Antibodies targeting human endothelin-1 receptors reveal different conformational states in cancer cells.

The endothelin axis (endothelins and their receptors) is strongly involved in physiological and pathological processes. ET-1 plays a crucial role in particular in tumor diseases. Endothelin-1 receptors (ET(A) and ET(B)) are deregulated and overexpressed in several tumors such as melanoma and glioma. We studied the binding of 24 monoclonal antibodies directed against human ET(B) receptors (hET(B)) to different melanoma cell lines. Few of these mAbs bound to all the melanoma cell lines. One of them, rendomab B49, bound to ET(B) receptors expressed at the surface of human glioma stem cells. More recently, we produced new antibodies directed against human ET(A) receptor (hET(A)). Several antibodies have been isolated and have been screened on different tumoral cells lines. As for the mAbs directed against the hET(B) receptor only some of new antibodies directed against ET(A) receptor are capable to bind the human tumoral cell lines. Rendomab A63 directed against hET(A) is one of them. We report the specificity and binding properties of these mAbs and consider their potential use in diagnosis by an in vivo imaging approach.

[Is lactate a good indicator of brain tissue hypoxia in the acute phase of traumatic brain injury? Results of a pilot study in 21 patients]. / ¿Es el lactato un buen indicador de hipoxia tisular? Resultados de un estudio piloto en 21 pacientes con un traumatismo craneoencefálico.

UNLABELLED: Lactate and the lactate-pyruvate index (LPI) are two hypoxia markers widely used to detect brain tissue hypoxia in patients with acute traumatic brain injury. These two markers have a more complex behavior than expected as they can be abnormally high in circumstances with no detectable brain hypoxia. This condition must be considered in the differential diagnosis because it also reflects an alteration of brain energy metabolism. OBJECTIVES: 1. To describe cerebral energy metabolism characteristics observed in the acute phase of traumatic brain injury (TBI) based on two traditional indicators of anaerobic metabolism: lactate and LPI, 2. To determine the concordance between these two biomarkers in order to classify the incidence of anaerobic metabolism and 3. To classify the different types of metabolic abnormalities found in patients with moderate and severe TBI using both lactate and LPI. MATERIALS AND METHODS: Twenty-one patients were randomly selected from a cohort of moderate or severe TBI patients admitted to the neurotraumatology intensive care unit. All of them who underwent both cerebral microdialysis and brain tissue oxygen monitoring (PtiO(2)). We analyzed the levels of lactate and the LPI for every microvial within the first 96 hours after head trauma. These data were correlated with PtiO(2) values. RESULTS: Lactate levels and the LPI were respectively increased during 49.5% and 38.4% of the monitoring time. The incidence and behavior of high levels of both markers were extremely heterogeneous. The concordance between these two biomarkers to determine episodes of dysfunctional metabolism was very weak (Kappa Index=0.29; IC 95%: 0.24-0.34). Based on the levels of lactate and the LPI, we defined four metabolic patterns: I: L>2.5 mmol/L and LPR>25; II: L>2.5 mmol/L and LPR< or = 25; III: L< or = 2.5 mmol/L and LPR< or = 25; IV: L< or = 2.5 mmol/L and LPR>25). In more than 80% of cases in which lactate or LPI were increased, PtiO(2) values were within the normal range (PtiO(2)> 15 mmHg). CONCLUSIONS: Increased lactate and LPI were frequent findings after acute TBI and in most cases they were not related to episodes of brain tissue hypoxia. Furthermore, the concordance between both biomarkers to classify metabolic dysfunction was weak. LPI and lactate should not be used indistinctly in everyday clinical practice because of the weak correlation between these two markers, the difficulty in their interpretation and the heterogeneous and complex nature of the pathophysiology. Other differential diagnoses apart from tissue hypoxia should always be considered when high lactate and/or LPI are detected in the acute injured brain.

¿Es el lactato un buen indicador de hipoxia tisular? Resultados de un estudio pilotoen 21 pacientes con un traumatismo craneoencefálico / Is lactate a good indicator of brain tissue hypoxia in the acute phase of traumatic brain injury? Results of a pilot study in 21 patients

El lactato y el índice lactato-piruvato (LP) son dosmarcadores utilizados para la detección de la hipoxiacerebral en pacientes que han sufrido un traumatismocraneoencefálico (TCE). Estos dos marcadores presentanun comportamiento más complejo de lo que seesperaría debido a que pueden estar anormalmenteelevados en circunstancias que no cursan con hipoxiatisular detectable. Este comportamiento debe ser consideradoen el diagnóstico diferencial puesto que reflejatambién una alteración del metabolismo energéticocerebral.Objetivos. 1. Describir las características del metabolismoenergético cerebral que se observa en la faseaguda de los pacientes que han sufrido un TCE en basea los dos indicadores tradicionales del metabolismoanaeróbico: lactato e índice LP, 2. Determinar la concordanciaentre ambos indicadores para clasificar laincidencia del metabolismo anaeróbico y 3. Clasificarlos diferentes tipos de alteración metabólica que seobserva en los pacientes con un TCE moderado o graveen base a estos dos indicadores.Material y métodos. Se seleccionaron aleatoriamenteveintiún pacientes de una cohorte de pacientes con TCEmoderado o grave admitidos en la unidad de cuidadosintensivos y monitorizados mediante microdiálisis(MD) cerebral y presión tisular de oxígeno (PtiO2). Seanalizaron los niveles de lactato e índice LP de cadamicrovial generado en las primeras 96 horas tras elTCE. Estos datos fueron correlacionados con los valoresde PtiO2.Resultados. El lactato y el índice LP estuvieronelevados el 49,5% y el 38,4% del tiempo totalmonitorizado respectivamente (..) (AU)

Lactate and the lactate-pyruvate index (LPI) aretwo hypoxia markers widely used to detect brain tissuehypoxia in patients with acute traumatic brain injury.These two markers have a more complex behavior thanexpected as they can be abnormally high in circumstances with no detectable brain hypoxia. This conditionmust be considered in the differential diagnosis becauseit also reflects an alteration of brain energy metabolism.Objectives. 1. To describe cerebral energy metabolismcharacteristics observed in the acute phase oftraumatic brain injury (TBI) based on two traditionalindicators of anaerobic metabolism: lactate and LPI,2. To determine the concordance between these twobiomarkers in order to classify the incidence of anaerobicmetabolism and 3. To classify the different types ofmetabolic abnormalities found in patients with moderateand severe TBI using both lactate and LPI.Materials and methods. Twenty-one patients wererandomly selected from a cohort of moderate orsevere TBI patients admitted to the neurotraumatologyintensive care unit. All of them who underwentboth cerebral microdialysis and brain tissue oxygenmonitoring (PtiO2). We analyzed the levels of lactateand the LPI for every microvial within the first 96hours after head trauma. These data were correlatedwith PtiO2 values.Results. Lactate levels and the LPI were respectivelyincreased during 49,5% and 38,4% of the monitoringtime. The incidence and behavior of high levels of bothmarkers were extremely heterogeneous. The concordancebetween these two biomarkers to determineepisodes of dysfucntional metabolism was very weak(Kappa Index=0,29; IC 95%: 0,24-0,34). Based on thelevels of lactate and the LPI, we defined four metabolicpatterns: I: L>2,5 mmol/L and LPR>25; II: L>2,5mmol/L and LPR≤ 25; III: L≤ 2,5 mmol/L and LPR≤25; IV: L≤ 2,5 mmol/L and LPR>25). In more than80% of cases in which lactate or LPI (..) (AU)