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[PMID]:29465563
[Au] Autor:Marginean CO; Melit LE; Horvath E; Gozar H; Chincesan MI
[Ad] Endereço:Department of Pediatrics I.
[Ti] Título:Non-Hodgkin lymphoma, diagnostic, and prognostic particularities in children - a series of case reports and a review of the literature (CARE compliant).
[So] Source:Medicine (Baltimore);97(8):e9802, 2018 Feb.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Non-Hodgkin lymphoma remains an unpredictable condition in pediatric patients. PATIENT CONCERNS: Our first case describes an 8-year-old boy with a history of iron deficiency anemia, admitted in our clinic for recurrent abdominal pain, weight loss, loss of appetite, diarrheic stools, and fever. The second case also describes an 8-year-old boy admitted for abdominal pain and vomiting. The 3rd case refers to a 4 years and 10 months old boy admitted in our clinic with abdominal pain and loss of appetite, who was initially admitted in the Pediatrics Surgery Clinic with the suspicion of appendicitis. Our 4th patient was a 5-year-old boy admitted in our clinic for abdominal pain and intermittent diarrheic stools. DIAGNOSES: In the first case, the laboratory tests showed anemia, thrombocytosis, elevated inflammatory biomarkers, a low level of iron, and hypoproteinemia. The abdominal ultrasound and CT exam revealed an abdominal mass, and the histopathological exam established the diagnosis of diffuse large B-cell lymphoma of the bowel. In the second case, the laboratory tests pointed out anemia, elevated ESR and lactate dehydrogenase level, while both abdominal ultrasound and CT exams showed an abdominal mass. The histopathological exam confirmed the diagnosis of Burkitt lymphoma. Regarding our 3rd case, the laboratory findings revealed leukocytosis, anemia, thrombocytosis, increased inflammatory biomarkers, elevated LDH, and a low level of iron. The abdominal ultrasound and the CT scan revealed an abdominal mass which, according to the histopathological exam, was a Burkitt lymphoma. Due to the cranial CT findings the patient was diagnosed with IV stage Burkitt lymphoma with central nervous system metastases. In our 4th patients we found leukocytosis, anemia, mildly increased inflammatory biomarkers, a high level of LDH, hypoproteinemia, and a low level of serum Ir. Both ultrasound and abdominal CT exams were negative, but the exploratory laparotomy identified an abdominal mass, and according to the histopathological exam the patient was diagnosed with Burkitt lymphoma. INTERVENTIONS: All the patients followed chemotherapy (B-NHL BFM 04 protocol) and supportive treatment. OUTCOMES: The first patient died approximately 4 months after the completion of chemotherapy due to tumor relapse, the second patient died after the first cure of chemotherapy and the fourth patient died at approximately 2 years after the diagnosis. The third patient is recurrence-free after 2 years. LESSONS: Despite the advances in the management, NHL remains a fatal condition in pediatrics.
[Mh] Termos MeSH primário: Linfoma não Hodgkin/diagnóstico
[Mh] Termos MeSH secundário: Dor Abdominal/etiologia
Anemia Ferropriva/etiologia
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Asparaginase/uso terapêutico
Criança
Pré-Escolar
Daunorrubicina/uso terapêutico
Diarreia/etiologia
Evolução Fatal
Seres Humanos
Linfoma não Hodgkin/complicações
Linfoma não Hodgkin/tratamento farmacológico
Masculino
Prednisona/uso terapêutico
Prognóstico
Resultado do Tratamento
Vincristina/uso terapêutico
Vômito/etiologia
Perda de Peso
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
5J49Q6B70F (Vincristine); EC 3.5.1.1 (Asparaginase); VB0R961HZT (Prednisone); ZS7284E0ZP (Daunorubicin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180222
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009802


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[PMID]:28461187
[Au] Autor:Garg DK; Kundu B
[Ad] Endereço:Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
[Ti] Título:Hyperthermophilic l-asparaginase bypasses monomeric intermediates during folding to retain cooperativity and avoid amyloid assembly.
