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[PMID]:29458674
[Au] Autor:Nair S; Poonacha N; Desai S; Hiremath D; Tuppad D; Mohan T; Chikkamadaiah R; Durgaiah M; Kumar S; Channabasappa S; Vipra A; Sharma U
[Ad] Endereço:GangaGen Biotechnologies Pvt Ltd., Bangalore, India.
[Ti] Título:Restoration of sensitivity of a diverse set of drug-resistant Staphylococcus clinical strains by bactericidal protein P128.
[So] Source:J Med Microbiol;67(3):296-307, 2018 Mar.
[Is] ISSN:1473-5644
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: P128, a phage-derived lysin, exerts antibacterial activity on staphylococci by cleaving the pentaglycine-bridge of peptidoglycan. We sought to determine whether the presence of P128 could re-sensitize drug-resistant bacteria to antibiotics by virtue of its cell wall degrading property. METHODOLOGY: P128 was tested in combination with standard-of-care (SoC) drugs by chequerboard assays on planktonic cells and biofilms of strains individually resistant to these drugs. The bactericidal effect of P128 and drug combinations on planktonic cells and biofilms was measured by c.f.u. reduction assays. A mouse model of MRSA bacteraemia was used to test the efficacy of P128 and oxacillin in combination. RESULTS: A combination of sub-MIC P128 (0.025-0.20 µg ml ) and 0.5 µg ml of oxacillin resulted in inhibition of bacterial growth in four MRSA strains. Similar results were seen with all the other drugs tested, wherein sub-MIC of P128 re-sensitized S. aureus and CoNS strains to SoC drugs. The chequerboard assays on strains of S. aureus and CoNS showed that combinations of P128 and antibiotics consistently inhibited bacterial growth on biofilms. Data from scanning electron microscopy and c.f.u. reduction assays on drug-resistant S. aureus and CoNS demonstrated that sub-MICs of P128 and SoC antibiotics could kill biofilm-embedded bacteria. In vivo, a combination of sub-therapeutic doses of P128 and oxacillin could help protect animals from fatal bacteraemia. CONCLUSION: The ability of P128 to re-sensitize bacteria to SoC drugs suggests that combinations of P128 and SoC antibiotics can potentially be developed to treat infections caused by drug-resistant strains of staphylococci.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Farmacorresistência Bacteriana/efeitos dos fármacos
Proteínas Recombinantes de Fusão/farmacologia
Staphylococcus aureus/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Biofilmes/efeitos dos fármacos
Biofilmes/crescimento & desenvolvimento
Modelos Animais de Doenças
Seres Humanos
Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos
Camundongos
Testes de Sensibilidade Microbiana
Oxacilina/farmacologia
Proteínas Recombinantes de Fusão/metabolismo
Infecções Estafilocócicas/microbiologia
Staphylococcus aureus/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (P128 antistaphylococcal chimeric protein); 0 (Recombinant Fusion Proteins); UH95VD7V76 (Oxacillin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180221
[St] Status:MEDLINE
[do] DOI:10.1099/jmm.0.000697


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[PMID]:29185091
[Au] Autor:Kolben T; Jeschke U; Reimer T; Karsten N; Schmoeckel E; Semmlinger A; Mahner S; Harbeck N; Kolben TM
[Ad] Endereço:Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany. Thomas.Kolben@med.uni-muenchen.de.
[Ti] Título:Induction of apoptosis in breast cancer cells in vitro by Fas ligand reverse signaling.
