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[PMID]:28738357
[Au] Autor:Ma W; Zhang Y; Zheng X; Yu T
[Ti] Título:Biphasically Modulating the Activity of Carboxypeptidase G2 with Ultrasound.
[So] Source:Cell Physiol Biochem;42(4):1614-1622, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Carboxypeptidase G2 (CPG2) has been used for cancer prodrug therapy to realize the targeted release of active drugs, but there yet lacks a means to modulate the CPG2 activity. Here ultrasound was used to modulate the CPG2 activity. METHODS: The activity of insonated CPG2 was determined, and then underlying biochemical (i.e., monomer, dimer and conformation) and ultrasonic (i.e., heat and cavitation) mechanisms were explored. RESULTS: Ultrasound (1.0 MHz) increased or decreased the enzymatic activity; the activity decreased as zero- or first-order kinetics, depending on the intensity. L1 (10 W/cm2 for 200 s) improved the activity via increasing the specific activity. L2 or L3 (20 W/cm2 for 1200 or 3000 s) decreased the activity via disassembling the dimer, degrading the monomer, inducing glycosylation, transforming conformation and decreasing the specific activity. An increase or a slight decrease of activity attributable to 10 W/cm2 was reversible, but the activity decrease due to 20 W/cm2 was irreversible. The enzymatic modulation was realized via cavitation. CONCLUSION: Ultrasound can biphasically modulate the CPG2 activity, and can be employed in the CPG2-prodrug therapy to adjust the release and moles of active drugs.
[Mh] Termos MeSH primário: Metotrexato/química
Pró-Fármacos/química
Sonicação
gama-Glutamil Hidrolase/química
[Mh] Termos MeSH secundário: Ensaios Enzimáticos
Estabilidade Enzimática
Seres Humanos
Cinética
Proteínas Recombinantes/química
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Prodrugs); 0 (Recombinant Proteins); EC 3.4.19.9 (gamma-Glutamyl Hydrolase); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE
[do] DOI:10.1159/000479402


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[PMID]:28417167
[Au] Autor:Sadahiro S; Suzuki T; Tanaka A; Okada K; Saito G; Miyakita H; Ogimi T; Nagase H
[Ad] Endereço:Department of Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. sadahiro@is.icc.tokai.ac.jp.
[Ti] Título:Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer.
[So] Source:Cancer Chemother Pharmacol;79(6):1077-1085, 2017 Jun.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV). METHODS: The subjects were 54 patients with locally advanced rectal cancer who received preoperative CRT with S-1 or UFT/LV. The pathological tumor response was assessed according to the tumor regression grade (TRG). The expression levels of 18 CRT-related genes were determined using RT-PCR assay. RESULTS: A pathological response (TRG 1-2) was observed in 23 patients (42.6%). In a multivariate logistic regression analysis for pathological response, the overall expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, were significant, and the accuracy rate of the predictive model was 83.3%. The effects of the gene expression levels of GGH on the response differed significantly according to the treatment regimen. The total pathological response rate of both high-GGH patients in the S-1 group and low-GGH patients in the UFT/LV group was 58.3%. CONCLUSION: Additional treatment with 5-FU-based chemotherapy during the interval between radiotherapy and surgery is not beneficial in patients who have received 5-FU-based CRT. The expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, in tumor tissues can predict the response to preoperative CRT including either S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for the appropriate use of S-1 and UFT/LV in CRT.