[So] Source:Arch Biochem Biophys;622:36-46, 2017 05 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In obligate dimeric proteins of hyperthermophilic origin the question whether the native dimer is obtained by association of folded monomers or through concomitant folding and assembly of subunits has intrigued researchers. To find an answer we studied the folding of a dimeric enzyme l-asparaginase from Pyrococcus furiosus (PfA) for which we reported earlier that it unfolds cooperatively without populating folded monomeric intermediates. However, in the present study we report the finding of a folded monomeric intermediate of PfA under acidic condition. This monomer, although inactive, displayed secondary and tertiary structural features identical to the native protein and re-assembled to active dimeric form upon reversal of pH. The monomer is conformationally flexible and thermodynamically and kinetically less stable than the native dimer. Interestingly, when incubated at 60 °C the folded monomer, with exposed ANS-binding hydrophobic surfaces, spontaneously converted to amyloid fibrils. On the basis of our data we propose that PfA directly assembles into a multimeric form perhaps as an evolutionary adaptation to avoid accumulation of aggregation prone monomeric intermediates.
[Mh] Termos MeSH primário: Amiloide/metabolismo
Asparaginase/metabolismo
Dobramento de Proteína
Pyrococcus furiosus/enzimologia
[Mh] Termos MeSH secundário: Amiloide/química
Asparaginase/química
Estabilidade Enzimática
Cinética
Modelos Moleculares
Multimerização Proteica
Pyrococcus furiosus/química
Pyrococcus furiosus/metabolismo
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amyloid); EC 3.5.1.1 (Asparaginase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:29200162
[Au] Autor:Valliyammai N; Nancy NK; Sagar TG; Rajkumar T
[Ad] Endereço:Departments of Molecular Oncology.
[Ti] Título:Study of NOTCH1 and FBXW7 Mutations and Its Prognostic Significance in South Indian T-Cell Acute Lymphoblastic Leukemia.
[So] Source:J Pediatr Hematol Oncol;40(1):e1-e8, 2018 Jan.
[Is] ISSN:1536-3678
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NOTCH1/FBXW7 mutations trigger oncogenic NOTCH1 signaling and its downstream target genes play crucial roles in the molecular pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). In the present study, NOTCH1 and FBXW7 mutations were studied in 25 primary T-ALL samples. All 34 exons of NOTCH1 and hotspot exons (exon 9 and exon 10) of FBXW7 were polymerase chain reaction amplified and sequenced for mutations. Our results showed that 13/25 (52%) were NOTCH1-mutated, of which 11 patients (44%) showed mutation in the hotspot exons. Four patients (16%) had mutations in non-hotspot exons of NOTCH1. Notably, 2 T-ALL patients (8%) harbored mutations in both hotspot and non-hotspot exons of NOTCH1, whereas 2 patients (8%) had mutations in the hotspot exons of FBXW7. In all, 7 mutations were identified which were not previously reported. The real-time polymerase chain reaction study in 15 patients revealed that increased expression of activated NOTCH1 was found in NOTCH1/FBXW7 hotspot exon-mutated cases. In addition, NOTCH1/FBXW7-mutated patients had showed upregulated HES1, c-MYC, NOTCH3 gene expression. When survival analysis was performed including samples (n=50) from our previous study, an early treatment response and better survival was observed in NOTCH1/FBXW7 hotspot-mutated patients. Our study suggests that NOTCH1/FBXW7 hotspot-mutated T-ALL cases had better response to ALL BFM-95 protocol.
[Mh] Termos MeSH primário: Proteína 7 com Repetições F-Box-WD/genética
Mutação
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
Prognóstico
Receptor Notch1/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Protocolos de Quimioterapia Combinada Antineoplásica
Asparaginase
Criança
Pré-Escolar
Ciclofosfamida
Citarabina
Análise Mutacional de DNA
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Índia/epidemiologia
Lactente
Recém-Nascido
Masculino
Mercaptopurina
Metotrexato
Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico
Leucemia-Linfoma Linfoblástico de Células T Precursoras/epidemiologia
Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade
Prednisona
Análise de Sobrevida
Vincristina
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (F-Box-WD Repeat-Containing Protein 7); 0 (FBXW7 protein, human); 0 (NOTCH1 protein, human); 0 (Receptor, Notch1); 04079A1RDZ (Cytarabine); 5J49Q6B70F (Vincristine); 8N3DW7272P (Cyclophosphamide); E7WED276I5 (Mercaptopurine); EC 3.5.1.1 (Asparaginase); VB0R961HZT (Prednisone); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180112
[Lr] Data última revisão:
180112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1097/MPH.0000000000001006


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[PMID]:27778143
[Au] Autor:Haverkos BM; Pan Z; Gru AA; Freud AG; Rabinovitch R; Xu-Welliver M; Otto B; Barrionuevo C; Baiocchi RA; Rochford R; Porcu P
[Ad] Endereço:Division of Hematology, University of Colorado, 1665 Aurora Ct., Mail Stop F754, Aurora, CO, 80045, USA. bradley.haverkos@ucdenver.edu.