[So] Source:J Cancer Res Clin Oncol;144(2):249-256, 2018 Feb.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: The Fas-antigen is a cell surface receptor that transduces apoptotic signals into cells. The purpose of this study was to evaluate FasL expression in breast cancer and to elucidate the role of its signaling in different breast cancer cell lines. METHODS: T47D and MCF7 cells were used and cultured in Dulbecco's modified Eagle's medium. FasL translocation to the membrane was achieved by culturing the cells in the presence of human interferon-γ (IFNγ). Translocation was detected by immunofluorescence. The ability of a Fas:Fc fusion protein to trigger apoptosis in these cells was investigated by cell death detection ELISA. After incubation with IFNγ for 4 h and 18 h, apoptosis was assessed in response to treatment with Fas:Fc. RESULTS: Immunofluorescence revealed that the used cell lines were positive for FasL which was increased and changed to more membrane-bound FasL expression after IFNγ stimulation. After stimulation with 50 IU/ml IFNγ, Fas:Fc significantly increased MCF7 apoptosis (1.39 ± 0.06-fold, p = 0.0004) after 18 h. After stimulation with 100 IU/ml, Fas:Fc significantly increased apoptosis both after 4 h (1.49 ± 0.15-fold, p = 0.018) and 18 h (1.30 ± 0.06-fold, p = 0.013). In T47D cells this effect was seen after 4 h of stimulation with 50 IU/ml and addition of Fas:Fc (1.6 ± 0.08-fold, p = 0.03). CONCLUSION: Membrane-bound FasL expression could be induced by IFNγ in a breast cancer cell model. More importantly, in the presence of IFNγ the Fas:Fc fusion protein was able to transmit pro-apoptotic signals to T47D and MCF7 cells, significantly inducing apoptosis. The current findings support further in vivo studies regarding FasL activation as a potential target for therapeutic intervention in breast cancer.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Proteína Ligante Fas/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Apoptose/fisiologia
Neoplasias da Mama/tratamento farmacológico
Ensaio de Imunoadsorção Enzimática
Proteína Ligante Fas/genética
Feminino
Imunofluorescência
Seres Humanos
Fragmentos Fc das Imunoglobulinas/genética
Interferon gama/farmacologia
Células MCF-7
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/farmacologia
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FASLG protein, human); 0 (Fas Ligand Protein); 0 (IFNG protein, human); 0 (Immunoglobulin Fc Fragments); 0 (Recombinant Fusion Proteins); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-017-2551-y


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[PMID]:29486762
[Au] Autor:Schmid MK; Reich O; Blozik E; Faes L; Bodmer NS; Locher S; Thiel MA; Rapold R; Kuhn M; Bachmann LM
[Ad] Endereço:University of Zurich, Zurich, Switzerland.
[Ti] Título:Outcomes and costs of Ranibizumab and Aflibercept treatment in a health-service research context.
[So] Source:BMC Ophthalmol;18(1):64, 2018 Feb 27.
[Is] ISSN:1471-2415
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: To compare anti-VEGF treatments for macular disease in terms of costs and clinical outcomes. METHODS: We identified patients suffering from macular disease and treated either with aflibercept, ranibizumab or both at the largest public eye clinic in Switzerland between January 1st and December 31st 2016 who were insured in one of the two participating health insurance companies. Clinical data were extracted from the electronic health record system. The health insurers provided the health claim costs for the ophthalmologic care and the total health care costs of each patient in the observation period. Using multivariate regression models, we assessed the monthly ophthalmologic and the monthly total costs of patients with no history of switching (ranibizumab vs. aflibercept), patients with a history of switching from ranibizumab to aflibercept, patients switching during the observation period and a miscellaneous group. We examined baseline differences in age, proportion of males, visual acuity (letters), central retinal thickness (CRT) and treatment history before entering the study. We investigated treatment intensity and compared the changes in letters and CRT. RESULTS: The analysis involved 488 eyes (361 patients), 182 on ranibizumab treatment, and 63 on aflibercept treatment, 160 eyes with a history of switching from ranibizumab to aflibercept, and 45 switchers during follow-up and 38 eyes of the miscellaneous group. Compared to ranibizumab, monthly costs of ophthalmologic treatment were slightly higher for aflibercept treatment + 175.0 CHF (95%CI: 1.5 CHF to 348.3 CHF; p = 0.048) as were the total monthly costs + 581.0 CHF (95%CI: 159.5 CHF to 1002.4 CHF; p = 0.007). Compared to ranibizumab, the monthly treatment intensity with aflibercept was similar (+ 0.057 injections/month (95%CI -0.023 to 0.137; p = 0.162), corresponding to a projected annual number of 5.4 injections for ranibizumab vs. 6.1 injections for aflibercept. During follow-up, visus dropped by 0.7 letters with ranibizumab and increased by 0.6 letters with aflibercept (p = 0.243). CRT dropped by - 14.9 µm with ranibizumab and by - 19.5 µm with aflibercept (p = 0.708). The monthly costs of all other groups examined were higher. CONCLUSION: These real-life data show that aflibercept treatment is equally expensive, and clinical outcomes between the two drugs are similar.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/economia
Custos de Cuidados de Saúde
Ranibizumab/economia
Proteínas Recombinantes de Fusão/economia
Doenças Retinianas/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Inibidores da Angiogênese/uso terapêutico
Feminino
Pesquisa sobre Serviços de Saúde
Seres Humanos
Masculino
Meia-Idade
Análise Multivariada
Ranibizumab/uso terapêutico
Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico
Proteínas Recombinantes de Fusão/uso terapêutico
Doenças Retinianas/economia
Acuidade Visual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Recombinant Fusion Proteins); 15C2VL427D (aflibercept); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor); ZL1R02VT79 (Ranibizumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180301
[St] Status:MEDLINE
[do] DOI:10.1186/s12886-018-0731-4


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[PMID]:29378528
[Au] Autor:Elwes F; Borooah S; Aspinall P; Sim PY; Loo CY; Armbrecht AM; Dhillon B; Cackett P
[Ad] Endereço:Royal Infirmary of Edinburgh, Edinburgh, UK.
