RESUMEN
Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC (AU)
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Humanos , Masculino , Femenino , Anciano , Linfocitos T Reguladores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Estudios Prospectivos , Proyectos Piloto , Análisis de SupervivenciaRESUMEN
PURPOSE: This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS: Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. CONCLUSIONS: Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Proteínas de Punto de Control Inmunitario/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Anciano , Albúminas/uso terapéutico , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/efectos de los fármacos , Carcinoma Ductal Pancreático/inmunología , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Factores de Transcripción Forkhead , Receptor 2 Celular del Virus de la Hepatitis A/análisis , Humanos , Proteínas de Punto de Control Inmunitario/análisis , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/uso terapéutico , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/inmunología , Proyectos Piloto , Receptor de Muerte Celular Programada 1/análisis , Receptor de Muerte Celular Programada 1/efectos de los fármacos , Supervivencia sin Progresión , Estudios Prospectivos , Linfocitos T Reguladores/química , GemcitabinaRESUMEN
The access to kinetic parameters of lipolytic enzyme adsorption onto lipids is essential for a better understanding of the overall catalytic process carried out by these interfacial enzymes. Gastric lipase, for instance, shows an apparent optimum activity on triglycerides (TAG) at acidic pH, which is controlled by its pH-dependent adsorption at lipid-water interfaces. Since gastric lipase acts on TAG droplets covered by phospholipids, but does not hydrolyze these lipids, phospholipid monolayers spread at the air-water interfaces can be used as biomimetic interfaces to study lipase adsorption and penetration through the phospholipid layer, independently from the catalytic activity. The adsorption of recombinant dog gastric lipase (rDGL) onto 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) monolayers can be monitored by surface tensiometry at various enzyme concentrations, pHs, and surface pressures (Π). These experimental data and the use of Langmuir adsorption isotherm and Verger-de Haas' lipase kinetics models further allow estimating various parameters including the adsorption equilibrium constant (KAds), the interfacial concentration [Formula: see text] , the molar fraction [Formula: see text] (ΦE*(%), mol%), and the molecular area [Formula: see text] of rDGL adsorbed onto the DLPC monolayer under various conditions. Additional insight into rDGL adsorption/insertion on phospholipid monolayers can be obtained by combining ellipsometry, Langmuir-Blodgett film transfer, and atomic force microscopy. When using multicomponent phospholipid monolayers with phase separation, these techniques allow to visualizing how rDGL preferentially partitions toward liquid expanded phase and at phase boundaries, gets adsorbed at various levels of insertion and impacts on the lateral organization of lipids.
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Lipasa/química , Fosfatidilcolinas/química , Triglicéridos/química , Agua/química , Adsorción , Animales , Perros , Concentración de Iones de Hidrógeno , Cinética , Lipasa/aislamiento & purificación , Microscopía de Fuerza Atómica , Modelos Moleculares , Dominios Proteicos , Estructura Secundaria de Proteína , Estómago/química , Estómago/enzimología , Propiedades de Superficie , Resistencia a la TracciónRESUMEN
BACKGROUND: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. METHODS: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. RESULTS: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. CONCLUSIONS: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/fisiopatología , Fármacos del Sistema Nervioso Central/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Fármacos del Sistema Nervioso Central/efectos adversos , Deglución , Método Doble Ciego , Femenino , Fuerza de la Mano , Humanos , Inyecciones Subcutáneas , Factor I del Crecimiento Similar a la Insulina/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proyectos de Investigación , Tromboembolia/inducido químicamente , Factores de Tiempo , Traqueostomía , Insuficiencia del TratamientoRESUMEN
BACKGROUND: The Department of Veterans Affairs (VA) Cooperative Studies Program has established a National Registry of Veterans with Amyotrophic Lateral Sclerosis (ALS). This article describes the objectives, methods, and sample involved in the registry. METHODS: United States military veterans with ALS were identified through national VA electronic medical record databases and nationwide publicity efforts for an enrollment period of 4 1/2 years. Diagnoses were confirmed by medical record reviews. Registrants were asked to participate in a DNA bank. Follow-up telephone interviews are conducted every 6 months to track participants' health status. RESULTS: As of September 30, 2007, 2,400 veterans had consented to participate in the registry, 2,068 were included after medical record review, 995 were still living and actively participating, and 1,573 consented to participate in the DNA bank. 979 participants had been enrolled in the registry for at least 1 year, 497 for at least 2 years, and 205 for at least 3 years. Fourteen studies have been approved to use registry data for epidemiological, observational, and interventional protocols. CONCLUSION: This registry has proven to be a successful model for identifying large numbers of patients with a relatively rare disease and enrolling them into multiple studies, including genetic protocols.
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Esclerosis Amiotrófica Lateral/epidemiología , Bases de Datos como Asunto/organización & administración , Sistema de Registros , Veteranos/estadística & datos numéricos , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/terapia , Femenino , Humanos , Clasificación Internacional de Enfermedades , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiologíaAsunto(s)
Cesárea/enfermería , Competencia Clínica , Enfermería Obstétrica/métodos , Cesárea/normas , Atención a la Salud/normas , Atención a la Salud/tendencias , Medicina Basada en la Evidencia , Femenino , Guías como Asunto , Humanos , Embarazo , Calidad de la Atención de Salud , Medición de Riesgo , Sociedades Médicas , Estados UnidosRESUMEN
Despite the growing emphasis for evidence-based practice, there are barriers to adopting this paradigm. These include (1) the lack of consistent method to measure clinical work, (2) task orientation in current measurement methods, and (3) a lack of awareness among staff nurses about evidence-based practice. In addition, clinical unit cultures are perceived as barriers and often described as cultures of "habit and opinion." Three conceptual models are discussed as a method to assist clinicians in conducting an evidenced-based clinical work assessment to advance evidence-based practice.
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Medicina Basada en la Evidencia , Atención de Enfermería/organización & administración , Garantía de la Calidad de Atención de Salud , Actitud del Personal de Salud , HumanosAsunto(s)
Educación Basada en Competencias/normas , Educación Continua en Enfermería/normas , Capacitación en Servicio/normas , Atención de Enfermería , Curriculum , Humanos , Capacitación en Servicio/organización & administración , Técnicas de Planificación , Preceptoría , Evaluación de Programas y Proyectos de SaludRESUMEN
Lactoferrin (LF) is an iron-binding glycoprotein common to exocrine secretions and the specific granules of neutrophils. Each molecule is capable of high-affinity coordinate-binding of two ferric ions with two bicarbonate or carbonic anions. The initial aspect of the present study was directed at determining the nature of anion involvement in LF bactericidal activity. It was found that selective anions were capable of inhibiting the expression of bactericidal activity by LF on S. mutans 10449. The ability to block LF expression was directly related to the capacity of the anion to serve as a coordinate ion in iron-binding by the transferrin molecules. These data support the hypothesis that the LF target site on the bacterial surface is anionic. There has been controversy in the literature regarding LF involvement in hydroxy radical generation. The second phase of these studies indicated that treatment of S. mutans with LF under anaerobic conditions abrogated the bactericidal effect of this molecule. LF-killing could be enhanced by the presence of thiocyanate and inhibited by catalase and lactoperoxidase; however, bovine serum albumin was equally effective as an inhibitor. The apparent requirement for oxygen in LF bactericidal effect on S. mutans is not inconsistent with a hydroxy radical mechanism.