[Ti] Título:Extranodal NK/T Cell Lymphoma, Nasal Type (ENKTL-NT): An Update on Epidemiology, Clinical Presentation, and Natural History in North American and European Cases.
[So] Source:Curr Hematol Malig Rep;11(6):514-527, 2016 Dec.
[Is] ISSN:1558-822X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE OF REVIEW: Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT) is an aggressive extranodal non-Hodgkin lymphoma most commonly occurring in East Asia and Latin America but with increasing incidence in the United States. Data on epidemiology, disease presentation, and outcome for European and North American ("Western") cases are very limited. We review published landmark clinical studies on ENKTL-NT in the West and report in detail recent data, including our institutional experience. RECENT FINDINGS: We highlight key observations in its epidemiology, natural history, and trends in clinical management. In the USA, ENKTL-NT is more common among Asian Pacific Islanders (API) and Hispanics compared to non-Hispanic whites. Published studies indicate less heterogeneity in clinical presentation in Western ENKTL-NT compared to Asian patients. While there is variation in age at diagnosis, presence of antecedent lymphoproliferative disorders, and outcomes among racial/ethnic groups, the universal association of ENKTL-NT with EBV and the poor response of this neoplasm to anthracycline-based therapy is consistent across all geographic areas. Data on epidemiology, disease presentation, and clinical outcomes in mature T cell and NK cell (T/NK cell) neoplasms, including ENKTL-NT, in Europe and North America are very limited. As the classification and diagnostic characterization of the currently recognized T/NK cell lymphoma disease entities continue to evolve, gaps and inconsistencies in data reporting across different studies are being recognized. Despite these limitations, several studies from the USA suggest that the incidence of ENKTL-NT is higher in Asian Pacific Islanders (API) and non-white Hispanics and that outcomes may be worse in non-whites. However, the universal association of ENKTL-NT with Epstein-Barr virus (EBV) across all ethnic groups suggests a common pathogenesis. Given the overlap between the entities included in the category of T/NK cell neoplasms, there is a need to further define biological and clinical differences that may affect diagnosis, treatment, and outcome.
[Mh] Termos MeSH primário: Linfoma Extranodal de Células T-NK/patologia
[Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico
Asparaginase/uso terapêutico
Biomarcadores/sangue
DNA Viral/análise
Europa (Continente)/epidemiologia
Herpesvirus Humano 4/genética
Herpesvirus Humano 4/isolamento & purificação
Herpesvirus Humano 4/fisiologia
Seres Humanos
Linfoma Extranodal de Células T-NK/tratamento farmacológico
Linfoma Extranodal de Células T-NK/epidemiologia
Linfoma Extranodal de Células T-NK/virologia
América do Norte/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers); 0 (DNA, Viral); EC 3.5.1.1 (Asparaginase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171201
[Lr] Data última revisão:
171201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1007/s11899-016-0355-9


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[PMID]:28837806
[Au] Autor:Zhdanov DD; Pokrovsky VS; Pokrovskaya MV; Alexandrova SS; Eldarov MA; Grishin DV; Basharov MM; Gladilina YA; Podobed OV; Sokolov NN
[Ad] Endereço:Institute of Biomedical Chemistry, Moscow, Russia. Electronic address: zhdanovdd@gmail.com.
[Ti] Título:Rhodospirillum rubruml-asparaginase targets tumor growth by a dual mechanism involving telomerase inhibition.