[Ti] Título:Clinical outcomes of switching to aflibercept using a pro re nata treatment regimen in patients with neovascular age-related macular degeneration who incompletely responded to ranibizumab.
[So] Source:BMC Ophthalmol;18(1):20, 2018 Jan 30.
[Is] ISSN:1471-2415
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: To assess the effect of switching patients previously incompletely treated with ranibizumab (RBZ) to aflibercept (AFL) using a pro re nata (PRN) treatment strategy in neovascular age-related macular degeneration (nvAMD). METHODS: A retrospective case series was conducted on patients who had persistent or recurrent intra- and/or sub-retinal fluid treated initially with RBZ and subsequently switched to AFL. The main outcome measures were best corrected visual acuity (BCVA) and central retinal thickness (CRT) measured at different stages of the study. Friedman analysis of variance and Wilcoxon test were used to examine differences in BCVA and CRT. RESULTS: Two hundred and seven eyes from 182 patients were included. BCVA and CRT improved significantly initially following 3 RBZ injections with a mean gain of 3.7 letters (p < 0.001) and a mean loss of 69 µm (p < 0.001) respectively. Following PRN RBZ therapy and immediately prior to switching to AFL (mean 129 weeks), there was a mean loss of 6.7 letters (p < 0.001) BCVA and a mean gain of 24 µm (p < 0.001) CRT. AFL loading resulted in a mean improvement of 0.7 letters (p = 0.28) BCVA and 55 µm (p < 0.001) CRT. At final follow-up following AFL PRN therapy (mean 85 weeks), there was a mean loss of 8.9 letters (p < 0.001) BCVA and a mean gain of 12 µm (p < 0.05) CRT. CONCLUSION: AFL loading resulted in a significant anatomical improvement but no significant change in visual acuity. However, the benefits of switching were gradually lost over time with AFL PRN dosing despite an increased injection rate when compared with RBZ PRN treatment. TRIAL REGISTRATION: Not applicable.
[Mh] Termos MeSH primário: Protocolos Clínicos
Substituição de Medicamentos/métodos
Ranibizumab/administração & dosagem
Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem
Proteínas Recombinantes de Fusão/administração & dosagem
Acuidade Visual
Degeneração Macular Exsudativa/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Inibidores da Angiogênese/administração & dosagem
Feminino
Seguimentos
Seres Humanos
Injeções Intravítreas
Masculino
Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
Estudos Retrospectivos
Fatores de Tempo
Tomografia de Coerência Óptica
Resultado do Tratamento
Degeneração Macular Exsudativa/diagnóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Recombinant Fusion Proteins); 15C2VL427D (aflibercept); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor); ZL1R02VT79 (Ranibizumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180131
[St] Status:MEDLINE
[do] DOI:10.1186/s12886-018-0688-3


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[PMID]:29187360
[Au] Autor:Fell G
[Ad] Endereço:Town Hall, Sheffield S1 2HH, UK.
[Ti] Título:The NHS must act on bevacizumab, for patients' sake.
[So] Source:BMJ;359:j5427, 2017 11 29.
