RESUMO
In this work, we present silver nanowire hybrid electrodes prepared through the addition of small quantities of pristine graphene by mechanical transfer deposition from surface-assembled Langmuir films. This technique is a fast, efficient, and facile method for modifying the optoelectronic performance of AgNW films. We demonstrate that it is possible to use this technique to perform two-step device production by selective patterning of the stamp used, leading to controlled variation in the local sheet resistance across a device. This is particularly attractive for producing extremely low cost sensors on arbitrarily large scales. Our aim is to address some of the concerns surrounding the use of AgNW films as replacements for indium tin oxide (ITO), namely, the use of scarce materials and poor stability of AgNWs against flexural and environmental degradation.
RESUMO
U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12â months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.
Assuntos
Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/complicações , Fumar/efeitos adversos , Adulto , Ansiedade/epidemiologia , Asma/tratamento farmacológico , Asma/epidemiologia , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Depressão/epidemiologia , Europa (Continente) , Feminino , Refluxo Gastroesofágico/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/análise , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Fumar/epidemiologia , Espirometria , Inquéritos e Questionários , Biologia de SistemasRESUMO
The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.
Assuntos
Neoplasias da Mama , Tetra-Hidronaftalenos , Animais , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Antagonistas do Receptor de Estrogênio/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Tamoxifeno , Estrogênios , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismoRESUMO
To describe the state variation, demographic and family characteristics of children eligible for public health insurance but uninsured. Using data from the National Survey of Children's Health we selected a subset of children living in households with incomes <200 % of the federal poverty level, who are generally eligible for Medicaid or CHIP. We used multiple logistic regression to examine associations between insurance status among this group of eligible children and certain demographic factors, family characteristics, and state of residence. In adjusted models children aged 6-11 and 12-17 years were more likely to be eligible but uninsured compared to those aged 0-5 years (AOR 1.57; 95 % CI 1.15-2.16 and AOR 1.93; 95 % CI 1.41-2.64). Children who received school lunch (AOR 0.67; 95 % CI 0.52-0.86) and SNAP (AOR 0.33; 95 % CI 0.24-0.46) were less likely to be eligible but uninsured compared to those children not receiving those needs based services; however, a majority (58.7 %) of eligible uninsured children were enrolled in the school lunch program. Five states (Texas, California, Florida, Georgia, New York) accounted for 46 % of the eligible uninsured children. Vermont had the lowest adjusted estimate of eligible uninsured children (3.6 %) and Nevada had the highest adjusted estimate (35.5 %). Using nationally representative data we have identified specific state differences, demographic and household characteristics that could help guide federal and local initiatives to improve public health insurance enrollment for children who are eligible but uninsured.
Assuntos
Proteção da Criança , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Medicaid/estatística & dados numéricos , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Adolescente , Criança , Serviços de Saúde da Criança/organização & administração , Pré-Escolar , Estudos Transversais , Características da Família , Feminino , Pesquisas sobre Atenção à Saúde , Acessibilidade aos Serviços de Saúde , Humanos , Renda , Modelos Logísticos , Masculino , Prevalência , Fatores de Risco , Fatores Socioeconômicos , Planos Governamentais de Saúde/organização & administração , Estados UnidosRESUMO
The role of the erythromycin 4''-hydroxyl group has been explored on the motilin agonist potential in the 9-dihydroerythromycin series of motilides. The compounds show potencies 2- to 4-fold superior to the corresponding hydroxylated compounds. The relationship is maintained when the 9-hydroxyl is alkylated to generate the corresponding 4''-deoxy-9-O-acetamido-9-dihydroerythromycins. However, concomitant with this increase in potency is an increase in hERG inhibition.
