RESUMEN
Canine bone marrow stromal cells (BMSCs), transduced ex vivo with retroviral vectors, expressed and secreted biologically active human and canine coagulation factor IX (hFIX and cFIX) in vitro, and on autologous reinfusion expressed hFIX into the circulation of normal (nonhemophiliac) dogs. Human FIX, when expressed in vitro by BMSCs of two dogs at 1.22 and 1.39 microg/10(6) cells/24 hr in medium supplemented with vitamin K, respectively, exhibited 28.1 and 27.3% normal biological activity as determined on the basis of a one-stage clotting assay. BMSCs of two additional dogs expressed 1.54 and 4.81 microg of cFIX/10(6) cells/24 hr in vitamin K-supplemented medium and the expressed cFIX possessed 58.4 and 32.9% normal activity, respectively. Between 2.33 and 3.35 x 10(8) transduced BMSCs, expressing 1.22 and 2.61 microg of hFIX/10(6) cells/24 hr or 3.24 and 7.82 microg of cFIX/10(6) cells/24 hr were reintroduced into the four donor dogs by intravenous infusion. Human FIX was detected in plasma for 7 or 12 days after BMSC reinfusion, with peak levels of 85.8 and 233.0 ng/ml observed at 2 days. Canine anti-hFIX antibodies, which were detected as early as 2-4 days after reinfusion of BMSCs expressing hFIX, may have masked potentially longer duration expression in vivo. Peak plasma levels of hFIX represented 2.1 and 5.8% normal human hFIX levels. When adjusted for percent normal one-stage clotting activity determined in vitro, these levels represented 0.6 and 1.6% normal human hFIX activity levels. Thus, we have demonstrated that retroviral vector-modified BMSCs can deliver human therapeutic levels of hFIX to the circulation of dogs.
Asunto(s)
Células de la Médula Ósea/metabolismo , Factor IX/metabolismo , Animales , Anticuerpos/sangre , Perros , Ensayo de Inmunoadsorción Enzimática , Factor IX/inmunología , Femenino , Vectores Genéticos/uso terapéutico , Humanos , Retroviridae , Células del Estroma/metabolismo , Células del Estroma/trasplante , Células del Estroma/virología , TransfecciónRESUMEN
Eighty-three patients with rapidly progressing breast cancer (RPBC) were entered into a study of primary chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil) and subsequent randomization to surgery or radiotherapy for control of local/regional disease. Eighty-three of these patients with redness, warmth, and edema compatible with clinical "inflammatory breast cancer" served as the focus for our analysis of factors associated with improved survival. The stage-specific disease-free intervals (DFI) of 36 and 21 months were substantially longer than in the earlier series (26 and 16 months) from the same institution. The evaluation of individual prognostic indicators revealed that the initial tumor size and the initial response to chemotherapy were the two independent factors most important in predicting the DFI. The continuing unmaintained 1-year remission in at least 12 patients supports the rationale for aggressive therapy in RPBC or "inflammatory breast cancer."
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Inducción de Remisión , Análisis de SupervivenciaRESUMEN
Consuming substantial quantities of n-3 fatty acids reduces atherogenesis in experimental models of atherosclerosis. The mechanisms of this beneficial effect remain uncertain. Monocyte-derived tissue macrophages are associated with atherogenesis, and inhibition of monocyte inflammatory activity could, hypothetically, be helpful in preventing atherosclerosis. We observed that stimulated human monocyte and/or macrophage production of superoxide and the occurrence of monocyte chemiluminescence, two indices of monocyte inflammatory activity, were significantly reduced by the ingestion of 6 g n-3 fatty acids/d for 6 wk. This effect was associated with a reduction of stearic and arachidonic acids whereas eicosapentaenoic and docosahexaenoic acid concentrations rose significantly. These results indicate that modest dietary n-3 fatty acid supplementation can reduce stimulated human-monocyte free-radical production and may impair the capability of macrophages derived from monocytes to promote oxidation of low-density-lipoprotein cholesterol and associated cellular toxicity.