[Is] ISSN:1756-1833
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Inibidores da Angiogênese/economia
Bevacizumab/economia
Análise Custo-Benefício/legislação & jurisprudência
Degeneração Macular/tratamento farmacológico
Oftalmologistas/ética
Ranibizumab/farmacologia
Proteínas Recombinantes de Fusão/farmacologia
Medicina Estatal/legislação & jurisprudência
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/farmacologia
Bevacizumab/farmacologia
Acesso aos Serviços de Saúde
Seres Humanos
Degeneração Macular/economia
Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
Reino Unido/epidemiologia
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Recombinant Fusion Proteins); 15C2VL427D (aflibercept); 2S9ZZM9Q9V (Bevacizumab); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor); ZL1R02VT79 (Ranibizumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1136/bmj.j5427


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[PMID]:28460483
[Au] Autor:Guo XF; Zhu XF; Cao HY; Zhong GS; Li L; Deng BG; Chen P; Wang PZ; Miao QF; Zhen YS
[Ad] Endereço:Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
[Ti] Título:A bispecific enediyne-energized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer.
[So] Source:Oncotarget;8(16):27286-27299, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) both overexpressed on non-small cell lung cancer (NSCLC) and are known cooperatively to promote tumor progression and drug resistance. This study was to construct a novel bispecific fusion protein EGF-IGF-LDP-AE consisting of EGFR and IGF-IR specific ligands (EGF and IGF-1) and lidamycin, an enediyne antibiotic with potent antitumor activity, and investigate its antitumor efficacy against NSCLC. Binding and internalization assays showed that EGF-IGF-LDP protein could bind to NSCLC cells with high affinity and then internalized into cells with higher efficiency than that of monospecific proteins. In vitro, the enediyne-energized analogue of bispecific fusion protein (EGF-IGF-LDP-AE) displayed extremely potent cytotoxicity to NSCLC cell lines with IC50<10-11 mol/L. Moreover, the bispecific protein EGF-IGF-LDP-AE was more cytotoxic than monospecific proteins (EGF-LDP-AE and LDP-IGF-AE) and lidamycin. In vivo, EGF-IGF-LDP-AE markedly inhibited the growth of A549 xenografts, and the efficacy was more potent than that of lidamycin and monospecific counterparts. EGF-IGF-LDP-AE caused significant cell cycle arrest and it also induced cell apoptosis in a dosage-dependent manner. Pretreatment with EGF-IGF-LDP-AE inhibited EGF-, IGF-stimulated EGFR and IGF-1R phosphorylation, and blocked two main downstream signaling molecules AKT and ERK activation. These data suggested that EGF-LDP-IGF-AE protein would be a promising targeted agent for NSCLC patients with EGFR and/or IGF-1R overexpression.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
Enedi-Inos
Fator de Crescimento Insulin-Like I/antagonistas & inibidores
Neoplasias Pulmonares/metabolismo
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Proteínas Recombinantes de Fusão/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Carcinoma Pulmonar de Células não Pequenas/patologia
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Modelos Animais de Doenças
Enedi-Inos/química
Feminino
Seres Humanos
Fator de Crescimento Insulin-Like I/metabolismo
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/patologia
Camundongos
Ligação Proteica
Receptor do Fator de Crescimento Epidérmico/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Transdução de Sinais/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enediynes); 0 (Recombinant Fusion Proteins); 67763-96-6 (Insulin-Like Growth Factor I); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15933


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[PMID]:28460472
[Au] Autor:Å Urga S; Nanut MP; Kos J; Sabotic J
[Ad] Endereço:Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
[Ti] Título:Fungal lectin MpL enables entry of protein drugs into cancer cells and their subcellular targeting.
[So] Source:Oncotarget;8(16):26896-26910, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lectins have been recognized as promising carrier molecules for targeted drug delivery. They specifically bind carbohydrate moieties on cell membranes and trigger cell internalization. Fungal lectin MpL (Macrolepiota procera lectin) does not provoke cancer cell cytotoxicity but is able to bind aminopeptidase N (CD13) and integrin α3ß1, two glycoproteins that are overexpressed on the membrane of tumor cells. Upon binding, MpL is endocytosed in a clathrin-dependent manner and accumulates initially in the Golgi apparatus and, finally, in the lysosomes. For effective binding and internalization a functional binding site on the α-repeat is needed. To test the potential of MpL as a carrier for delivering protein drugs to cancer cells we constructed fusion proteins consisting of MpL and the cysteine peptidase inhibitors cystatin C and clitocypin. The fused proteins followed the same endocytic route as the unlinked MpL. Peptidase inhibitor-MpL fusions impaired both the intracellular degradation of extracellular matrix and the invasiveness of cancer cells. MpL is thus shown in vitro to be a lectin that can enable protein drugs to enter cancer cells, enhance their internalization and sort them to lysosomes and the Golgi apparatus.