[Mh] Termos MeSH primário: Adenocarcinoma/terapia
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Quimiorradioterapia/métodos
Neoplasias Retais/terapia
gama-Glutamil Hidrolase/biossíntese
gama-Glutamil Hidrolase/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/tratamento farmacológico
Adenocarcinoma/cirurgia
Adulto
Idoso
Antídotos/administração & dosagem
Antimetabólitos Antineoplásicos/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Biomarcadores Tumorais/sangue
Terapia Combinada
Combinação de Medicamentos
Feminino
Fluoruracila/administração & dosagem
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Leucovorina/administração & dosagem
Masculino
Meia-Idade
Ácido Oxônico/administração & dosagem
Neoplasias Retais/tratamento farmacológico
Neoplasias Retais/cirurgia
Reprodutibilidade dos Testes
Tegafur/administração & dosagem
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidotes); 0 (Antimetabolites, Antineoplastic); 0 (Biomarkers, Tumor); 0 (Drug Combinations); 150863-82-4 (S 1 (combination)); 1548R74NSZ (Tegafur); 5VT6420TIG (Oxonic Acid); EC 3.4.19.9 (gamma-Glutamyl Hydrolase); Q573I9DVLP (Leucovorin); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-017-3295-8


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[PMID]:28278270
[Au] Autor:Li Y; Liu S; Wang H; Mai H; Yuan X; Li C; Chen X; Wen F
[Ad] Endereço:Division of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China.
[Ti] Título:Methylation level of CpG islands in GGH gene promoter in pediatric acute leukemia.
[So] Source:PLoS One;12(3):e0173472, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: γ-Glutamyl hydrolase (GGH) regulates intracellular folates and antifolates such as methotrexate (MTX) for proper nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. In addition to genetic polymorphism and karyotypic abnormalities, methylation of CpG island 1 (CpG1) in the promoter region is found to modulate GGH activity by reducing GGH mRNA expression in acute lymphoblastic leukemia (ALL) cells. We aim to investigate methylation status of two CpG islands (CpG1 and CpG2) in the GGH promoter region in pediatric patients with ALL and acute myelogenous leukemia (AML). METHODS: 70B-ALL, 29 AML, 10 ITP (idiopathic thrombocytopenic purpura) and 40 healthy children are recruited in the present study. MS-HRM (methylation-sensitive high-resolution melting) and bisulfite sequencing PCR (BSP) are used to detect methylation change and its level in CpG1 and CpG2 in the GGH promoter region. GGH mRNA expression is quantified by real-time PCR. Correlation between CpG island methylation and GGH mRNA expression is assessed by statistical software. RESULTS: Methylations of CpG1 are detected in leukemia cells samples obtained from 30.9% (21/68) of patients with ALL and 20.7% (6/29) of patients with AML. These methylations are not detected in the controls. Methylations of CpG2 are detected in leukemia cell samples obtained from 44.1% (30/68) of the ALL patients and 37.9% (11/29) of the AML patients. These percentages are significantly higher than that observed in the control cell samples: 6.0% (3/50) (Fisher's exact test, P = 0.000). The abundance of CpG1 methylation in all leukemia cell samples is classified as Grade I (methylation level is less than 10%) and the abundance of CpG2 methylation in leukemia cell samples is classified in separate grades. Our results indicate that methylation of CpG1 or hypermethylation (the methylation level is greater than 10%) of CpG2 could significantly reduce GGH mRNA expression in leukemia cells from the ALL and AML patients (ALL-CpG1: t = 4.632, P = 0.000; ALL-CpG2: t = 3.250, P = 0.006; AML-CpG1: t = -2.254, P = 0.037; AML-CpG2: t = 1.328, P = 0.202). CONCLUSION: Either methylation of CpG1 or hypermethylation of CpG2 in GGH promoter region can significantly reduce GGH mRNA expression in pediatric patients with acute leukemia, which can improve the response to treatment.
[Mh] Termos MeSH primário: Ilhas de CpG/genética
Metilação de DNA
Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
Regiões Promotoras Genéticas/genética
gama-Glutamil Hidrolase/genética
[Mh] Termos MeSH secundário: Sequência de Bases
Criança
Pré-Escolar
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.4.19.9 (gamma-Glutamyl Hydrolase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173472


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[PMID]:28160000
[Au] Autor:Yachnin BJ; Khare SD
[Ad] Endereço:Department of Chemistry & Chemical Biology and the Center for Integrative Proteomics, Rutgers University, Piscataway, NJ 08854, USA.
[Ti] Título:Engineering carboxypeptidase G2 circular permutations for the design of an autoinhibited enzyme.
[So] Source:Protein Eng Des Sel;30(4):321-331, 2017 Apr 01.