[So] Source:Biochem Biophys Res Commun;492(2):282-288, 2017 Oct 14.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rhodospirillum rubruml-asparaginase mutant RrA E149R, V150P, F151T (RrA) was previously identified to down-regulate telomerase activity along with catalyzing the hydrolysis of l-asparagine. The aim of this study was to define the effect of prolonged RrA exposure on telomerase activity, maintenance of telomeres and proliferation of cancer cells in vitro and in vivo. RrA could inhibit telomerase activity in SCOV-3, SkBr-3 and A549 human cancer cell lines due to its ability to down-regulate the expression of telomerase catalytic subunit hTERT. Telomerase activity in treated cells did not exceeded 29.63 ± 12.3% of control cells. Continuous RrA exposure of these cells resulted in shortening of telomeres followed by cell death in vitro. Using real time PCR we showed that length of telomeres in SCOV-3 cells has been gradually decreasing from 10105 ± 2530 b.p. to 1233 ± 636 b.p. after 35 days of cultivation. RrA treatment of xenograft models in vivo showed slight inhibition of tumor growth accompanied with 49.5-53.3% of decrease in hTERT expression in the all tumors. However down-regulation of hTERT expression, inhibition of telomerase activity and the loss of telomeres was significant in response to RrA administration in xenograft models. These results should facilitate further investigations of RrA as a potent therapeutic protein.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Asparaginase/uso terapêutico
Regulação para Baixo/efeitos dos fármacos
Inibidores Enzimáticos/uso terapêutico
Neoplasias/tratamento farmacológico
Rhodospirillum/enzimologia
Telomerase/genética
[Mh] Termos MeSH secundário: Animais
Asparaginase/genética
Linhagem Celular Tumoral
Feminino
Seres Humanos
Camundongos Endogâmicos BALB C
Camundongos Nus
Neoplasias/genética
Neoplasias/patologia
Mutação Puntual
Rhodospirillum/genética
Encurtamento do Telômero/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); EC 2.7.7.49 (Telomerase); EC 3.5.1.1 (Asparaginase)
[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:170825
[St] Status:MEDLINE


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[PMID]:28817702
[Au] Autor:Kuang Q; Zhang S; Wu P; Chen Y; Li M; Jiang H; Wu G
[Ad] Endereço:Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China.
[Ti] Título:Global gene expression analysis of the response of physic nut (Jatropha curcas L.) to medium- and long-term nitrogen deficiency.
[So] Source:PLoS One;12(8):e0182700, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Jatropha curcas L. is an important biofuel plant with excellent tolerance of barren environments. However, studies on the regulatory mechanisms that operate in this plant in response to nitrogen (N) shortage are scarce. In this study, genome-wide transcriptional profiles of the roots and leaves of 8-week old physic nut seedlings were analyzed after 2 and 16 days of N starvation. Enrichment results showed that genes associated with N metabolism, processing and regulation of RNA, and transport predominated among those showing alterations in expression. Genes encoding transporter families underwent major changes in expression in both roots and leaves; in particular, those with roles in ammonia, amino acid and peptide transport were generally up-regulated after long-term starvation, while AQUAPORIN genes, whose products function in osmoregulation, were down-regulated. We also found that ASPARA-GINASE B1 and SARCOSINE OXIDASE genes were up-regulated in roots and leaves after 2 and 16 d N starvation. Genes associated with ubiquitination-mediated protein degradation were significantly up-regulated. In addition, genes in the JA biosynthesis pathway were strongly activated while expression of those in GA signaling was inhibited in leaves. We showed that four major classes of genes, those with roles in N uptake, N reutilization, C/N ratio balance, and cell structure and synthesis, were particularly influenced by long-term N limitation. Our discoveries may offer clues to the molecular mechanisms that regulate N reallocation and reutilization so as to maintain or increase plant performance even under adverse environmental conditions.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica de Plantas
Jatropha/genética
Nitrogênio/deficiência
Transcriptoma
[Mh] Termos MeSH secundário: Aquaporinas/genética
Aquaporinas/metabolismo
Asparaginase/genética
Asparaginase/metabolismo
Jatropha/metabolismo
Proteínas de Plantas/genética
Proteínas de Plantas/metabolismo
Sarcosina Oxidase/genética
Sarcosina Oxidase/metabolismo
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aquaporins); 0 (Plant Proteins); EC 1.5.3.1 (Sarcosine Oxidase); EC 3.5.1.1 (Asparaginase); N762921K75 (Nitrogen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182700


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[PMID]:28787435
[Au] Autor:Piatopoulou D; Avgeris M; Marmarinos A; Xagorari M; Baka M; Doganis D; Kossiva L; Scorilas A; Gourgiotis D
[Ad] Endereço:Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, 'P &A Kyriakou' Children's Hospital, Levadias 13 Street, Athens 11527, Greece.
[Ti] Título:miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment.