[Mh] Termos MeSH primário: Portadores de Fármacos
Proteínas Fúngicas/metabolismo
Lectinas/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Membrana Celular/metabolismo
Colágeno Tipo IV/metabolismo
Endocitose
Glicoproteínas/metabolismo
Seres Humanos
Espaço Intracelular/metabolismo
Ligação Proteica
Transporte Proteico
Proteólise
Proteínas Recombinantes de Fusão/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Collagen Type IV); 0 (Drug Carriers); 0 (Fungal Proteins); 0 (Glycoproteins); 0 (Lectins); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15849


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[PMID]:28460033
[Au] Autor:Ram S; Shaughnessy J; de Oliveira RB; Lewis LA; Gulati S; Rice PA
[Ad] Endereço:Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
[Ti] Título:Gonococcal lipooligosaccharide sialylation: virulence factor and target for novel immunotherapeutics.
[So] Source:Pathog Dis;75(4), 2017 Jun 01.
[Is] ISSN:2049-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gonorrhea has become resistant to most conventional antimicrobials used in clinical practice. The global spread of multidrug-resistant isolates of Neisseria gonorrhoeae could lead to an era of untreatable gonorrhea. New therapeutic modalities with novel mechanisms of action that do not lend themselves to the development of resistance are urgently needed. Gonococcal lipooligosaccharide (LOS) sialylation is critical for complement resistance and for establishing infection in humans and experimental mouse models. Here we describe two immunotherapeutic approaches that target LOS sialic acid: (i) a fusion protein that comprises the region in the complement inhibitor factor H (FH) that binds to sialylated gonococci and IgG Fc (FH/Fc fusion protein) and (ii) analogs of sialic acid that are incorporated into LOS but fail to protect the bacterium against killing. Both molecules showed efficacy in the mouse vaginal colonization model of gonorrhea and may represent promising immunotherapeutic approaches to target multidrug-resistant isolates. Disabling key gonococcal virulence mechanisms is an effective therapeutic strategy because the reduction of virulence is likely to be accompanied by a loss of fitness, rapid elimination by host immunity and consequently, decreased transmission.
[Mh] Termos MeSH primário: Gonorreia/prevenção & controle
Lipopolissacarídeos/metabolismo
Neisseria gonorrhoeae/fisiologia
Ácidos Siálicos/metabolismo
Fatores de Virulência/metabolismo
[Mh] Termos MeSH secundário: Animais
Fator H do Complemento/genética
Fator H do Complemento/metabolismo
Modelos Animais de Doenças
Feminino
Fragmentos Fc das Imunoglobulinas/genética
Fragmentos Fc das Imunoglobulinas/metabolismo
Camundongos
Neisseria gonorrhoeae/efeitos dos fármacos
Ligação Proteica
Proteínas Recombinantes de Fusão/metabolismo
Vagina/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin Fc Fragments); 0 (Lipopolysaccharides); 0 (Recombinant Fusion Proteins); 0 (Sialic Acids); 0 (Virulence Factors); 0 (lipid-linked oligosaccharides); 80295-65-4 (Complement Factor H)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1093/femspd/ftx049


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[PMID]:29373591
[Au] Autor:Xu K; Zhao Q; Wen X; Wu R; Wen Y; Huang X; Huang Y; Yan Q; Han X; Ma X; Chang YF; Cao S
[Ad] Endereço:Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
[Ti] Título:A trivalent Apx-fusion protein delivered by E. coli outer membrane vesicles induce protection against Actinobacillus pleuropneumoniae of serotype 1 and 7 challenge in a murine model.