Assuntos
Eritromicina/química , Eritromicina/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Radical Hidroxila , Motilina/agonistas , Células Cultivadas , Canal de Potássio ERG1 , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/farmacologia , Humanos , Radical Hidroxila/química , Radical Hidroxila/farmacologia , Concentração Inibidora 50 , Estrutura MolecularRESUMO
The epothilones represent a promising class of natural product-based antitumor drug candidates. Although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. We have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself. We report herein the results of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone. Iso-fludelone, in particular, exhibits a number of properties that render it an excellent candidate for preclinical development, including biological stability, excellent solubility in water, and remarkable potency relative to other epothilones. In nude mouse xenograft settings, iso-fludelone was able to achieve therapeutic cures against a number of human cancer cell lines, including mammarian-MX-1, ovarian-SK-OV-3, and the fast-growing, refractory, subcutaneous neuroblastoma-SK-NAS. Strong therapeutic effect was observed against drug-resistant lung-A549/taxol and mammary-MCF-7/Adr xenografts. In addition, iso-fludelone was shown to exhibit a significant therapeutic effect against an intracranially implanted SK-NAS tumor.
Assuntos
Epotilonas/uso terapêutico , Microtúbulos/metabolismo , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Administração Oral , Animais , Proliferação de Células , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Epotilonas/administração & dosagem , Epotilonas/química , Epotilonas/farmacocinética , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias/patologia , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinéticaRESUMO
A series of 9-dihydroerythromycin A and B analogues with modification of the desosamine nitrogen have been synthesized and screened for motilin agonist activity, antibiotic activity, tachyphylaxis and hERG channel current inhibition. Small alkyl groups resulted in the potency while compounds with a primary or secondary amine resulted in the low motilin agonist potency. Several compounds were identified as non-antibiotic motilin receptor agonists with minimal tachyphylaxis and low hERG interaction.
Assuntos
Eritromicina/análogos & derivados , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Amino Açúcares/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Canal de Potássio ERG1 , Eritromicina/síntese química , Eritromicina/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Coelhos , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Neuropeptídeos/metabolismo , Taquifilaxia/fisiologiaRESUMO
A series of derivatives of the amine of 9-dihydro-9-O-ethylamino-N-desmethyl-N-isopropyl erythromycin A derivatives were synthesized as motilin agonists. The compounds were developed for potency without showing antibacterial activity and inhibition of the hERG potassium channel. The formamide of the amide series was found to show the optimal combination of properties relative to carbamates, ureas, thioureas, and amines. This prompted an investigation of heterocyclic isosteres for the amide. In this series the triazole had the optimal combination of properties. From the study, two compounds met the criteria for detailed pharmacokinetic studies.
Assuntos
Antibacterianos/química , Eritromicina/análogos & derivados , Éteres/química , Motilina/agonistas , Antibacterianos/síntese química , Antibacterianos/farmacologia , Canal de Potássio ERG1 , Eritromicina/síntese química , Eritromicina/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Éteres/síntese química , Éteres/farmacocinética , Humanos , Testes de Sensibilidade Microbiana , Motilina/metabolismo , Relação Estrutura-AtividadeRESUMO
Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-'omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective. We list some of the key advantages and learnings from the perspective of the authors, and also improvements that we feel could be made in future projects.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Biomarcadores/metabolismo , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Parcerias Público-Privadas , Animais , Asma/diagnóstico , Asma/fisiopatologia , Consenso , Comportamento Cooperativo , Descoberta de Drogas/organização & administração , Indústria Farmacêutica/organização & administração , Humanos , Comunicação Interdisciplinar , Relações Interinstitucionais , Fenótipo , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Parcerias Público-Privadas/organização & administração , Participação dos Interessados , Fluxo de TrabalhoRESUMO
The syntheses and biological evaluation of six epothilone D analogues are reported. These side-chain variants of the (E)-9,10-didehydroepothilone scaffold contain C-15 thiazole appendages that are derived from bromomethyl ketone intermediates. Although each of these analogues is less cytotoxic than the parent (E)-9,10-didehydroepothilone D, three maintain IC(50) values in the double-digit nanomolar range against both susceptible and resistant cell lines.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Epotilonas/síntese química , Epotilonas/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Epotilonas/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Tiazóis/químicaRESUMO
[Structure: see text] The design, syntheses, and biological evaluation of nine totally synthetic analogues of the microtubule-stabilizing agent (+)-14-normethyldiscodermolide (2) are reported. Simplification at the C(21)-C(24) terminal diene and at the C(1)-C(5) lactone moieties reveals significant structure-activity relationships.
