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Background. Transarterial chemoembolization (TACE) has been investigated in patients with liver metastases from colorectal cancer (LMCRC). Limited experience and available data suggest that TACE can achieve disease stabilization or improvement, even in heavily pretreated patients. Methods. Patients with LMCRC, ECOG 0-2, who failed at least 1 line of systemic chemotherapy, received embolizations with 2 mL of microspheres preloaded with 100 mg of irinotecan. Beads were delivered selectively into hepatic arteries. Primary endpoint was overall survival (OS), analyzed using the Kaplan-Meier method. Secondary endpoint was safety, assessed using CTCAE version 4.0. Results. 27 patients were treated using DEBIRI. Patient median age was 57 years (range was 45-82 years). The median number of total embolizations was 1.3 (range 1-3). The median OS was 5.4 months (95% CI; 1.1-22.7 months). The most reported postembolization events were nausea (8/27), vomiting (6/27), right upper quadrant pain (16/27), fatigue (9/27), and the development of ascites (6/27). 5/26 patients required hospitalization after TACE for severe pain. Hospitalization was also required for 1 case of allergic reaction and 1 case of infection. Conclusion. Our data suggest that TACE with DEBIRI could be efficacious in a palliative setting for patients with LMCRC, but they do not necessarily support routine use in clinical practice.
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Flavanoid-rich dark chocolate consumption benefits cardiovascular health, but underlying mechanisms are elusive. We investigated the acute effect of dark chocolate on the reactivity of prothrombotic measures to psychosocial stress. Healthy men aged 20-50 years (mean ± SD: 35.7 ± 8.8) were assigned to a single serving of either 50 g of flavonoid-rich dark chocolate (n=31) or 50 g of optically identical flavonoid-free placebo chocolate (n=34). Two hours after chocolate consumption, both groups underwent an acute standardised psychosocial stress task combining public speaking and mental arithmetic. We determined plasma levels of four stress-responsive prothrombotic measures (i. e., fibrinogen, clotting factor VIII activity, von Willebrand Factor antigen, fibrin D-dimer) prior to chocolate consumption, immediately before and after stress, and at 10 minutes and 20 minutes after stress cessation. We also measured the flavonoid epicatechin, and the catecholamines epinephrine and norepinephrine in plasma. The dark chocolate group showed a significantly attenuated stress reactivity of the hypercoagulability marker D-dimer (F=3.87, p=0.017) relative to the placebo chocolate group. Moreover, the blunted D-dimer stress reactivity related to higher plasma levels of the flavonoid epicatechin assessed before stress (F=3.32, p = 0.031) but not to stress-induced changes in catecholamines (p's=0.35). There were no significant group differences in the other coagulation measures (p's≥0.87). Adjustments for covariates did not alter these findings. In conclusion, our findings indicate that a single consumption of flavonoid-rich dark chocolate blunted the acute prothrombotic response to psychosocial stress, thereby perhaps mitigating the risk of acute coronary syndromes triggered by emotional stress.
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Cacao , Dulces , Alimentos Funcionales , Estrés Psicológico/terapia , Trombosis/prevención & control , Enfermedad Aguda , Adulto , Biomarcadores/sangre , Catequina/sangre , Epinefrina/sangre , Factor VIII/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Fibrinógeno/metabolismo , Voluntarios Sanos , Humanos , Masculino , Conceptos Matemáticos , Persona de Mediana Edad , Norepinefrina/sangre , Método Simple Ciego , Habla , Estrés Psicológico/sangre , Estrés Psicológico/diagnóstico , Estrés Psicológico/etiología , Suiza , Trombosis/sangre , Trombosis/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven , Factor de von Willebrand/metabolismoRESUMEN
Early detection of the cyanobacterium Pseudomonas aeruginosa in the lungs of young children with cystic fibrosis (CF) is considered the key to delaying chronic pulmonary disease. We investigated whether cyanide in bronchoalveolar lavage (BAL) fluid could be used as an early diagnostic biomarker of infection. Cyanide was measured in 226 BAL samples (36 P. aeruginosa infected) obtained from 96 infants and young children with CF participating in an early surveillance programme involving annual BAL. Cyanide was detected in 97.2% of P. aeruginosa infected and 60.5% of uninfected samples. Cyanide concentrations were significantly higher in BALs infected with P. aeruginosa (median (25th-75th percentile) 27.3 (22.1-33.3) µM) than those which were not (17.2 (7.85-23.0) µM, p<0.001). The best sensitivity, specificity, positive and negative predictive values were obtained with a cut-off concentration of 20.6 µM, and were 83%, 66%, 32% and 96%, respectively. Neutrophil number in BAL was a significant predictor of cyanide concentration (p<0.001). Cyanide concentration can distinguish between P. aeruginosa infected and uninfected BALs as a group, but not individually; therefore, cyanide is a poor diagnostic biomarker of P. aeruginosa infection. Cyanide levels in BAL are related to the level of neutrophilic inflammation.
