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[PMID]:29396713
[Au] Autor:Kiladjian JJ; Guglielmelli P; Griesshammer M; Saydam G; Masszi T; Durrant S; Passamonti F; Jones M; Zhen H; Li J; Gadbaw B; Perez Ronco J; Khan M; Verstovsek S
[Ad] Endereço:Centre d'Investigations Cliniques (CIC1427), Hôpital Saint-Louis, AP-HP, INSERM, CLIP2 "Saint-Louis - Paris Nord," Early Phase Research Center, Université Paris Diderot, 1, Avenue Claude Vellefaux, 75010, Paris, France. jean-jacques.kiladjian@aphp.fr.
[Ti] Título:Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies.
[So] Source:Ann Hematol;97(4):617-627, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov .
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Interferons/uso terapêutico
Janus Quinases/antagonistas & inibidores
Policitemia Vera/tratamento farmacológico
Inibidores de Proteínas Quinases/uso terapêutico
Pirazóis/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Antineoplásicos/efeitos adversos
Sangria/efeitos adversos
Terapia Combinada/efeitos adversos
Estudos Cross-Over
Monitoramento de Medicamentos
Resistência a Múltiplos Medicamentos
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Hidroxiureia/efeitos adversos
Hidroxiureia/uso terapêutico
Interferons/efeitos adversos
Janus Quinases/metabolismo
Masculino
Meia-Idade
Policitemia Vera/metabolismo
Policitemia Vera/fisiopatologia
Policitemia Vera/terapia
Padrões de Prática Médica
Inibidores de Proteínas Quinases/efeitos adversos
Pirazóis/efeitos adversos
Reprodutibilidade dos Testes
Esplenomegalia/etiologia
Esplenomegalia/prevenção & controle
[Pt] Tipo de publicação:CLINICAL TRIAL; CLINICAL TRIAL, PHASE III; COMPARATIVE STUDY; EQUIVALENCE TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (INCB018424); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 9008-11-1 (Interferons); EC 2.7.10.2 (Janus Kinases); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180204
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3225-1


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[PMID]:29242203
[Au] Autor:Odame I
[Ad] Endereço:THE HOSPITAL FOR SICK CHILDREN.
[Ti] Título:Hydroxyurea for SCA in Africa: no malaria harm.
[So] Source:Blood;130(24):2575-2576, 2017 12 14.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Antidrepanocíticos
Hidroxiureia
[Mh] Termos MeSH secundário: África
Anemia Falciforme
Seres Humanos
Malária
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Antisickling Agents); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-10-812974


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[PMID]:29074595
[Au] Autor:Harrison CN; Mead AJ; Panchal A; Fox S; Yap C; Gbandi E; Houlton A; Alimam S; Ewing J; Wood M; Chen F; Coppell J; Panoskaltsis N; Knapper S; Ali S; Hamblin A; Scherber R; Dueck AC; Cross NCP; Mesa R; McMullin MF
[Ad] Endereço:Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
[Ti] Título:Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide.
[So] Source:Blood;130(17):1889-1897, 2017 Oct 26.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT ( = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716.
[Mh] Termos MeSH primário: Resistência a Medicamentos
Hidroxiureia/uso terapêutico
Pirazóis/uso terapêutico
Trombocitemia Essencial/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Progressão da Doença
Feminino
Hemorragia/complicações
Seres Humanos
Masculino
Meia-Idade
Pirazóis/efeitos adversos
Trombocitemia Essencial/complicações
Trombocitemia Essencial/genética
Trombocitemia Essencial/patologia
Resultado do Tratamento
Suspensão de Tratamento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (INCB018424); 0 (Pyrazoles); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171028
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-05-785790