[So] Source:Br J Cancer;117(6):801-812, 2017 Sep 05.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Despite the favourable survival rates of childhood acute lymphoblastic leukaemia (ALL), a significant number of patients present resistance to antileukaemic agents and dismal prognosis. In this study, we analysed miR-125b expression in childhood ALL and evaluated its clinical utility for patients treated with Berlin-Frankfurt-Münster (BFM) protocol. METHODS: The study included 272 bone marrow specimens obtained on diagnosis and on BFM day 33 from 125 patients and 64 healthy children. Following extraction, RNA was polyadenylated and reverse transcribed. miR-125b levels were quantified by quantitative PCR. Cytogenetics, immunohistotype and MRD were analysed according to international guidelines. RESULTS: Downregulated miR-125b levels were detected in childhood ALL patients and correlated with adverse prognosis. Following BFM induction, miR-125b levels were significantly increased, however, elevated day 33/diagnosis miR-125b ratio was associated with unfavourable disease features. Loss of miR-125b during diagnosis and higher day 33/diagnosis ratio were correlated with stronger risk for disease short-term relapse and patients' worse survival. Moreover, multivariate regression models highlighted the independent prognostic value of miR-125b for childhood ALL. Finally, the combination of miR-125b with clinically used disease markers clearly enhanced the prediction of patients' resistance to BFM chemotherapy. CONCLUSIONS: miR-125b significantly improves the prognosis of childhood ALL patients' outcome under BFM treatment.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
MicroRNAs/metabolismo
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
[Mh] Termos MeSH secundário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Asparaginase/administração & dosagem
Biomarcadores Tumorais/análise
Biomarcadores Tumorais/metabolismo
Medula Óssea/patologia
Criança
Pré-Escolar
DNA Complementar
Daunorrubicina/administração & dosagem
Progressão da Doença
Regulação para Baixo
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Lactente
Estimativa de Kaplan-Meier
Masculino
MicroRNAs/análise
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade
Prednisona/administração & dosagem
Prognóstico
Reação em Cadeia da Polimerase em Tempo Real
Análise de Regressão
Resultado do Tratamento
Vincristina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (DNA, Complementary); 0 (MIRN125 microRNA, human); 0 (MicroRNAs); 5J49Q6B70F (Vincristine); EC 3.5.1.1 (Asparaginase); VB0R961HZT (Prednisone); ZS7284E0ZP (Daunorubicin)
[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:170809
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.256


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[PMID]:28736188
[Au] Autor:Wolthers BO; Frandsen TL; Baruchel A; Attarbaschi A; Barzilai S; Colombini A; Escherich G; Grell K; Inaba H; Kovacs G; Liang DC; Mateos M; Mondelaers V; Möricke A; Ociepa T; Samarasinghe S; Silverman LB; van der Sluis IM; Stanulla M; Vrooman LM; Yano M; Zapotocka E; Schmiegelow K; Ponte di Legno Toxicity Working Group
[Ad] Endereço:Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
[Ti] Título:Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study.
[So] Source:Lancet Oncol;18(9):1238-1248, 2017 Sep.
[Is] ISSN:1474-5488
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. METHODS: Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark. FINDINGS: Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p<0·0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea; 96 [44%] of 217 patients with affected vital signs vs 11 [24%] of 46 patients without affected vital signs, p=0·02). 1 year after diagnosis of asparaginase-associated pancreatitis, 31 (11%) of 275 patients still needed insulin or had recurrent abdominal pain or both. Both the risk of persisting need for insulin therapy and recurrent abdominal pain were associated with having had pseudocysts (odds ratio [OR] 9·48 [95% CI 3·01-35·49], p=0·0002 for insulin therapy; OR 11·79 [4·30-37·98], p<0·0001 for recurrent abdominal pain). Within 8 years of asparaginase-associated pancreatitis, risk of abdominal symptoms dropped from 8% (26 of 312) to 0% (0 of 35) but the need for insulin therapy remained constant (9%, three of 35). 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-associated pancreatitis (abdominal pain or pancreatic enzymes at least three times the ULN or both lasting longer than 72 h). 44 (46%) patients developed a second asparaginase-associated pancreatitis, 22 (52%) of 43 being severe. Risk of persisting need for insulin or abdominal pain after having had two versus one asparaginase-associated pancreatitis did not differ (three [7%] of 42 vs 28 [12%] of 233, p=0·51). Risk of a second asparaginase-associated pancreatitis was not associated with any baseline patient characteristics. INTERPRETATION: Since the risk of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an increased risk of complications, asparaginase re-exposure should be determined mainly by the anticipated need for asparaginase for antileukaemic efficacy. A study of the genetic risk factors identifying patients in whom asparaginase exposure should be restricted is needed. FUNDING: The Danish Childhood Cancer Foundation and The Danish Cancer Society (R150-A10181).
[Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos
Asparaginase/efeitos adversos
Pancreatite/induzido quimicamente
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Estudos de Coortes
Feminino
Seres Humanos
Lactente
Masculino
Pancreatite/epidemiologia
Pancreatite/terapia
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Antineoplastic Agents); EC 3.5.1.1 (Asparaginase)
[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:170725
[St] Status:MEDLINE


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[PMID]:28671857
[Au] Autor:Hardy KK; Embry L; Kairalla JA; Helian S; Devidas M; Armstrong D; Hunger S; Carroll WL; Larsen E; Raetz EA; Loh ML; Yang W; Relling MV; Noll RB; Winick N
[Ad] Endereço:Kristina K. Hardy, Children's National Medical Center, Washington, DC; Leanne Embry, The University of Texas Health Science Center at San Antonio, San Antonio; Naomi Winick, University of Texas Southwestern Medical Center, Dallas, TX; John A. Kairalla and Meenakshi Devidas, Colleges of Medicine, Pub
[Ti] Título:Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report From the Children's Oncology Group.
[So] Source:J Clin Oncol;35(23):2700-2707, 2017 Aug 10.
[Is] ISSN:1527-7755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Cognição/efeitos dos fármacos
Inteligência/efeitos dos fármacos
Memória de Curto Prazo/efeitos dos fármacos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico
Tempo de Reação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Corticosteroides/administração & dosagem
Adultos Sobreviventes de Eventos Adversos na Infância
Fatores Etários
Asparaginase/administração & dosagem
Criança
Dexametasona/administração & dosagem
Feminino
Seres Humanos
Seguro Saúde
Leucovorina/administração & dosagem
Masculino
Medicaid
Metotrexato/administração & dosagem
Polietilenoglicóis/administração & dosagem
Leucemia-Linfoma Linfoblástico de Células Precursoras B/psicologia
Prednisona/administração & dosagem
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Adrenal Cortex Hormones); 30IQX730WE (Polyethylene Glycols); 7D96IR0PPM (pegaspargase); 7S5I7G3JQL (Dexamethasone); EC 3.5.1.1 (Asparaginase); Q573I9DVLP (Leucovorin); VB0R961HZT (Prednisone); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1200/JCO.2016.71.7587


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[PMID]:28671681
[Au] Autor:Iraci N; Gaude E; Leonardi T; Costa ASH; Cossetti C; Peruzzotti-Jametti L; Bernstock JD; Saini HK; Gelati M; Vescovi AL; Bastos C; Faria N; Occhipinti LG; Enright AJ; Frezza C; Pluchino S
[Ad] Endereço:Wellcome Trust-Medical Research Council Stem Cell Institute, Department of Clinical Neurosciences-Division of Stem Cell Neurobiology, and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK.
[Ti] Título:Extracellular vesicles are independent metabolic units with asparaginase activity.
[So] Source:Nat Chem Biol;13(9):951-955, 2017 Sep.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Extracellular vesicles (EVs) are membrane particles involved in the exchange of a broad range of bioactive molecules between cells and the microenvironment. Although it has been shown that cells can traffic metabolic enzymes via EVs, much remains to be elucidated with regard to their intrinsic metabolic activity. Accordingly, herein we assessed the ability of neural stem/progenitor cell (NSC)-derived EVs to consume and produce metabolites. Our metabolomics and functional analyses both revealed that EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1). Critically, we show that Asrgl1 activity is selective for asparagine and is devoid of glutaminase activity. We found that mouse and human NSC EVs traffic Asrgl1. Our results demonstrate, for the first time, that NSC EVs function as independent metabolic units that are able to modify the concentrations of critical nutrients, with the potential to affect the physiology of their microenvironment.
[Mh] Termos MeSH primário: Asparaginase/metabolismo
Vesículas Extracelulares/metabolismo
Modelos Biológicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.5.1.1 (Asparaginase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2422



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