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Lavado Broncoalveolar , Cianuros/metabolismo , Fibrosis Quística/complicaciones , Infecciones por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/metabolismo , Biomarcadores/metabolismo , Calibración , Niño , Preescolar , Fibrosis Quística/diagnóstico , Fibrosis Quística/microbiología , Femenino , Humanos , Lactante , Estudios Longitudinales , Enfermedades Pulmonares/microbiología , Masculino , Microscopía Fluorescente/métodos , Neutrófilos/patología , Valor Predictivo de las Pruebas , Infecciones por Pseudomonas/metabolismoRESUMEN
BACKGROUND: beta(3)-Integrins are involved in platelet aggregation via alpha(IIb)beta(3) [glycoprotein (GP)IIb-GPIIIa], and in angiogenesis via endothelial alpha(V)beta(3). Cross-reactive ligands with antiaggregatory and proangiogenic effects, both desirable in peripheral vasculopathies, have not yet been described. OBJECTIVES: In vitro and in vivo characterization of antiaggregatory and proangiogenic effects of two recombinant human Fab fragments, with emphasis on beta(3)-integrins. METHODS: Recombinant Fab fragments were obtained by phage display technology. Specificity, affinity and IC(50) were determined by immunodot assays, enzyme-linked immunosorbent assay (ELISA), and Scatchard plot analysis, and by means of human umbilical vein endothelial cells (HUVECs). Functional analyses included ELISA for interaction with fibrinogen binding to GPIIb-GPIIIa, flow cytometry for measurement of activation parameters and competitive inhibition experiments, human platelet aggregometry, and proliferation, tube formation and the chorioallantoic membrane (CAM) assay for measurement of angiogenic effects. RESULTS: We observed specific and high-affinity binding to an intact GPIIb-GPIIIa receptor complex of two human Fab autoantibody fragments, with no platelet activation. Dose-dependent fibrinogen binding to GPIIb-GPIIIa and platelet aggregation were completely inhibited. One Fab fragment was competitively inhibited by abciximab and its murine analog monoclonal antibody (mAb) 7E3, whereas the other Fab fragment bound to cultured HUVECs, suggesting cross-reactivity with alpha(V)beta(3), and also demonstrated proangiogenic effects in tube formation and CAM assays. CONCLUSIONS: These Fab fragments are the first entirely human anti-GPIIb-GPIIIa Fab fragments with full antiaggregatory properties; furthermore, they do not activate platelets. The unique dual-specificity anti-beta(3)-integrin Fab fragment may represent a new tool for the study and management of peripheral arterial vasculopathies.
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Anticuerpos Biespecíficos/farmacología , Integrina beta3/inmunología , Integrinas/inmunología , Anticuerpos Biespecíficos/inmunología , Autoanticuerpos , Humanos , Fragmentos Fc de Inmunoglobulinas , Integrina alfaVbeta3/inmunología , Inhibidores de Agregación Plaquetaria , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/inmunologíaRESUMEN
Epidermal growth factor receptor (EGFR) mutation is frequently observed in human cancer and contributes to the growth, survival and therapeutic resistance of tumors. EGFRvIII is an oncogenic EGFR mutant resulting from the deletion of exons 2-7 and is the most common EGFR mutant observed in glioblastoma multiforme, an aggressive brain tumor. EGFRvIII is constitutively active but poorly ubiquitinated, leading to inefficient receptor trafficking to lysosomes and unattenuated oncogenic signaling. The mechanism by which EGFRvIII evades downregulation is not fully understood although recent studies suggest that its interaction with the ubiquitin ligase Cbl may be compromised. In this study, we examine the regulation of EGFRvIII by the recently identified negative regulator, LRIG1, which targets EGFR through recognition of its extracellular domain. Here, we determine whether the extracellular domain deletion in EGFRvIII renders it refractory to LRIG1 regulation. We find that EGFRvIII retains interaction with LRIG1 and is in fact more sensitive to LRIG1 action than wild-type receptor. We demonstrate that LRIG1 regulation of EGFRvIII is distinct from the only other known mechanism of EGFR regulation, Cbl-mediated degradation. Ectopic expression of LRIG1 in EGFRvIII(+) glioblastoma cells opposes EGFRvIII-driven tumor cell proliferation, survival, motility and invasion. Finally, RNAi-mediated silencing of LRIG1 alters EGFRvIII intracellular trafficking and leads to enhanced EGFRvIII expression, suggesting that loss of LRIG1 in tumors may contribute to a permissive environment for EGFRvIII overexpression, contributing to EGFRvIII oncogenesis.