Assuntos
Alcenos/química , Antineoplásicos/química , Antineoplásicos/síntese química , Carbamatos/química , Carbamatos/síntese química , Lactonas/química , Pironas/química , Pironas/síntese química , Antineoplásicos/farmacologia , Carbamatos/farmacologia , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pironas/farmacologia , Relação Estrutura-AtividadeRESUMO
[Structure: see text] The design, syntheses, and biological evaluation of 22 totally synthetic analogues of the potent microtubule-stabilizing agent (+)-discodermolide (1) have been achieved. Structure-activity relationships of the C(19) carbamate were defined, exploiting two synthetically simplified scaffolds, as well as the parent (+)-discodermolide framework.
Assuntos
Alcanos/química , Alcanos/síntese química , Carbamatos/química , Lactonas/química , Lactonas/síntese química , Pironas/química , Pironas/síntese química , Alcanos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carbamatos/síntese química , Carbamatos/metabolismo , Carbamatos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Lactonas/farmacologia , Estrutura Molecular , Pironas/farmacologia , Relação Estrutura-AtividadeRESUMO
Natural products have been used as medicinal agents for many years. In addition, these compounds have served as the starting points for semisynthetic analogs with improved properties. This review highlights work on several classes of natural products and their derivatives, including both well established and emerging structural classes that are in, or nearing, clinical use for a variety of important indications.
Assuntos
Epotilonas/química , Eritromicina/química , Bactérias Gram-Positivas/química , Taxoides/química , Alcanos/química , Alcanos/isolamento & purificação , Antifúngicos/química , Antifúngicos/isolamento & purificação , Carbamatos/química , Carbamatos/isolamento & purificação , Epotilonas/isolamento & purificação , Eritromicina/isolamento & purificação , Furanos , Lactonas/química , Lactonas/isolamento & purificação , Lipídeos , Macrolídeos/química , Macrolídeos/isolamento & purificação , Modelos Químicos , Pironas , Relação Estrutura-Atividade , Taxoides/isolamento & purificaçãoRESUMO
An array of 15-amido substituted erythromycin A compounds was synthesized using a chemobiosynthesis approach. It was found that while the in vitro antibacterial activities of aryl amides were inferior to erythromycin A, substituted benzylamides showed equivalent and in some cases improved activity against the macrolide-resistant strains. The 15-amidoerythromycins represent a new class of antibacterial macrolides.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Eritromicina/análogos & derivados , Antibacterianos/química , Eritromicina/síntese química , Eritromicina/química , Eritromicina/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Streptococcus pneumoniae/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Osteoprotegerin (OPG) is a key regulator of osteoclastogenesis. Recent reports suggest that OPG may function as a protector of arterial calcification and survival of endothelial cells. However, the role and expression of OPG in vascular wall is unclear. Here we report that OPG was highly expressed in vascular smooth muscle cells (VSMC) but not in endothelial cells. Platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, tumor necrosis factor alpha and interleukin-1beta upregulated OPG expression in VSMC. Moreover, inhibition of phosphatidylinositol 3-kinase/Akt or P38-signal pathway abrogated PDGF-induced OPG expression. Our results suggest that OPG may be an important determinant of vascular homeostasis.
Assuntos
Endotélio Vascular/metabolismo , Expressão Gênica , Glicoproteínas/genética , Músculo Liso Vascular/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteínas Serina-Treonina Quinases , Receptores Citoplasmáticos e Nucleares/genética , Receptores do Fator de Necrose Tumoral/genética , Angiotensina II/farmacologia , Becaplermina , Proteínas de Transporte/genética , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Interleucina-1/farmacologia , Ligantes , Sistema de Sinalização das MAP Quinases , Glicoproteínas de Membrana/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Osteoprotegerina , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-sis , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
[reaction: see text] Diastereoselective acetalization of pseudo-C(2)-symmetric 1,3,5-triol systems is a general strategy for the rapid generation of polyketides. The oxidative acetalization reaction shown above was studied under both kinetic and thermodynamic conditions, using synthetic 1,3,5-triol units. In addition, all possible stereochemical variants of a 1,3,5-triol system were prepared from the corresponding acetal to expand the synthetic versatility of this method.