[Is] ISSN:1741-0134
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Carboxypeptidase G2 (CPG2) is an Food and Drug Administration (FDA)-approved enzyme drug used to treat methotrexate (MTX) toxicity in cancer patients receiving MTX treatment. It has also been used in directed enzyme-prodrug chemotherapy, but this strategy has been hampered by off-site activation of the prodrug by the circulating enzyme. The development of a tumor protease activatable CPG2, which could be achieved using a circular permutation of CPG2 fused to an inactivating 'prodomain', would aid in these applications. We report the development of a protease accessibility-based screen to identify candidate sites for circular permutation in proximity of the CPG2 active site. The resulting six circular permutants showed similar expression, structure, thermal stability, and, in four cases, activity levels compared to the wild-type enzyme. We rationalize these results based on structural models of the permutants obtained using the Rosetta software. We developed a cell growth-based selection system, and demonstrated that when fused to periplasm-directing signal peptides, one of our circular permutants confers MTX resistance in Escherichia coli with equal efficiency as the wild-type enzyme. As the permutants have similar properties to wild-type CPG2, these enzymes are promising starting points for the development of autoinhibited, protease-activatable zymogen forms of CPG2 for use in therapeutic contexts.
[Mh] Termos MeSH primário: Mutação
gama-Glutamil Hidrolase
[Mh] Termos MeSH secundário: Precursores Enzimáticos/biossíntese
Precursores Enzimáticos/química
Precursores Enzimáticos/genética
Estabilidade Enzimática
gama-Glutamil Hidrolase/biossíntese
gama-Glutamil Hidrolase/química
gama-Glutamil Hidrolase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Precursors); EC 3.4.19.9 (gamma-Glutamyl Hydrolase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170205
[St] Status:MEDLINE
[do] DOI:10.1093/protein/gzx005


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[PMID]:28146062
[Au] Autor:Melling N; Rashed M; Schroeder C; Hube-Magg C; Kluth M; Lang D; Simon R; Möller-Koop C; Steurer S; Sauter G; Jacobsen F; Büscheck F; Wittmer C; Clauditz T; Krech T; Tsourlakis MC; Minner S; Huland H; Graefen M; Budäus L; Thederan I; Salomon G; Schlomm T; Wilczak W
[Ad] Endereço:Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. n.melling@uke.de.
[Ti] Título:High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer.
[So] Source:Int J Mol Sci;18(2), 2017 Jan 29.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers ( < 0.0001), advanced pathological tumor stage, and high Gleason grade ( < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers ( < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry ( < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.
[Mh] Termos MeSH primário: Biomarcadores Tumorais
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/mortalidade
Regulador Transcricional ERG/deficiência
gama-Glutamil Hidrolase/metabolismo
[Mh] Termos MeSH secundário: Proliferação Celular
Expressão Gênica
Seres Humanos
Imuno-Histoquímica
Metástase Linfática
Masculino
Margens de Excisão
Gradação de Tumores
Estadiamento de Neoplasias
Proteínas de Fusão Oncogênicas/genética
Proteínas de Fusão Oncogênicas/metabolismo
Prognóstico
Antígeno Prostático Específico
Neoplasias da Próstata/diagnóstico
Neoplasias da Próstata/cirurgia
Receptores Androgênicos/genética
Receptores Androgênicos/metabolismo
Recidiva
Deleção de Sequência
Regulador Transcricional ERG/genética
gama-Glutamil Hidrolase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Oncogene Proteins, Fusion); 0 (Receptors, Androgen); 0 (TMPRSS2-ERG fusion protein, human); 0 (Transcriptional Regulator ERG); EC 3.4.19.9 (gamma-Glutamyl Hydrolase); EC 3.4.21.77 (Prostate-Specific Antigen)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170420
[Lr] Data última revisão:
170420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE


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[PMID]:27966809
[Au] Autor:Svahn T; Mellgren K; Harila-Saari A; Åsberg A; Kanerva J; Jónsson Ó; Vaitkeviciene G; Stamm Mikkelssen T; Schmiegelow K; Heldrup J
[Ad] Endereço:Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
[Ti] Título:Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia.
