Lancet Oncol;18(4):515-524, 2017 Apr.
[Is] ISSN:1474-5488
[Cp] Pa韘 de publica玢o:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. METHODS: In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 10-179 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m once per day and methotrexate 20 mg/m once per week, targeted to a leucocyte count of 15-30鈥堊鈥10 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. FINDINGS: Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 46 years (IQR 31-61). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 081 per 100 fmol/礸 DNA increase, 95% CI 067-098; p=0029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<00001). INTERPRETATION: Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. FUNDING: Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.
[Mh] Termos MeSH prim醨io: Protocolos de Quimioterapia Combinada Antineopl醩ica/sangue
Protocolos de Quimioterapia Combinada Antineopl醩ica/uso terap陁tico
DNA/qu韒ica
Recidiva Local de Neoplasia/mortalidade
Leucemia-Linfoma Linfobl醩tico de C閘ulas Precursoras/mortalidade
Tioguanina/sangue
[Mh] Termos MeSH secund醨io: Adolescente
Crian鏰
Pr-Escolar
Feminino
Seguimentos
Seres Humanos
Lactente
Masculino
Mercaptopurina/administra玢o & dosagem
Metotrexato/administra玢o & dosagem
Metotrexato/an醠ogos & derivados
Recidiva Local de Neoplasia/sangue
Recidiva Local de Neoplasia/tratamento farmacol骻ico
Estadiamento de Neoplasias
羉ido Poliglut鈓ico/administra玢o & dosagem
羉ido Poliglut鈓ico/an醠ogos & derivados
Leucemia-Linfoma Linfobl醩tico de C閘ulas Precursoras/sangue
Leucemia-Linfoma Linfobl醩tico de C閘ulas Precursoras/tratamento farmacol骻ico
Progn髎tico
Estudos Prospectivos
Taxa de Sobrevida
Tioguanina/qu韒ica
[Pt] Tipo de publica玢o:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de subst鈔cia:
25513-46-6 (Polyglutamic Acid); 82334-40-5 (methotrexate polyglutamate); 9007-49-2 (DNA); E7WED276I5 (Mercaptopurine); FTK8U1GZNX (Thioguanine); YL5FZ2Y5U1 (Methotrexate)
[Em] M阺 de entrada:1706
[Cu] Atualiza玢o por classe:171116
[Lr] Data 鷏tima revis鉶:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170305
[St] Status:MEDLINE


  8 / 2409 MEDLINE  
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[PMID]:28233441
[Au] Autor:Roy Moulik N; M Taj M
[Ad] Endere鏾:Department of Paediatrics, The Royal Marsden Hospital, Sutton, SM2 5PT, UK.
[Ti] T韙ulo:Long-term risk of portal hypertension and related complications in children treated with 6-thioguanine for acute lymphoblastic leukemia: A single-center experience.
[So] Source:Pediatr Blood Cancer;64(10), 2017 Oct.
[Is] ISSN:1545-5017
[Cp] Pa韘 de publica玢o:United States
[La] Idioma:eng
[Ab] Resumo:Long-term follow-up of 11 children with 6-thioguanine-induced hepatoportal toxicity is described. Features of persistent portal hypertension in eight patients after 9.7 3.4 years (mean SD) of treatment were more common in late presenters. Splenomegaly, thrombocytopenia and altered hepatic echotexture were seen in six, eight and seven patients, respectively. One of the thrombocytopenic patients had heavy menstrual bleeding and pregnancy loss. Five of six patients who underwent upper gastrointestinal endoscopy had esophageal varices and four underwent banding. Late presentation in a subset of patients mandates long-term surveillance and follow-up for all patients treated with 6-thioguanine for early detection and management of hepatoportal complications.
[Mh] Termos MeSH prim醨io: Hipertens鉶 Portal/induzido quimicamente
Hipertens鉶 Portal/epidemiologia
Leucemia-Linfoma Linfobl醩tico de C閘ulas Precursoras/tratamento farmacol骻ico
Leucemia-Linfoma Linfobl醩tico de C閘ulas Precursoras/epidemiologia
Tioguanina/efeitos adversos
[Mh] Termos MeSH secund醨io: Adolescente
Crian鏰
Pr-Escolar
Feminino
Seguimentos
Seres Humanos
Masculino
Fatores de Risco
Esplenomegalia/induzido quimicamente
Esplenomegalia/epidemiologia
Tioguanina/administra玢o & dosagem
Trombocitopenia/induzido quimicamente
Trombocitopenia/epidemiologia
Fatores de Tempo
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1710
[Cu] Atualiza玢o por classe:171016
[Lr] Data 鷏tima revis鉶:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1002/pbc.26495