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Receptores ErbB/fisiología , Glioblastoma/genética , Glicoproteínas de Membrana/fisiología , Apoptosis , Glioblastoma/patología , Humanos , Glicoproteínas de Membrana/química , Mutación , Fosforilación , Proteínas Proto-Oncogénicas c-cbl/fisiologíaRESUMEN
Seven experiments were conducted to evaluate the iron milk most probable number method for enumeration of Clostridium perfringens in the diet and the intestine of broiler chicks. Levels of 50 ppm of neomycin and 20 ppm of polymixin improved the iron milk tube method when compared to the TSN (tryptone-sulfite-neomycin) agar plate method. Low numbers of the organism, approximately 5 per gram, were detected in the practical diet fed to the chicks. Vegetative cell numbers of C. perfringens increased from 1.7 log10 in the duodenum of chicks to greater than 9.2 log10 in the ceca. Spores of the organism were detected in the ileum and ceca. Results of two experiments demonstrated that C. perfringens became established in the ileum of chicks early in life, before initiation of feeding at 2 days of age.
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Alimentación Animal , Pollos/microbiología , Clostridium perfringens/aislamiento & purificación , Medios de Cultivo , Microbiología de Alimentos , Intestino Delgado/microbiología , Animales , Contenido Digestivo/análisis , Hierro , Masculino , LecheRESUMEN
Five experiments were conducted to evaluate the effects of diet and antimicrobials on weight gain, feed efficiency, ileal weight, and Clostridium perfringens in the ileum of broiler chicks. In the first experiment, glucose, sucrose, and fructose were added to a semipurified diet and the results were compared with those from a practical corn and soybean meal diet. All of the diets were fed with and without bacitracin at a level of 55 ppm. Fructose resulted in the greatest depression in weight gain, followed by sucrose. Bacitracin significantly improved weight gain and feed efficiency of chicks fed the fructose, sucrose, and practical diets. Highly significant inverse correlations were obtained between ileal weight and weight gain and the number of C. perfringens in the ileum and weight gain. In other experiments bacitracin, penicillin, chlortetracycline, oxytetracycline, erythromycin, tylosin, virginiamycin, lincomycin, bambermycins, and carbadox, all at a level of 55 ppm, improved weight gain and feed efficiency and significantly reduced the weight of the ileum and the number of C. perfringens in the ileum of chicks fed the practical diet. The antibacterial agents 3-nitro-4-hydroxy-phenylarsonic acid, arsanilic acid, furazolidone, and sulfathiazole had little to no effect on the 4 parameters evaluated. Virginiamycin and lincomycin at 16.5 and 4.4 ppm, respectively, were shown to be effective. In vitro activities of the antimicrobials against C. perfringens did not directly relate to in vivo activities and the effects on growth and feed efficiency. The results of these experiments support the concept of antimicrobials as growth permittants and provide further evidence for C. perfringens as a causative bacteria for growth depression.
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Alimentación Animal , Antibacterianos/farmacología , Pollos/crecimiento & desarrollo , Clostridium perfringens/efectos de los fármacos , Carbohidratos de la Dieta/administración & dosificación , Íleon/microbiología , Animales , Bacitracina/farmacología , Peso Corporal/efectos de los fármacos , Metabolismo Energético , Aditivos Alimentarios , Fructosa/administración & dosificación , Glucosa/administración & dosificación , Íleon/anatomía & histología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Sacarosa/administración & dosificaciónRESUMEN
Experiments were conducted to determine the potential of the antibiotic efrotomycin as a growth permittant for poultry and to further elucidate the mode of action of antimicrobial agents for that purpose. Efrotomycin as the semipurified antibiotic and as fermentation solids demonstrated excellent activity against Clostridium perfringens at .1 to .2 ppm based on suppression of gas production in an anaerobic tube test. Supplementing a soybean protein and sucrose-based diet with levels of 2.2, 11, and 55 ppm of the antibiotic, from the two sources each with two different purities, improved weight gain of chicks an average of 23% and improved feed efficiency an average of 13% at the higher levels (all P less than .01). Computed indexes for each antibiotic treatment, which represent the combined effects of both weight gain and feed efficiency, showed that a maximum response was generally obtained at the 11 ppm level and that the antibiotic as fermentation solids was slightly more active than the semipurified material. Supplementing the soybean protein and sucrose-based diet with levels of 1.1, 5.5, 16.5, and 55 ppm of efrotomycin reduced the numbers of C. perfringens organisms in ileal contents of chicks (all P less than .01). The effects were dose-related. Control chicks in this experiment averaged greater than 7.7 log10 of C. perfringens counts per gram of contents. The results of these experiments show that efrotomycin has excellent growth-permittant activity and the activity correlates with the antibacterial activity against C. perfringens.