[So] Source:Pediatr Blood Cancer;64(7), 2017 Jul.
[Is] ISSN:1545-5017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Carboxypeptidase G2 (CPDG ) can be used as rescue treatment in cases of delayed methotrexate elimination (DME) and Mtx-induced nephrotoxicity. PROCEDURE: Between July 2008 and December 2014, all children (1.0-17.9 years) in the Nordic countries diagnosed with Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) were treated according to the Nordic Organization for Pediatric Hematology and Oncology (NOPHO) ALL 2008 protocol, including administration of six to eight high-dose (5 g/m /24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG administration in cases of DME (clinicaltrials.gov NCT01305655). RESULTS: Forty-seven of the 1,286 children (3.6%) received CPDG during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG was used during the first HDMtx course. Within a median of 6 hr from CPDG administration, the Mtx concentration decreased by 75% when measured with immune-based methods, and by 100% when measured with high-performance liquid chromatography. The median time from the start of Mtx infusion to plasma levels ≤ 0.2 µM was 228 hr (range: 48-438). The maximum increase in plasma creatinine was 375% (range: 100-1,310). Creatinine peaked after a median of 48 hr (range: 36-86). Mtx elimination time was shorter in patients with body surface area < 1 m (median 198.5 vs. 257 hr; P = 0.004) and was inversely correlated to the maximum creatinine increase (209 vs. 258 hr; P = 0.034). All patients normalized their renal function as measured with s-creatinine. CONCLUSIONS: CPDG administration is highly effective as rescue in case of delayed Mtx clearance. Subsequent HDMtx courses could be administered without events in most of the patients.
[Mh] Termos MeSH primário: Lesão Renal Aguda/prevenção & controle
Antimetabólitos Antineoplásicos/efeitos adversos
Metotrexato/efeitos adversos
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
gama-Glutamil Hidrolase/uso terapêutico
[Mh] Termos MeSH secundário: Lesão Renal Aguda/induzido quimicamente
Adolescente
Antimetabólitos Antineoplásicos/administração & dosagem
Antimetabólitos Antineoplásicos/sangue
Criança
Pré-Escolar
Feminino
Seres Humanos
Lactente
Rim/efeitos dos fármacos
Testes de Função Renal
Masculino
Metotrexato/administração & dosagem
Metotrexato/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); EC 3.4.19.9 (gamma-Glutamyl Hydrolase); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161215
[St] Status:MEDLINE
[do] DOI:10.1002/pbc.26395


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[PMID]:27496039
[Au] Autor:Howard SC; McCormick J; Pui CH; Buddington RK; Harvey RD
[Ad] Endereço:School of Health Studies, University of Memphis, Memphis, Tennessee, USA Scott.howard@worldchildcancer.us.
[Ti] Título:Preventing and Managing Toxicities of High-Dose Methotrexate.
[So] Source:Oncologist;21(12):1471-1482, 2016 Dec.
[Is] ISSN:1549-490X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m , is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. IMPLICATIONS FOR PRACTICE: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m , is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos/efeitos adversos
Metotrexato/efeitos adversos
[Mh] Termos MeSH secundário: Lesão Renal Aguda/induzido quimicamente
Lesão Renal Aguda/tratamento farmacológico
Medula Óssea/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Cristalização
Seres Humanos
Leucovorina/uso terapêutico
Metotrexato/química
Metotrexato/farmacocinética
Mucosite/induzido quimicamente
gama-Glutamil Hidrolase/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); EC 3.4.19.9 (gamma-Glutamyl Hydrolase); Q573I9DVLP (Leucovorin); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160807
[St] Status:MEDLINE


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[PMID]:27387303
[Au] Autor:Karube Y; Kobayashi S; Maeda S; Sado T; Ishihama H; Chida M
[Ad] Endereço:Deparment of General Thoracic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, 321-0294, Japan.
[Ti] Título:Tumor-related gene expression levels in thymic carcinoma and Type B3 thymoma.
