RESUMEN
Microphthalmia transcription factor (MITF) is a basic helix-loop-helix leucine zipper (bHLH-Zip) DNA-binding protein. This transcription factor plays a crucial role in the physiological and pathological functions of distinct cell types. MITF transcriptional activity is inhibited by the histidine triad nucleotide-binding protein 1 (HINT1) through direct binding. We previously reported that this association is disrupted by the binding of the second messenger Ap4A to HINT1. Ap4A is mainly produced in the mammalian cells by S207-phosphorylated Lysyl-tRNA synthetase. In this study, we found first that HINT1 was subjected to K21 acetylation and Y109 phosphorylation in activated mast cells, together with the Ap4A-triggered HINT1 dissociation from MITF. Mutational analysis confirmed that these modifications promote MITF transcriptional and oncogenic activity in melanoma cell lines, derived from human melanoma patients. Thus, we provided here an example that manipulation of the LysRS-Ap4A-HINT1-MITF signalling pathway in melanoma through post-translational modifications of HINT1 can affect the activity of the melanoma oncogene MITF.
Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Melanoma/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Procesamiento Proteico-Postraduccional , Neoplasias Cutáneas/metabolismo , Activación Transcripcional , Acetilación , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Análisis Mutacional de ADN , Humanos , Mastocitos/metabolismo , Melanoma/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Proteínas del Tejido Nervioso/genética , Fosforilación , Unión Proteica , Transducción de Señal , Neoplasias Cutáneas/genéticaRESUMEN
The aims of the study were to evaluate the diagnostic accuracy and utility of the mean region of interest (ROI) and mean and maximum volume of interest (VOI) analysis methods for 99mTc MDP SPECT scintigraphy in the diagnosis of active unilateral condylar hyperplasia (UCH). Inactive UCH (n=43) and active UCH (n=8) patients, and patients without condylar hyperplasia (controls, n=41) were analyzed. Inter-observer agreement was good for all methods. Condylar uptake was not normally distributed, with a longer right tail in UCH patients compared to control patients. Receiver operating characteristic curve analysis indicated that the ROI method was slightly superior to both VOI methods for the diagnosis of active UCH (area under the curve=0.866, 0.811, and 0.817, and J=0.642, 0.596, and 0.573, respectively). The 'traditional' 55% cut-off value proved optimal for ROI and mean VOI methods, but a cut-off of 56.125% was optimal for maximum VOI. Sensitivity was 88% for all three methods using these cut-off values, while specificity was 77%, 65%, and 70% for mean ROI, mean VOI, and maximum VOI, respectively. These results indicate that corrective surgery for negative scan patients can be performed without delay, with an error rate of only 3%, but not in positive scan patients.
Asunto(s)
Cóndilo Mandibular/diagnóstico por imagen , Cóndilo Mandibular/patología , Radiofármacos , Medronato de Tecnecio Tc 99m , Adulto , Anciano , Femenino , Humanos , Hiperplasia/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
AIM: Renal function is one of the most important prognostic factors following cardiac surgery. Whether aspirin affects cardiopulmonary bypass related renal injury is investigated in this study. METHODS: Ninety-four patients with impaired renal function (creatinine = or >1.5 mg/dl) undergoing coronary artery bypass grafting (CABG) were categorized into 2 groups according to aspirin administration before surgery. Serum creatinine, urinary output and creatinine clearance along with other perioperative factors were compared between the 2 groups prior to surgery, 24 hours and 48 hours following cardiopulmonary bypass. RESULTS: Creatinine levels increased significantly in the second postoperative day only in the non-aspirin (control) group (3.7+/-1.6 vs 2.9+/-1.7 mg/dl, p=0.03). Aspirin (study) group had lower creatinine levels in day 1 (p=0.03) and day 2 (p=0.001). Furthermore, in the study group creatinine clearance was higher in day 1 (34.3+/-14.3 vs 30.9+/-13.1 ml/min, p=0.01) and in day 2 (32.6+/-13.8 vs 26.4+/-9.8 ml, p<0.0001). Creatinine levels at discharge were elevated compared to the preoperative levels in the control group (p=0.01). However, the study group had lower creatinine levels at discharge (2.6+/-1.4 vs 3.8+/-1.6 mg/dl, p<0.0001). Urinary output was higher in the study group in the first postoperative day compared to the control group (p=0.01). Postoperative bleeding was slightly increased in the study group compared to the control group (760+/-230 ml vs 530+/-210 ml, p=0.01). CONCLUSIONS: Continuation of aspirin administration until the day of surgery may have a protective effect against renal injury resulting from cardiopulmonary bypass, with only a negligible increase in bleeding. Possible explanations for this effect are antiplatelet activity of aspirin during cardiopulmonary bypass causing inhibition of vasoconstrictive agents like thromboxane, and improvement of renal perfusion by reducing blood viscosity.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Puente Cardiopulmonar , Puente de Arteria Coronaria , Insuficiencia Renal/prevención & control , Adulto , Anciano , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/cirugía , Creatinina/metabolismo , Femenino , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios , Insuficiencia Renal/complicaciones , Insuficiencia Renal/metabolismo , Resultado del TratamientoRESUMEN
Expression of catalytically active protein was detected in a murine mast cell line. The primary type of AChE mRNA produced by these cells was found to be the brain and muscle type by PCR amplification of alternative exons from the 3' of mast cells AChE cDNA. AChE was further found to be expressed in the HMC-1 the human mast cell precursor line. Furthermore, utilizing the single cell RT-PCR method we detected AChE mRNA expression in Fc epsilon RI-positive single cells derived from human colonic mucosal biopsies. Our findings predict the involvement of mast cell AChE in neuronal-mast cell interactions.