[So] Source:PLoS One;13(1):e0191286, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Actinobacillus pleuropneumoniae (APP) causes serious economic losses in the swine industry, and is the etiologic agent of porcine pleuropneumonia. In this study we have engineered a trivalent Apx fusion protein enclosed in outer membrane vesicles (Apxr-OMV) and studied its immunoprotective efficacy against APP serotypes 1 and 7 challenge in mice. The results showed that the IgG levels in the Apxr-OMVs immune group were significantly higher than those of the negative control (P < 0.05). Up-regulation of both Th1 (IFN-γ, IL-2) and Th2 (IL-4) cytokines were detected in splenocytes of Apxr-OMVs immune group. The survival rates 87.5% and 62.5% were observed against APP strain 1516 of serotype 7 and APP strain 2701 of serotype 1 in the groups of Apxr-OMVs immune group, respectively. Histopathological lesions of the pulmonary structure alveoli were found to be minimal in APX-OMV group challenged with APP serotypes 1 and 7. These results strongly indicated that engineered OMVs could effectively induce specific humoral or cellular immune responses. Moreover, Apxr-OMVs used as novel vaccine provides cross-protective immunity against different serotype 1 and 7 of APP infection in a mouse model. In contrast, the OMV-empty and PBS as negative controls or inactivated strain of APP-2701 and APP-1516 as positive controls for the animal study cannot provide protection or cross-protection.
[Mh] Termos MeSH primário: Actinobacillus pleuropneumoniae/fisiologia
Vacinas Bacterianas/imunologia
Membrana Celular/metabolismo
Escherichia coli/citologia
Escherichia coli/genética
Engenharia de Proteínas
Proteínas Recombinantes de Fusão/imunologia
[Mh] Termos MeSH secundário: Actinobacillus pleuropneumoniae/imunologia
Animais
Vacinas Bacterianas/genética
Proliferação Celular
Citocinas/metabolismo
Feminino
Imunidade Celular
Linfócitos/citologia
Camundongos
Camundongos Endogâmicos BALB C
Proteínas Recombinantes de Fusão/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Vaccines); 0 (Cytokines); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191286


  10 / 87475 MEDLINE  
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[PMID]:29352320
[Au] Autor:Zhou X; Desai R; Zhang Y; Stec WJ; Miller KW; Jounaidi Y
[Ad] Endereço:Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
[Ti] Título:High-level production and purification in a functional state of an extrasynaptic gamma-aminobutyric acid type A receptor containing α4ß3δ subunits.
[So] Source:PLoS One;13(1):e0191583, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The inhibitory γ-aminobutyric acid type A receptors are implicated in numerous physiological processes, including cognition and inhibition of neurotransmission, rendering them important molecular targets for many classes of drugs. Functionally, the entire GABAAR family of receptors can be subdivided into phasic, fast acting synaptic receptors, composed of α-, ß- and γ-subunits, and tonic extrasynaptic receptors, many of which contain the δ-subunit in addition to α- and ß-subunits. Whereas the subunit arrangement of the former group is agreed upon, that of the αßδ GABAARs remains unresolved by electrophysiological and pharmacological research. To resolve such issues will require biophysical techniques that demand quantities of receptor that have been previously unavailable. Therefore, we have engineered a stable cell line with tetracycline inducible expression of human α4-, ß3- and N-terminally Flag-tagged δ-subunits. This cell line achieved a specific activity between 15 and 20 pmol [3H]muscimol sites/mg of membrane protein, making it possible to obtain 1 nmole of purified α4ß3δ GABAAR from sixty 15-cm culture dishes. When induced, these cells exhibited agonist-induced currents with characteristics comparable to those previously reported for this receptor and a pharmacology that included strong modulation by etomidate and the δ-subunit-specific ligand, DS2. Immunoaffinity purification and reconstitution in CHAPS/asolectin micelles resulted in the retention of equilibrium allosteric interactions between the separate agonist, anesthetic and DS2 sites. Moreover, all three subunits retained glycosylation. The establishment of this well-characterized cell line will allow molecular level studies of tonic receptors to be undertaken.
[Mh] Termos MeSH primário: Receptores de GABA-A/biossíntese
[Mh] Termos MeSH secundário: Fenômenos Eletrofisiológicos
Células HEK293
Seres Humanos
Cinética
Engenharia de Proteínas
Subunidades Proteicas
Ensaio Radioligante
Receptores de GABA-A/genética
Receptores de GABA-A/isolamento & purificação
Proteínas Recombinantes de Fusão/biossíntese
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/isolamento & purificação
Transfecção
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein Subunits); 0 (Receptors, GABA-A); 0 (Recombinant Fusion Proteins); 56-12-2 (gamma-Aminobutyric Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191583



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