[So] Source:J Cardiothorac Surg;11(1):85, 2016 May 26.
[Is] ISSN:1749-8090
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Thymic carcinoma (TC) is a rare type of malignant neoplasm that develops in the anterior mediastinum and associated with poor prognosis. Type B3 thymoma (B3) occasionally demonstrates malignant tumor characteristics, especially in the advanced stage. We investigated the expressions of tumor-related genes in resected TC and B3 specimens. METHODS: TC and B3 specimens resected from 1999 through 2012 were investigated. Tumor segments were collected from the specimens by micro-dissection to extract mRNA, then RT-PCR was performed according to Dannenberg's tumor profile method for semi-quantitation of tumor-related gene mRNA. To compare with other types of cancer, data from lung cancer (LC) cases in our database were also examined. RESULTS: The gene expression levels of thymidylate synthase were significantly higher in TC and B3 as compared to LC specimens (p < 0.02), while no difference were observed between TC and B3 tumors. The ratio of folypolyglutamyl synthase (FPGS) to gamma-glutamyl hydrolase (GGH) mRNA was significantly lower in TC than in B3 (p < 0.05), with lower FPGS/GGH in those tumors related to overall survival. Also, the gene expression of vascular endothelial growth factor (VEGF) was significantly higher in TC as compared to B3 (p = 0.04), with higher VEGF gene expression in TC and B3 specimens related to overall survival of affected patients. Epidermal growth factor receptor (EGFR) expression was significantly higher in B3 as compared to both TC and LC specimens (p < 0.01). However, there were no EGFR gene mutations detected in any of the specimens. CONCLUSIONS: These results indicate that elevated expressions of the tumor-related genes FPGS/GGH and VEGF are correlated with malignancy of TC and B3 tumors. Additional examinations will be necessary to investigate their chemosensitivity.
[Mh] Termos MeSH primário: Neoplasias Pulmonares/genética
Timoma/genética
Timoma/patologia
Neoplasias do Timo/genética
Neoplasias do Timo/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Diagnóstico Diferencial
Feminino
Expressão Gênica
Seres Humanos
Masculino
Meia-Idade
Estadiamento de Neoplasias
Peptídeo Sintases/genética
RNA Mensageiro/análise
RNA Neoplásico/análise
Receptor do Fator de Crescimento Epidérmico/genética
Taxa de Sobrevida
Timidilato Sintase/genética
Fator A de Crescimento do Endotélio Vascular/genética
gama-Glutamil Hidrolase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (RNA, Neoplasm); 0 (Vascular Endothelial Growth Factor A); EC 2.1.1.45 (Thymidylate Synthase); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 3.4.19.9 (gamma-Glutamyl Hydrolase); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.17 (folylpolyglutamate synthetase)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160709
[St] Status:MEDLINE
[do] DOI:10.1186/s13019-016-0468-1


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[PMID]:27374188
[Au] Autor:Jeyaharan D; Aston P; Garcia-Perez A; Schouten J; Davis P; Dixon AM
[Ad] Endereço:Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
[Ti] Título:Soluble expression, purification and functional characterisation of carboxypeptidase G2 and its individual domains.
[So] Source:Protein Expr Purif;127:44-52, 2016 Nov.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Due to its applications in the treatment of cancer and autoimmune diseases, the 42 kDa zinc-dependent metalloenzyme carboxypeptidase G2 (CPG2) is of great therapeutic interest. An X-ray crystal structure of unliganded CPG2 reported in 1997 revealed the domain architecture and informed early rational drug design efforts, however further efforts at co-crystallization of CPG2 with ligands, substrates or inhibitors have not been reported. Thus key features of CPG2 such as the location of the active site, the presence of additional ligand-binding sites, stability, oligomeric state, and the molecular basis of activity remain largely unknown, with the current working understanding of CPG2 activity based primarily on computational modelling. To facilitate renewed efforts in CPG2 structural biology, we report the first high-yield (250 mg L(-1)) recombinant expression (and purification) of soluble and active CPG2 using the Escherichia coli expression system. We used this protocol to produce full-length enzyme, as well as protein fragments corresponding to the individual catalytic and dimerization domains, and the activity and stability of each construct was characterised. We adapted our protocol to allow for uniform incorporation of NMR labels ((13)C, (15)N and (2)H) and present preliminary solution-state NMR spectra of high quality. Taken together, our results offer a route for production and solution-state characterization that supports renewed effort in CPG2 structural biology as well as design of significantly truncated CPG2 proteins, which retain activity while yielding (potentially) improved immunogenicity.