  9 / 2409 MEDLINE  
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[PMID]:28212467
[Au] Autor:Mei S; Li X; Gong X; Zhang X; Li X; Yang L; Zhu L; Zhou H; Liu Y; Zhou A; Zhang X; Zhao Z
[Ad] Endere鏾:Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
[Ti] T韙ulo:Comparison of 6-mercaptopurine with 6-thioguanine for the analysis of thiopurine S-methyltransferase activity in human erythrocyte by LC-MS/MS.
[So] Source:Biomed Chromatogr;31(9), 2017 Sep.
[Is] ISSN:1099-0801
[Cp] Pa韘 de publica玢o:England
[La] Idioma:eng
[Ab] Resumo:Thiopurines (TPDs) are first-line drugs in treating neuromyelitis optica spectrum disorders (NMOSD). Evaluation of thiopurine S-methyltransferase activity (TPMT), a major determinant of TPD toxicity, before TPD treatment using 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrate was suggested. However, the equivalent of the two substrates in TPMT activity evaluation was unknown, and an alternative substrate was required in TPMT activity evaluation in patients who were already taking 6-MP or 6-TG. Before evaluating the agreement of 6-MP and 6-TG in TPMT activity measurement in patients with NMOSD, the affinity of the two substrates for the active center of TPMT should be established. A computer-based simulation indicated that 6-MP and 6-TG had similar affinities for the two active sites of TPMT. According to the guidelines, an LC-MS/MS method was developed and validated to evaluate the TPMT activity in human erythrocyte hemolysate using 6-MP or 6-TG as substrates via 1 h incubation at 37癈. The method was applied in 81 patients with NMOSD. Evaluated by Bland-Altman plot, 6-methylmercaptopurine and 6-methylthioguanine represented TPMT activities were in agreement with each other. Further studies are warranted to confirm the results.
[Mh] Termos MeSH prim醨io: Cromatografia L韖uida/m閠odos
Eritr骳itos/enzimologia
Mercaptopurina/metabolismo
Metiltransferases/sangue
Metiltransferases/metabolismo
Espectrometria de Massas em Tandem/m閠odos
Tioguanina/metabolismo
[Mh] Termos MeSH secund醨io: Adolescente
Adulto
Idoso
Estabilidade de Medicamentos
Feminino
Seres Humanos
Modelos Lineares
Masculino
Mercaptopurina/qu韒ica
Meia-Idade
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
Tioguanina/qu韒ica
Adulto Jovem
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
E7WED276I5 (Mercaptopurine); EC 2.1.1.- (Methyltransferases); EC 2.1.1.67 (thiopurine methyltransferase); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1709
[Cu] Atualiza玢o por classe:171116
[Lr] Data 鷏tima revis鉶:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170218
[St] Status:MEDLINE
[do] DOI:10.1002/bmc.3959


  10 / 2409 MEDLINE  
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[PMID]:28204548
[Au] Autor:Varghese S; Cotter M; Chevot F; Fergus C; Cunningham C; Mills KH; Connon SJ; Southern JM; Kelly VP
[Ad] Endere鏾:School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Ireland.
[Ti] T韙ulo:In vivo modification of tRNA with an artificial nucleobase leads to full disease remission in an animal model of multiple sclerosis.
[So] Source:Nucleic Acids Res;45(4):2029-2039, 2017 02 28.
[Is] ISSN:1362-4962
[Cp] Pa韘 de publica玢o:England
[La] Idioma:eng
[Ab] Resumo:Queuine is a modified pyrrolopyrimidine nucleobase derived exclusively from bacteria. It post-transcriptionally replaces guanine 34 in transfer RNA isoacceptors for Asp, Asn, His and Tyr, in almost all eukaryotic organisms, through the activity of the ancient tRNA guanine transglycosylase (TGT) enzyme. tRNA hypomodification with queuine is a characteristic of rapidly-proliferating, non-differentiated cells. Autoimmune diseases, including multiple sclerosis, are characterised by the rapid expansion of T cells directed to self-antigens. Here, we demonstrate the potential medicinal relevance of targeting the modification of tRNA in the treatment of a chronic multiple sclerosis model璵urine experimental autoimmune encephalomyelitis. Administration of a de novo designed eukaryotic TGT substrate (NPPDAG) led to an unprecedented complete reversal of clinical symptoms and a dramatic reduction of markers associated with immune hyperactivation and neuronal damage after five daily doses. TGT is essential for the therapeutic effect, since animals deficient in TGT activity were refractory to therapy. The data suggest that exploitation of the eukaryotic TGT enzyme is a promising approach for the treatment of multiple sclerosis.
[Mh] Termos MeSH prim醨io: Encefalomielite Autoimune Experimental/terapia
Terapia Gen閠ica/m閠odos
Esclerose M鷏tipla/terapia
Pirimidinonas/farmacologia
Pirr骾s/farmacologia
RNA de Transfer阯cia/farmacologia
[Mh] Termos MeSH secund醨io: Animais
Enc閒alo/patologia
Modelos Animais de Doen鏰s
Encefalomielite Autoimune Experimental/gen閠ica
Encefalomielite Autoimune Experimental/patologia
Camundongos Endog鈓icos C57BL
Esclerose M鷏tipla/gen閠ica
Pentosiltransferases/gen閠ica
Pentosiltransferases/metabolismo
Pirimidinonas/qu韒ica
Pirr骾s/qu韒ica
RNA de Transfer阯cia/qu韒ica
Tioguanina/qu韒ica
[Pt] Tipo de publica玢o:JOURNAL ARTICLE
[Nm] Nome de subst鈔cia:
0 (NPPDAG compound); 0 (Pyrimidinones); 0 (Pyrroles); 9014-25-9 (RNA, Transfer); EC 2.4.2.- (Pentosyltransferases); EC 2.4.2.29 (queuine tRNA-ribosyltransferase); FTK8U1GZNX (Thioguanine)
[Em] M阺 de entrada:1710
[Cu] Atualiza玢o por classe:171024
[Lr] Data 鷏tima revis鉶:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkw847



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