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[PMID]:28915422
[Au] Autor:Legrand T; Rakotoson MG; Galactéros F; Bartolucci P; Hulin A
[Ad] Endereço:Laboratoire de Pharmacologie-Toxicologie, Hôpitaux Universitaires Henri Mondor, Assistance Publique des Hôpitaux de Paris, 94000 Créteil, France. Electronic address: tiphaine.legrand@aphp.fr.
[Ti] Título:Determination of hydroxyurea in human plasma by HPLC-UV using derivatization with xanthydrol.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1064:85-91, 2017 Oct 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A simple and rapid high performance liquid chromatography (HPLC) method using ultraviolet (UV) detection was developed to determine hydroxyurea (HU) concentration in plasma sample after derivatization with xanthydrol. Two hundred microliters samples were spiked with methylurea (MeU) as internal standard and proteins were precipitated by adding methanol. Derivatization of HU and MeU was immediately performed by adding 0.02M xanthydrol and 1.5M HCl in order to obtain xanthyl-derivatives of HU and MeU that can be further separated using HPLC and quantified using UV detection at 240nm. Separation was achieved using a C18 column with a mobile phase composed of 20mM ammonium acetate and acetonitrile in gradient elution mode at a flow rate of 1mL/min. The total analysis time did not exceed 18min. The method was found linear from 5 to 400µM and all validation parameters fulfilled the international requirements. Between- and within-run accuracy error ranged from -4.7% to 3.2% and precision was lower than 12.8%. This simple method requires small volume samples and can be easily implemented in most clinical laboratories to develop pharmacokinetics studies of HU and to promote its therapeutic monitoring.
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão/métodos
Hidroxiureia/sangue
Xantenos/química
[Mh] Termos MeSH secundário: Anemia Falciforme/tratamento farmacológico
Seres Humanos
Hidroxiureia/uso terapêutico
Modelos Lineares
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Xanthenes); 7131M69IKF (xanthydrol); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE


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[PMID]:28891355
[Au] Autor:Ghafuri DL; Stimpson SJ; Day ME; James A; DeBaun MR; Sharma D
[Ad] Endereço:a Department of Pediatrics, Division of Hematology/Oncology, Vanderbilt-Meharry-Matthew Walker Center for Excellence in Sickle Cell Disease , Vanderbilt University Medical Center , Nashville , TN , USA.
[Ti] Título:Fertility challenges for women with sickle cell disease.
[So] Source:Expert Rev Hematol;10(10):891-901, 2017 Oct.
[Is] ISSN:1747-4094
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD.
[Mh] Termos MeSH primário: Anemia Falciforme/complicações
Fertilidade
Infertilidade/etiologia
Insuficiência Ovariana Primária/etiologia
[Mh] Termos MeSH secundário: Anemia Falciforme/terapia
Transfusão de Sangue
Dor Crônica/etiologia
Dor Crônica/terapia
Feminino
Preservação da Fertilidade/métodos
Terapia Genética
Transplante de Células-Tronco Hematopoéticas
Seres Humanos
Hidroxiureia/efeitos adversos
Hidroxiureia/uso terapêutico
Gravidez
Saúde Reprodutiva
Condicionamento Pré-Transplante/efeitos adversos
Condicionamento Pré-Transplante/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1080/17474086.2017.1367279


