RESUMEN
Drug resistance is a major obstacle to the successful treatment of cancer as tumor cells either fail to reduce in size following chemotherapy or the cancer recurs after an initial response. The phenomenon of multidrug resistance (MDR) is particularly problematic as it involves the simultaneous resistance to numerous chemotherapeutics of different classes. MDR is predominantly attributed to the overexpression of efflux transporters such as P-glycoprotein (P-gp) and the Multidrug Resistance-Associated Protein 1 (MRP1). P-gp and MRP1 are members of the ATP Binding Cassette (ABC) superfamily of transporters and are capable of effluxing many chemotherapeutics out of cancer cells, allowing them to survive the toxic insult. Numerous strategies have been developed over the years to circumvent MDR. Of these, the discovery and implementation of P-gp and MRP1 inhibitors have been most extensively studied. However, these inhibitors have not been able to be used clinically. While research continues in this area, it must also be acknowledged that other avenues must be explored. Recently, the novel 'non-genetic' acquisition of P-gp-mediated MDR by microparticles (MPs) has been reported. MPs are vesicles 0.1-1µm in diameter that are released via plasma membrane blebbing. They are important mediators of inflammation, coagulation and vascular homeostasis. In addition to surface P-gp protein, MPs also carry various nucleic acid species as cargo. This 'non-genetic' intercellular transfer provides an alternative pathway for the cellular acquisition and dissemination of traits and implicates MPs as important mediators in the spread of MDR and provides a novel pathway for the circumvention of MDR.
Asunto(s)
Micropartículas Derivadas de Células/fisiología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Humanos , MicroARNs , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismoRESUMEN
Local TNF-alpha production in different organs may affect HIV replication and pathogenesis. Alveolar macrophages (AMs) obtained by bronchoalveolar lavage from asymptomatic HIV-seropositive and HIV-seronegative individuals did not spontaneously release TNF-alpha, but LPS stimulation of these cells significantly increased TNF-alpha production. We tested whether NF-kappa B affects TNF-alpha production by AMs using N-tosyl-
Asunto(s)
Seropositividad para VIH/inmunología , Proteínas I-kappa B , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , FN-kappa B/fisiología , Factor de Necrosis Tumoral alfa/biosíntesis , Adulto , Adhesión Celular/genética , Adhesión Celular/inmunología , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidor NF-kappaB alfa , FN-kappa B/genética , FN-kappa B/metabolismo , Reacción en Cadena de la Polimerasa , Etiquetado in Situ Primed , Estudios Prospectivos , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Inhibidores de Serina Proteinasa/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Clorometilcetona de Tosilfenilalanila/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Fosfolipasas de Tipo C/antagonistas & inhibidores , Tirosina/análogos & derivados , Tirosina/farmacologíaRESUMEN
OBJECTIVE: To present the earliest Australian case of the acquired immunodeficiency syndrome (AIDS) reported to date. CLINICAL FEATURES: A 72-year-old man developed a prolonged illness, beginning in February 1981, characterised by anorexia, malaise, weight loss and an episode of herpes zoster. In July he noted the insidious onset of dyspnoea with a productive cough. He was admitted to hospital in August, where Pneumocystis carinii pneumonia was diagnosed from a transbronchial lung biopsy. Splenomegaly and generalised lymphadenopathy were noted but a scalene lymph node biopsy examined at that time failed to establish an underlying diagnosis. The patient was single and lived alone in an inner suburb of Sydney. He had never left Australia and had never received a blood transfusion. His sexual history is not recorded, nor is there any documented history of intravenous drug use. OUTCOME: The patient died in September 1981. Recent re-examination of the preserved lymph node specimen by means of an in-situ hybridisation method detected human immunodeficiency virus (HIV). Preserved prostatic tissue from a resection performed in January 1980 on the same patient was also found to be HIV positive. CONCLUSION: AIDS existed in Australia as early as July 1981, around the time of the publication of the first American case reports. Whether this represents an isolated case in a man who progressed rapidly because of his relatively advanced age, or whether HIV was present earlier in Australia than previously thought, remains unanswered.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/epidemiología , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Neumonía por Pneumocystis/etiología , Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Síndrome de Inmunodeficiencia Adquirida/patología , Anciano , Australia/epidemiología , VIH-1/aislamiento & purificación , Humanos , Hibridación in Situ , Ganglios Linfáticos/microbiología , Ganglios Linfáticos/patología , Masculino , Neumonía por Pneumocystis/epidemiologíaRESUMEN
In two studies comparing detection of human cytomegalovirus (HCMV) in 118 patients (93 of whom were immunocompromised) by the polymerase chain reaction (PCR) and virus isolation using either early antigen detection by culture-immunofluorescence or conventional cytopathic effect, DNA-PCR was found to be the most sensitive, followed by culture-immunofluorescence, then by cytopathic effect. Urine was inhibitory to the action of Taq polymerase; this was overcome by concentration of HCMV with PEG 6000 prior to gene amplification. Without PEG treatment, HCMV-DNA in 6 of the 11 specimens positive by culture-immunofluorescence was not detectable by PCR. In healthy seropositive individuals, HCMV-DNA was not detected in leucocytes. However, in immunocompromised patients with AIDS or transplants, and therefore at high risk of HCMV infection or reactivation, blood leucocytes were usually positive for HCMV-DNA (19/20), some for as long as 20 weeks after initial detection and persisting for long after culture-immunofluorescence became negative. Neither HCMV-RNA nor infectious HCMV were detected in the follow-up blood leucocyte specimens from immunocompromised patients who had detectable HCMV-DNA in these cells. These data suggest that persistence of HCMV-DNA in blood leucocytes of immunocompromised patients after reactivation or primary infection may be due to persistence of non-viable virus, residual HCMV genomic DNA, or latent HCMV-DNA.