[Mh] Termos MeSH primário: Proteínas de Bactérias
Escherichia coli/metabolismo
Expressão Gênica
Pseudomonas/genética
gama-Glutamil Hidrolase
[Mh] Termos MeSH secundário: Proteínas de Bactérias/biossíntese
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Proteínas de Bactérias/isolamento & purificação
Escherichia coli/genética
Ressonância Magnética Nuclear Biomolecular
Domínios Proteicos
Pseudomonas/enzimologia
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/isolamento & purificação
gama-Glutamil Hidrolase/biossíntese
gama-Glutamil Hidrolase/química
gama-Glutamil Hidrolase/genética
gama-Glutamil Hidrolase/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Recombinant Proteins); EC 3.4.19.9 (gamma-Glutamyl Hydrolase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160705
[St] Status:MEDLINE


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[PMID]:27264099
[Au] Autor:Umegaki K; Sekine Y; Sato Y; Chiba T; Sonoda M
[Ad] Endereço:Information Center, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition.
[Ti] Título:Effect of Tea Catechins on Folate Analysis in Green Tea by Microbiological Assay.
[So] Source:J Nutr Sci Vitaminol (Tokyo);62(2):134-8, 2016.
[Is] ISSN:1881-7742
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Green tea is thought to be a primary source of folate in the Japanese diet, based on folate content analyzed by a microbiological assay. Green tea also contains high amount of catechins, in particular, epigallocatechin gallate (EGCg), which was demonstrated to be able to inhibit the digestive enzyme activities and microbial growth in the folate assay. In the present study, we examined whether tea catechins interfered with components of the folate assay for green tea. A marked inhibitory effect of EGCg on microbial growth was observed at an inhibitory concentration of higher than 10 µg/mL. Tea catechins without the galloyl moiety did not show an inhibitory effect. EGCg inhibited the activity of the three enzymes used for assay sample preparation at an inhibitory concentration of higher than 750 µg/mL for α-amylase, 1,000 µg/mL for protease, and 50 µg/mL for conjugase. However, with each step of the assay, the actual concentration of EGCg was decreased to below the inhibitory concentration of each analytical step. Lack of influence of EGCg on green tea folate assay was confirmed by an addition of folate standard in tea infusion. These results suggested that tea catechins have no practical impact on folate analysis in green tea, using the general microbiological assay.
[Mh] Termos MeSH primário: Catequina/farmacologia
Ácido Fólico/farmacologia
Chá/química
[Mh] Termos MeSH secundário: Aspergillus oryzae/efeitos dos fármacos
Aspergillus oryzae/enzimologia
Catequina/análogos & derivados
Inibidores Enzimáticos/farmacologia
Ácido Fólico/análise
Lactobacillus acidophilus/efeitos dos fármacos
Lactobacillus acidophilus/enzimologia
Peptídeo Hidrolases/metabolismo
Streptomyces griseus/efeitos dos fármacos
Streptomyces griseus/enzimologia
alfa-Amilases/antagonistas & inibidores
alfa-Amilases/farmacologia
gama-Glutamil Hidrolase/antagonistas & inibidores
gama-Glutamil Hidrolase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Tea); 8R1V1STN48 (Catechin); 935E97BOY8 (Folic Acid); BQM438CTEL (epigallocatechin gallate); EC 3.2.1.1 (alpha-Amylases); EC 3.4.- (Peptide Hydrolases); EC 3.4.19.9 (gamma-Glutamyl Hydrolase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160607
[St] Status:MEDLINE
[do] DOI:10.3177/jnsv.62.134



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