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[PMID]:28863145
[Au] Autor:Teixeira RS; Terse-Ramos R; Ferreira TA; Machado VR; Perdiz MI; Lyra IM; Nascimento VL; Boa-Sorte N; Andrade BB; Ladeia AM
[Ad] Endereço:Bahiana School of Medicine and Public Health, Bahia Foundation for the Development of Sciences Salvador, Salvador, Bahia, Brazil.
[Ti] Título:Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia.
[So] Source:PLoS One;12(9):e0184076, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hematological changes can drive damage of endothelial cells, which potentially lead to an early endothelial dysfunction in patients with sickle cell anemia (SCA). An association may exist between endothelial dysfunction and several clinical manifestations of SCA. The present study aims to evaluate the links between changes in endothelial function and clinical and laboratory parameters in children and adolescents with SCA. METHODS: This study included 40 children and adolescents with stable SCA as well as 25 healthy children; aged 6-18 years. All study subjects were evaluated for endothelial function using Doppler ultrasonography. In addition, a number of laboratory assays were performed, including reticulocyte and leukocyte counts as well as measurement of circulating levels of total bilirubin, C-reactive protein (CRP), glucose, lipoproteins and peripheral oxyhemoglobin saturation. These parameters were also compared between SCA patients who were undertaking hydroxyurea (HU) and those who were not. RESULTS: Flow-mediated vasodilation (FMD) values were found to be reduced in SCA patients compared with those detected in healthy controls. SCA individuals with lower FMD values exhibited higher number of hospital admissions due to vaso-occlusive events. Additional analyses revealed that patients who had decreased FMD values exhibited higher odds of acute chest syndrome (ACS) episodes. A preliminary analysis with limited number of individuals failed to demonstrate significant differences in FMD values between SCA individuals who were treated with HU and those who were not. CONCLUSIONS: Children and adolescents with SCA exhibit impaired endothelial function. Reductions in FMD values are associated with ACS. These findings underline the potential use of FMD as screening strategy of SCA patients with severe prognosis at early stages.
[Mh] Termos MeSH primário: Anemia Falciforme/sangue
Anemia Falciforme/complicações
Endotélio Vascular/fisiopatologia
Doenças Vasculares/sangue
Doenças Vasculares/complicações
[Mh] Termos MeSH secundário: Adolescente
Antidrepanocíticos/uso terapêutico
Bilirrubina/sangue
Proteína C-Reativa/análise
Estudos de Casos e Controles
Criança
Células Endoteliais/patologia
Feminino
Glucose/análise
Seres Humanos
Hidroxiureia/uso terapêutico
Contagem de Leucócitos
Lipoproteínas/sangue
Masculino
Oxiemoglobinas/análise
Reticulócitos/citologia
Ultrassonografia Doppler
Doenças Vasculares/diagnóstico por imagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antisickling Agents); 0 (Lipoproteins); 0 (Oxyhemoglobins); 9007-41-4 (C-Reactive Protein); IY9XDZ35W2 (Glucose); RFM9X3LJ49 (Bilirubin); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170902
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184076


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[PMID]:28837865
[Au] Autor:Tian Y; Liu G; Wang H; Tian Z; Cai Z; Zhang F; Luo Y; Wang S; Guo G; Wang X; Powell S; Feng Z
[Ad] Endereço:Department of Occupational Health and Occupational Medicine, The Public Health School, Shandong University, Shandong, Jinan, 250012, China.
[Ti] Título:Valproic acid sensitizes breast cancer cells to hydroxyurea through inhibiting RPA2 hyperphosphorylation-mediated DNA repair pathway.
[So] Source:DNA Repair (Amst);58:1-12, 2017 Oct.
[Is] ISSN:1568-7856
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:It was reported that valproic acid (VPA, a histone deacetylase inhibitor) can sensitize cancer cells to hydroxyurea (HU, a ribonucleotide reductase inhibitor) for chemotherapy, although the mechanism of VPA-induced HU sensitization is unclear. In this study, we systematically characterized VPA-induced HU sensitization of breast cancer cells. Multiple breast cancer cell models were employed to investigate whether the safe concentration of 0.5mM VPA and 2mM HU can result in DNA double-strand breaks (DSBs) and impact cell survival. Furthermore, the underlying mechanism was explored through cell biology assays, including clonogenic survival, homologous recombination (HR) activity, immunoblot and immunofluorescence. We found that VPA and HU cooperatively suppressed cancer cell survival. VPA resulted in the accumulation of more DNA double-strand breaks (DSBs) in response to HU-induced replication arrest and was able to block HU-stimulated homologous recombination (HR) through inhibiting the activity of two key HR repair proteins by hyperphosphorylation of replication protein A2 (RPA2-p) and recombinase Rad51. However, apoptosis was not detected under this condition. In addition, the results from the survival fraction in the cells expressing defective RPA2-p showed that VPA disrupted the HU-induced RPA2-p-Rad51-mediated HR pathway. Importantly, these findings were further supported by analyzing primary-culture cells from the tissue of chemical carcinogen (DMBA)-induced breast cancer in rats. Thus, our data demonstrated that VPA and HU synergistically suppressed tumor cells via disturbing RPA2-p-mediated DNA repair pathway, which provides a new way for combining chemotherapeutic drugs to sensitize breast cancer cells.
[Mh] Termos MeSH primário: Neoplasias da Mama/tratamento farmacológico
Hidroxiureia/uso terapêutico
Reparo de DNA por Recombinação/efeitos dos fármacos
Proteína de Replicação A/antagonistas & inibidores
Ácido Valproico/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Neoplasias da Mama/metabolismo
DNA/metabolismo
Quebras de DNA de Cadeia Dupla
Replicação do DNA/efeitos dos fármacos
Feminino
Seres Humanos
Rad51 Recombinase/metabolismo
Ratos
Proteína de Replicação A/metabolismo
Ácido Valproico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Replication Protein A); 0 (Rpa2 protein, rat); 614OI1Z5WI (Valproic Acid); 9007-49-2 (DNA); EC 2.7.7.- (Rad51 Recombinase); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170825
[St] Status:MEDLINE


