RESUMEN
A common phenomenon in cancer patients is a suppressed cell-mediated immunity, characterized by the inability of immune effector cells to mount efficient anti-tumor responses. Immunosuppressive factors, released by the tumor, contribute to this phenomenon and thus to tolerance. Prostaglandins, catalyzed by the cyclooxygenases (COX-1 and COX-2) from arachidonic acid, are one class of these factors. Since at least one of the COX enzymes is often expressed at high level in human cancers, the enzymes were ascribed a causal role in tumor etiology and progression. Non-steroidal antiinflammatory drugs (NSAIDs) like aspirin, which block COX activity, have demonstrated their antitumor effects in preclinical and clinical trials. Pro-apoptotic and anti-angiogenic effects in tumor cells may account for this activity. In addition, by inhibiting the release of prostaglandins from the tumor and by blocking COX activity in immune effector cells, NSAIDs may also bias the function of immune cells towards a more tumoricidal phenotype. We show here that tumor cells inhibit the physiological function of immune cells, and that NSAIDs restore this function. These data contribute to an understanding of the antineoplastic effect ascribed to NSAIDs and support the prophylactic use of these drugs in high-risk patients.
Asunto(s)
Carcinoma de Células Escamosas/inmunología , Inhibidores de la Ciclooxigenasa/farmacología , Neoplasias de Cabeza y Cuello/inmunología , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/fisiología , Macrófagos/inmunología , Monocitos/inmunología , Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Complejo CD3/inmunología , Celecoxib , Línea Celular Tumoral , Células Cultivadas , Técnicas de Cocultivo , Curcumina/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Dinoprostona/biosíntesis , Regulación hacia Abajo , Citometría de Flujo , Humanos , Inmunohistoquímica , Pirazoles/farmacología , Fracciones Subcelulares/inmunología , Sulfonamidas/farmacologíaRESUMEN
Viral gene vectors often rely on packaging cell lines, which provide the necessary factors in trans for the formation of virus-like particles. Previously, we reported on a first-generation packaging cell line for gene vectors, which are based on the B-lymphotropic Epstein-Barr virus (EBV), a human gamma-herpesvirus. This 293HEK-derived packaging cell line harbors a helper virus genome with a genetic modification that prevents the release of helper virions, but efficiently packages vector plasmids into virus-like particles with transducing capacity for human B cells. Here, we extended this basic approach towards a non-transforming, virus-free packaging cell line, which harbors an EBV helper virus genome with seven genetic alterations. In addition, we constructed a novel gene vector plasmid, which is devoid of a prokaryotic antibiotic resistance gene, and thus more suitable for in vivo applications in human gene therapy. We demonstrate in this paper that EBV-based gene vectors can be efficiently generated with this much-improved packaging cell line to provide helper virus-free gene vector stocks with transducing capacity for established human B-cell lines and primary B cells.
Asunto(s)
Linfocitos B/virología , Ingeniería Genética , Vectores Genéticos/genética , Transducción Genética/métodos , Ensamble de Virus , Línea Celular , ADN Viral/análisis , Citometría de Flujo , Expresión Génica , Proteínas Fluorescentes Verdes/genética , Virus Helper , Herpesvirus Humano 4 , Humanos , Reacción en Cadena de la Polimerasa , Recombinación Genética , Transfección/métodosRESUMEN
OBJECTIVE: Current management of acute stroke is characterised by an aggressive approach including specific therapy i. e. reperfusion therapy. However currently stroke patients often arrive too late in hospitals offering adequate treatment. Therefore optimized logistics play a predominant role in modern stroke management. AIMS OF THE STUDY: 1. Does teaching of EMS staff and the public result in reduced prehospital latencies 2. Will EMS personnel be able to effectively screen patients potentially suitable for thrombolysis? METHODS: During a six week-period all EMS patients presenting with possible signs of an acute stroke were prospectively registered (period 1). Data of interest were age, mode of primary contact, prehospital latencies, mode of transportation, destination and final diagnosis. Next an algorithm was established allowing EMS personnel to transfer patients with an assumed stroke to the best suitable hospital. Teaching comprised clinical signs, indication of CT scanning, pathophysiology, specific therapeutic options (thrombolysis), and criteria to identify patients suitable for thrombolysis. In a second step the public was continuously taught about stroke symptoms and the necessity to instantly seek EMS assistance. After 12 months data were compared to baseline (period 2). RESULTS: (period 2 vs. Period 1): Rate of patients transferred to a stroke center: 60 % vs. 54 %; rate of those transported to hospitals not offering CT scans: 17 % vs. 26 % (p < 0.05). Percentage of patients primarily contacting the EMS system: 33 % vs. 24 %. Median interval between onset of symptoms and emergency call: 54 vs. 263 minutes Median interval between the emergency call and arrival at the emergency department: 44 vs. 58 minutes (p < 0.01). Rate of patients admitted with a diagnosis other than stroke: 18 % vs. 25 % (n. s.). Median interval between onset of symptoms and hospital admission: 140 vs. 368 minutes (p < 0.001). Median age: 69 vs. 75 years (p < 0.01). CONCLUSION: This study demonstrates the efficacy of educational efforts in reducing latencies and in screening patients potentially suitable for thrombolysis. Future efforts will comprise more intense education of a high risk subpopulation.