RESUMEN
ORF47, a serine/threonine protein kinase encoded by varicella-zoster virus (VZV), has often been compared to the ubiquitous cellular kinase, casein kinase II (CKII). However, no direct comparison of the two protein kinases has been carried out. Herein, we show that the ORF47 kinase was resistant to heparin, while CKII activity is profoundly inhibited by the acidic molecule in vitro. ORF47 required the presence of polyamines (aliphatic, positively-charged molecules) for in vitro activity. When polyamines were depleted from MeWo cells prior to VZV infection by pretreatment with D,L-alpha-difluoromethylornithine, VZV replication was reduced by 80%. Finally, the substrate specificity of the ORF47 kinase was defined using an in vitro assay. The ORF47 kinase phosphorylated maltose-binding protein, the mouse IgG2A heavy chain, the rabbit IgG heavy chain, casein, VZV ORF62, and VZV ORF63. The ORF47 kinase failed to phosphorylate an ORF62 truncation mutant, glutathione-S-transferase, or VZV gB. In contrast, CKII weakly phosphorylated VZV gB in vitro. By analyzing the sequences of these substrates, the minimal ORF47 consensus sequence was deduced to be the following motif: S/T-X-D/E-D/E, with a marked preference for additional acidic amino acids in the -1 and +1 position.
Asunto(s)
Herpesvirus Humano 3/enzimología , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Secuencia de Aminoácidos , Animales , Quinasa de la Caseína II , Línea Celular , Secuencia de Consenso , Eflornitina/farmacología , Inhibidores Enzimáticos/farmacología , Células HeLa , Heparina/farmacología , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/fisiología , Humanos , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas/genética , Proteínas/metabolismo , Especificidad por Sustrato , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: It has been suggested that suppression of adrenal androgens may provide benefit to patients with metastatic prostate cancer refractory to initial hormonal therapy (e.g., orchiectomy). METHODS: The records of 38 patients with metastatic prostate cancer that had progressed after orchiectomy who were placed subsequently on low dose dexamethasone (DXM) with no other concurrent therapy (36 patients received 0.75 mg twice daily and two received 0.75 mg three times daily) were reviewed. Symptomatic status, prostate specific antigen (PSA) measurements, and available radiographic assessments were recorded. Bone scans were reviewed by an independent, blinded evaluator. RESULTS: Symptomatic improvement was experienced by 24 patients (63%), 20 (83%) of whom also had decreases in PSA. Prostate specific antigen values decreased in 30 patients (79%) with decreases 50% or greater and 80% or greater in 23 (61%) and 13 (34%) patients, respectively. Of the 23 patients with PSA decreases 50% or greater, 8 (35%) had radiographic evidence of disease regression, 5 (22%) were stable, 7 (30%) had disease progression, and 3 (13%) did not have serial radiographic exams. Flutamide was discontinued shortly before DXM treatment for 2 of the 23 patients. CONCLUSIONS: Low dose DXM may produce important symptomatic improvement and decreased PSA levels in the majority of patients with hormone-refractory prostate cancer. In addition, a substantial percentage of those patients with decreases in PSA also will have radiographic evidence of disease regression. These results suggest the need for additional prospective controlled studies of DXM as a therapy for hormone-refractory prostate cancer.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Dexametasona/administración & dosificación , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Orquiectomía , Neoplasias de la Próstata/sangre , Estudios RetrospectivosRESUMEN
Athletes, like all people, have special nutritional needs based on their age, lifestyle, health status, level of physical activity, physical conditioning, and type of sport. The diets of many athletes are inadequate due to overly restrictive eating habits, nutrition misinformation, dietary fads, and/or obsession with weight and food. There is a growing need for sports nutrition counseling and education to help athletes improve their eating habits. However, before attempting to develop intervention strategies, sports nutritionists should assess the metabolic changes that take place during exercise and how these changes affect nutrition status. In addition, it is important to consider how psychosocial factors may influence an athlete's eating habits and his/her ability to make positive changes. A two-pronged model is introduced that can be used as a guide for the practitioner in interpreting relevant data and integrating physiological and psychological considerations for the design of individualized nutrition care plans for athletes.