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[PMID]:28750923
[Au] Autor:Caslin HL; McLeod JJA; Spence AJ; Qayum AA; Kolawole EM; Taruselli MT; Paranjape A; Elford HL; Ryan JJ
[Ad] Endereço:Department of Biology, Virginia Commonwealth University, Richmond, VA, 23284, United States.
[Ti] Título:Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IL-33-induced cytokine production in primary mouse mast cells.
[So] Source:Cell Immunol;319:10-16, 2017 Sep.
[Is] ISSN:1090-2163
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:While IgE is considered the primary mediator of mast cell activation, IL-33 contributes substantially in asthma, allergic rhinitis, and atopic dermatitis. To develop effective treatments for allergic disease, it is important to understand the role of therapeutic agents on IL-33 activation. We examined the effect of Didox (3,4-dihydroxybenzohydroxamic acid), an antioxidant and ribonucleotide reductase (RNR) inhibitor, on IL-33-mediated mast cell activation. Didox suppressed IL-6, IL-13, TNF, and MIP-1α (CCL3) production in bone marrow derived mast cells following IL-33 activation. This suppression was observed in different genetic backgrounds and extended to peritoneal mast cells. The antioxidant N-acetylcysteine mimicked the suppression of Didox, albeit at a much higher dose, while the RNR inhibitor hydroxyurea had no effect. Didox substantially suppressed IL-33-mediated NFκB and AP-1 transcriptional activities. These results suggest that Didox attenuates IL-33-induced mast cell activation and should be further studied as a potential therapeutic agent for inflammatory diseases involving IL-33.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica/efeitos dos fármacos
Ácidos Hidroxâmicos/farmacologia
Imunossupressores/farmacologia
Interleucina-33/farmacologia
Mastócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilcisteína/farmacologia
Animais
Células da Medula Óssea/citologia
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/imunologia
Quimiocina CCL3/antagonistas & inibidores
Quimiocina CCL3/genética
Quimiocina CCL3/imunologia
Feminino
Regulação da Expressão Gênica/imunologia
Genes Reporter
Hidroxiureia/farmacologia
Interleucina-13/antagonistas & inibidores
Interleucina-13/genética
Interleucina-13/imunologia
Interleucina-33/antagonistas & inibidores
Lipopolissacarídeos/farmacologia
Luciferases/genética
Luciferases/imunologia
Masculino
Mastócitos/citologia
Mastócitos/imunologia
Camundongos
Camundongos Endogâmicos C57BL
NF-kappa B/antagonistas & inibidores
NF-kappa B/genética
NF-kappa B/imunologia
Cultura Primária de Células
Transdução de Sinais
Fator de Transcrição AP-1/antagonistas & inibidores
Fator de Transcrição AP-1/genética
Fator de Transcrição AP-1/imunologia
Fator de Necrose Tumoral alfa/antagonistas & inibidores
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ccl3 protein, mouse); 0 (Chemokine CCL3); 0 (Hydroxamic Acids); 0 (Il33 protein, mouse); 0 (Immunosuppressive Agents); 0 (Interleukin-13); 0 (Interleukin-33); 0 (Lipopolysaccharides); 0 (NF-kappa B); 0 (Transcription Factor AP-1); 0 (Tumor Necrosis Factor-alpha); EC 1.13.12.- (Luciferases); L106XFV0RQ (3,4-dihydroxybenzohydroxamic acid); WYQ7N0BPYC (Acetylcysteine); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE


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[PMID]:28749973
[Au] Autor:Li W; Yi J; Agbu P; Zhou Z; Kelley RL; Kallgren S; Jia S; He X
[Ad] Endereço:Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
[Ti] Título:Replication stress affects the fidelity of nucleosome-mediated epigenetic inheritance.
[So] Source:PLoS Genet;13(7):e1006900, 2017 Jul.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The fidelity of epigenetic inheritance or, the precision by which epigenetic information is passed along, is an essential parameter for measuring the effectiveness of the process. How the precision of the process is achieved or modulated, however, remains largely elusive. We have performed quantitative measurement of epigenetic fidelity, using position effect variegation (PEV) in Schizosaccharomyces pombe as readout, to explore whether replication perturbation affects nucleosome-mediated epigenetic inheritance. We show that replication stresses, due to either hydroxyurea treatment or various forms of genetic lesions of the replication machinery, reduce the inheritance accuracy of CENP-A/Cnp1 nucleosome positioning within centromere. Mechanistically, we demonstrate that excessive formation of single-stranded DNA, a common molecular abnormality under these conditions, might have correlation with the reduction in fidelity of centromeric chromatin duplication. Furthermore, we show that replication stress broadly changes chromatin structure at various loci in the genome, such as telomere heterochromatin expanding and mating type locus heterochromatin spreading out of the boundaries. Interestingly, the levels of inheritable expanding at sub-telomeric heterochromatin regions are highly variable among independent cell populations. Finally, we show that HU treatment of the multi-cellular organisms C. elegans and D. melanogaster affects epigenetically programmed development and PEV, illustrating the evolutionary conservation of the phenomenon. Replication stress, in addition to its demonstrated role in genetic instability, promotes variable epigenetic instability throughout the epigenome.
[Mh] Termos MeSH primário: Efeitos da Posição Cromossômica/genética
Proteínas Cromossômicas não Histona/genética
Replicação do DNA/genética
Epigênese Genética/genética
Proteínas de Schizosaccharomyces pombe/genética
[Mh] Termos MeSH secundário: Animais
Caenorhabditis elegans/genética
Centrômero/genética
Cromatina/efeitos dos fármacos
Cromatina/genética
DNA de Cadeia Simples/efeitos dos fármacos
Drosophila melanogaster/genética
Epigênese Genética/efeitos dos fármacos
Heterocromatina/efeitos dos fármacos
Heterocromatina/genética
Histonas/genética
Hidroxiureia/farmacologia
Nucleossomos/genética
Schizosaccharomyces/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (Chromosomal Proteins, Non-Histone); 0 (Cnp1 protein, S pombe); 0 (DNA, Single-Stranded); 0 (Heterochromatin); 0 (Histones); 0 (Nucleosomes); 0 (Schizosaccharomyces pombe Proteins); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006900


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[PMID]:28737505
[Au] Autor:Pace S; Pergola C; Dehm F; Rossi A; Gerstmeier J; Troisi F; Pein H; Schaible AM; Weinigel C; Rummler S; Northoff H; Laufer S; Maier TJ; Rådmark O; Samuelsson B; Koeberle A; Sautebin L; Werz O
[Ad] Endereço:Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, University Hospital Jena, Jena, Germany.
[Ti] Título:Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.
[So] Source:J Clin Invest;127(8):3167-3176, 2017 Aug 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.
[Mh] Termos MeSH primário: Androgênios/metabolismo
Leucotrienos/biossíntese
Fatores Sexuais
Testosterona/administração & dosagem
[Mh] Termos MeSH secundário: Proteínas Ativadoras de 5-Lipoxigenase/metabolismo
Animais
Araquidonato 5-Lipoxigenase/metabolismo
Di-Hidrotestosterona/metabolismo
Feminino
Seres Humanos
Hidroxiureia/análogos & derivados
Hidroxiureia/farmacologia
Leucócitos/metabolismo
Inibidores de Lipoxigenase/farmacologia
Masculino
Camundongos
Pirróis/administração & dosagem
Ratos
Ratos Wistar
Sulindaco/administração & dosagem
Sulindaco/análogos & derivados
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-Lipoxygenase-Activating Proteins); 0 (Androgens); 0 (Leukotrienes); 0 (Lipoxygenase Inhibitors); 0 (Pyrroles); 08J2K08A3Y (Dihydrotestosterone); 184SNS8VUH (Sulindac); 3XMK78S47O (Testosterone); 6UVA8S2DEY (sulindac sulfide); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); P5T6BYS22Y (licofelone); V1L22WVE2S (zileuton); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE



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