Asunto(s)
Grasas Insaturadas en la Dieta/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Superóxidos/sangre , Adulto , Arteriosclerosis/prevención & control , Aceite de Hígado de Bacalao/administración & dosificación , Grasas Insaturadas en la Dieta/farmacología , Ácidos Grasos Omega-3/farmacología , Femenino , Radicales Libres , Humanos , Leucocitos/análisis , Masculino , Persona de Mediana EdadRESUMEN
Enhanced dietary omega-3 fatty acid consumption is thought to be associated with a reduced incidence of atherothrombotic disorders. This effect may be mediated in part through suppression of in vivo platelet activity by omega-3 fatty acids. We observed that platelet survival, a sensitive indicator of in vivo platelet activity was prolonged from 6.4 +/- 1.5 days to 7.7 +/- 1.4 days by moderate amounts of dietary omega-3 fatty acid supplementation for 6 weeks in a group of hyperlipidemic patients with preexisting, established atherothrombotic disorders. This effect on platelet survival was associated with a decrease in platelet arachidonic acid levels from 26.7 +/- 3.5% to 20.9% +/- 2.5% and a rise in platelet eicosapentaenoic and docosahexaenoic acid measurements from essentially undetectable to 2.8% +/- 1.6% and 1.9% +/- 1.0%. Plasma total cholesterol, low-density lipoprotein cholesterol, and serum apolipoprotein B levels rose significantly during the omega-3 fatty acid supplementation period. Platelet aggregation did not change. This study demonstrates that a modest amount of dietary omega-3 fatty acid supplementation can significantly effect in vivo platelet activity in a population at high risk for recurrent atherothrombotic disorders.
Asunto(s)
Arteriosclerosis/dietoterapia , Plaquetas/fisiología , Ácido Eicosapentaenoico/uso terapéutico , Hiperlipidemias/dietoterapia , Adulto , Anciano , Apolipoproteínas B/sangre , Arteriosclerosis/sangre , Arteriosclerosis/etiología , Plaquetas/metabolismo , Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/complicaciones , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
Polymorphonuclear leukocytes (PMNLs) are an important contributor to inflammation and are thus a part of the pathophysiology of many human diseases. We assessed the effect of fish oil on PMNL inflammatory potential by measuring chemiluminescence and superoxide production before and after six weeks of daily cod liver oil ingestion by healthy volunteers. Phagocytosing PMNLs demonstrated a 27% decrease in chemiluminescence (P less than 0.05) and a 64% decrease in superoxide production (P less than 0.01), following the cod liver oil supplementation. Analysis of PMNL and platelet fatty acids revealed the appearance of eicosapentaenoic acid and a significant decrease in arachidonic acid in both types of cells.
Asunto(s)
Grasas de la Dieta/farmacología , Aceites de Pescado/farmacología , Inflamación/fisiopatología , Neutrófilos/fisiología , Humanos , Técnicas In Vitro , Cinética , Mediciones Luminiscentes , Neutrófilos/efectos de los fármacos , Superóxidos/sangreRESUMEN
We studied the effect of cod-liver oil on the development and progression of coronary artery disease in swine subjected to coronary balloon abrasion and fed an atherogenic diet for eight months. Sections from serial 3-mm segments of the coronary arteries were analyzed morphometrically in 7 pigs given a cod-liver-oil supplement and 11 control animals not given the supplement. Significantly less disease was seen in the sections from the animals fed cod-liver oil. The mean lesion area per vessel, mean luminal encroachment per vessel, and mean maximal luminal encroachment per vessel were reduced in animals fed cod-liver oil, as compared with controls, (P = 0.05, P = 0.016, and P = 0.011, respectively). Both groups of animals had severe hyperlipidemia throughout the study. Differences in the extent of coronary atherosclerosis were not related to differences in plasma lipid levels. Platelet arachidonate was markedly reduced, platelet eicosapentaenoic acid was increased, and serum thromboxane was decreased in the oil-fed group as compared with the control group. We conclude that in our animal mode, dietary cod-liver oil retarded the development of coronary artery disease, possibly through changes in prostaglandin metabolism.