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Antibacterianos/farmacología , Pollos/fisiología , Animales , Peso Corporal/efectos de los fármacos , Pollos/microbiología , Clostridium perfringens/efectos de los fármacos , Dieta , Metabolismo Energético/efectos de los fármacos , Aditivos Alimentarios , Intestino Delgado/microbiología , Masculino , Piridonas/farmacologíaRESUMEN
Experiments were conducted to demonstrate the activity of bacitracin as a growth permittant for poultry and to further elucidate the mode of action of antimicrobial agents for that purpose. Supplementing a soybean protein and sucrose-based diet with 2.2, 11, and 55 ppm of bacitracin resulted in significant improvements in weight gain and feed efficiency of chicks fed the higher levels. In a second experiment, graded levels of bacitracin from 1.1 to 55 ppm were fed. A regression analysis of the index scores, the combined effects of both weight gain and feed efficiency, on the log of the significant dose levels of 5.5 to 27.5 ppm gave a linear response line with r = .996. Based on the equation, the ineffective level of the antibiotic was determined to be 4 ppm and the maximum effective level 31 ppm. Supplementing the soybean protein and sucrose-based diet with levels of 5.5, 16.5, and 55 ppm of bacitracin reduced the numbers of Clostridium perfringens organisms in ileal contents of chicks (all P less than .05). Chicks fed a level of 1.1 ppm, a level that did not give a growth response, had numbers of the organism present that were not significantly different from controls. Supplementing a soybean meal and corn-based diet with a level of 55 ppm of bacitracin did not significantly affect weight gain, feed efficiency, or numbers of C. perfringens in the ileum of chicks.(ABSTRACT TRUNCATED AT 250 WORDS)
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Bacitracina/farmacología , Pollos/fisiología , Clostridium perfringens/efectos de los fármacos , Dieta , Intestinos/microbiología , Animales , Peso Corporal/efectos de los fármacos , Pollos/microbiología , Metabolismo Energético/efectos de los fármacos , Aditivos Alimentarios , Íleon/microbiología , MasculinoRESUMEN
Experiments were conducted to determine the potential of the antibiotic thiopeptin as a growth permittant for poultry. Thiopeptin as the semipurified antibiotic and as fermentation solids demonstrated activity against Clostridium perfringens at .03 ppm based on suppression of gas production in an anaerobic tube test. Supplementing a soybean protein and sucrose-based diet with levels of 2.2, 11, and 55 ppm of thiopeptin from each of the two sources resulted in significant improvements in weight gain and feed efficiency of chicks fed the higher levels. Computed indexes for each antibiotic treatment showed that the antibiotic as fermentation solids was slightly more active than the semipurified material at the lower levels. Supplementing the soybean protein and sucrose-based diet with 1.1, 5.5, 16.5, and 55 ppm thiopeptin reduced significantly (P less than .01) the numbers of C. perfringens organisms in ileal contents of chicks. Chicks fed 5.5, 16.5, and 55 ppm thiopeptin also had significantly fewer C. perfringens organisms in the intestine than those fed 1.1 ppm. A discussion is presented of the biological responses of thiopeptin relative to the antibiotics efrotomycin and bacitracin.
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Antibacterianos/farmacología , Pollos/fisiología , Clostridium perfringens/efectos de los fármacos , Animales , Péptidos Catiónicos Antimicrobianos , Peso Corporal/efectos de los fármacos , Pollos/microbiología , Metabolismo Energético/efectos de los fármacos , Aditivos Alimentarios , Intestino Delgado/microbiología , Masculino , Péptidos/farmacologíaRESUMEN
Six experiments were conducted to evaluate the effects of diet, bacitracin, and body weight restrictions on the intestine of the broiler chick. Bacitracin, at levels of 11 and 55 ppm, significantly increased body weight, significantly reduced small intestine weight, but had no significant effect on liver weight of chicks fed a soybean protein and sucrose-based diet. The greatest effects were observed in the ileum where weight, moisture, length per unit of body weight, and dry matter per unit of length were all significantly reduced. The least effects were observed in the duodenum where weight and length per unit of body weight were significantly reduced and dry matter per unit of length was significantly increased. Intestinal weight, as a percent of body weight, was not significantly affected when body weight was suppressed with a high level of nicarbazin added to a practical diet, but it was significantly reduced when bacitracin was added to the semipurified diet and chicks were restricted in food intake to 70% of controls. A level of 55 ppm of bacitracin added to the practical diet had no significant effect on body weight, intestinal weight, or liver weight. As discussed, the observed changes in the intestine, due to bacitracin, are probably indirect and most likely reflect the action of the antibiotic on the intestinal microflora.